Vitrectomy for Diabetic Macular Edema
What do we know, and when is vitrectomy indicated?
BOZHO TODORICH, MD, PhD • HARRY W. FLYNN, JR., MD • TAMER H. MAHMOUD, MD, PhD
Diabetic retinopathy is a leading cause of blindness in working-age adults,1 and diabetic macular edema is the most common cause of vision loss in patients with diabetes.2,3 Historically, macular laser (focal and grid) has been standard of care in treatment of DME,4-8 yet despite adequate laser, up to 25% of patients at three years of follow-up progressed to moderate vision loss.9
Over the last decade, a multitude of pharmacotherapeutic approaches have been developed to treat DME, including anti-VEGF agents (pegaptanib sodium [Macugen, Valeant Ophthalmics, Bridgewater, NJ], bevacizumab [Avastin, Genentech, South San Francisco, CA], ranibizumab [Lucentis, Genentech], and aflibercept [Eylea, Regeneron, Tarrytown, NY])10-15 and intravitreal steroids.16-19
Since then, anti-VEGF therapy has become the first-line treatment for DME, with steroids and macular laser used as adjuvants or combination agents when patients fail to respond or when DME becomes recurrent.
However, despite a significantly expanded treatment armamentarium, there is no established consensus for the treatment of persistent and recurrent DME. Surgical options, including pars plana vitrectomy with removal of posterior hyaloid and internal limiting membrane peeling, have generally been reserved for cases of DME associated with vitreomacular interface abnormalities or as an intervention of last resort in cases of chronic, recalcitrant DME.
Bozho Todorich, MD, PhD, is a resident in ophthalmology at Duke University Eye Center in Durham, NC. Harry W. Flynn, Jr., MD, is professor and J. Donald M. Gass Distinguished Chair of Ophthalmology at Bascom Palmer Eye Institute in Miami, FL. Tamer H. Mahmoud, MD, PhD, is associate professor of vitreoretinal surgery and program director of the Vitreoretinal Fellowship at Duke University Eye Center. Drs. Todorich and Flynn report no financial interests in any products mentioned here. Dr. Mahmoud reports financial interests as a consultant for Alcon, Alimera, and Allergan. Dr. Mahmoud can be reached at tamer.mahmoud@dm.duke.edu.
What is the mechanism by which vitrectomy may benefit this subgroup of patients with refractory DME?
PATHOGENESIS OF DME
To understand and optimize use of PPV in patients with DME, it is important to understand the pathogenesis of the disease. Multiple biochemical, vascular, inflammatory, and biomechanical factors converge to produce the macular pathology observed in DME.
Compromise and increased permeability of the blood-retina barrier (BRB), particularly the inner BRB, appear to be the principal driving mechanisms of fluid accumulation in the macula, with formation of characteristic cystic changes.20
Chronic hyperglycemia results in the formation of advanced glycation end-products (AGEs), which promote pericyte loss, neurovascular injury, and hypoxia.21 Hypoxia subsequently drives the upregulation of VEGF and other proangiogenic factors that lead to further breakdown of the BRB and cause increased permeability to fluid.22
Altered extracellular receptor signaling leads to over-expression of cell adhesion molecules (ICAM1, VCAM1, PECAM-1, and P-selectin), resulting in the accumulation of leukocytes and inflammatory cells with secondary production of proinflammatory cytokines (TNF-α, angiopoetins, and chemokines).15,23,24 This process may drive the inflammatory component of DME, which could underlie chronicity of DME and further compromise the BRB.
Of particular interest are the vitreomacular interface changes occurring in patients with diabetes. The advent of high-resolution optical coherence tomography has allowed for the visualization of altered vitreomacular anatomy, which can mechanically exacerbate and prevent the resolution of underlying DME in response to pharmacological therapy.
The posterior hyaloid in diabetic patients is much more adherent to the macula, and eyes with DME are much less likely to have clinically evident posterior vitreous detachment than eyes without DME.25
Furthermore, posterior cortical vitreous may appear “taut” on slit-lamp biomicroscopy, which on OCT is demonstrated as sheets or strands of hyaloid with horizontal and vertical insertion to the fovea.26
Underlying Mechanisms
The mechanism driving this process may be increased lysyl-oxidase and nonenzymatically mediated collagen crosslinking in patients with diabetes.27 The thickening and adherence of the cortical vitreous may be exacerbated by the infiltration of glial and inflammatory cells and deposition of cytokeratin and glial fibrillary acidic protein (GFAP).28
VEGF and fibroblast growth factor (FGF-2) seem to be localized on the posterior hyaloid, and they are thought to drive proliferation of astrocytes and hyalocytes further.29 Liquefaction of the central vitreous promotes traction of the adherent cortical vitreous, which may drive the progression of DME in a macula already made susceptible by underlying microvascular pathology.
Thus, the process of vitreous syneresis can incite anteroposterior vitreomacular traction (VMT) and even shallow macular detachments.30,31 Vitreoschisis observed in diabetic eyes may further act as a scaffold for fibrovascular proliferation of glial cells and astrocytes that can lead to formation of epiretinal membranes,32 exerting tangential traction on the surface of the macula.
Conversely, the formation of contractile lamellae, visible on electron microscopy in diabetic eyes,28,33 can result in the formation of a “taut ILM,” which can contribute to the tangential traction on the macula driving progression of DME.34 Both anteroposterior and tangential traction on the maculas of diabetic eyes are thought to contribute significantly to the development and persistence of DME.
VITRECTOMY AS A TREATMENT FOR DME
What is the mechanism by which vitrectomy surgery promotes the resolution of DME? One clear benefit of vitrectomy is that it relieves mechanical forces driving the progression of DME.
In eyes with anteroposterior traction, such as a taut posterior hyaloid or vitreomacular interface abnormalities, vitrectomy with removal of posterior cortical vitreous relieves anteroposterior traction.
In addition, membrane peeling in patients with significant ERM and macular pucker can remove the tangential traction on the macula. Complete peeling of the ILM may not only help to alleviate tangential traction and reduce the occurrence of ERM, but it might also ensure complete removal of posterior hyaloid because collagen fibers have been observed to extend from the vitreous cavity to the Müller cells in diabetic patients.35
For these reasons, some authors advocate ILM peeling in all cases of diabetic vitrectomy for DME.36 Additional benefits of vitrectomy include removal of proinflammatory cytokines and proangiogenic factors (VEGF), improved oxygenation, and macular perfusion,37 as well as an opportunity to administer additional peripheral laser and/or steroid depot in the vitreous cavity.38 Therefore, the added benefits of vitrectomy may extend beyond tractional DME.
Vitrectomy for Tractional DME
The most compelling outcomes after vitrectomy in eyes with DME are associated with anteroposterior or tangential traction. In a small retrospective study published in 1992, prior to the availability of OCT, Lewis and colleagues were the first authors to report the use of PPV in 10 patients with diffuse DME associated with a taut posterior hyaloid refractive to prior macular laser treatment.39 The vision improved in nine of 10 eyes after surgery, and macular edema either resolved or improved in all eyes.39
Since then, multiple papers have reported visual and anatomical benefits of PPV for tractional DME.40-44 In one retrospective study, 24 eyes with chronic diffuse DME underwent PPV, removal of the posterior hyaloid, and membrane peeling.45 There was a net reduction in central macular thickness of 120 µm, but overall, no change in mean visual acuity occurred in response to the surgery, which suggested anatomic, but not necessarily functional, improvement in diabetic vitrectomy for DME in this subset of patients.45
Protocol D
The highest level of evidence comes from the DRCRnet protocol D study, which was designed as a prospective cohort study of patients who underwent PPV for DME associated with VMT or that was refractory to the macular laser.46 The study was conducted at 50 DRCRnet sites in the United States, and the inclusion criteria for the study are given in Table 1.
| At least one eye meeting all of the following criteria: | |
| • | DME on clinical exam |
| • | BCVA letter score > 20/400 |
| • | Presence of vitreomacular traction associated with macular edema OR judgment that edema will not to respond to focal/grid photocoagulation |
Surgery was performed according to the investigator’s usual routine so that, in addition to PPV and removal of the posterior hyaloid, 61% of patients underwent ERM peeling, 54% underwent ILM peeling, 40% underwent panretinal photocoagulation, and 64% underwent injection of steroids at the conclusion of the procedure.46
The results of the study are summarized in Table 2. For the subgroup of 87 eyes undergoing vitrectomy for DME associated with VMT, at six months, central subfield thickness on OCT decreased in most eyes. Although overall mean VA did not change, it did improve in 38% of patients, and anatomic and visual parameters were maintained at one year of follow-up.46
| Protocol D Conclusions | |||
| Vitrectomy for DME resulted in: | |||
| • | Little change in mean visual acuity between baseline and 6 months | ||
| • | 38% improved by 10 or more letters | ||
| • | 22% declined by 10 or more letters | ||
| • | Marked anatomic improvement (OCT central subfield thickness mean from 500 to approximately 300 microns) | ||
| • | Presence of ERM and worse baseline visual acuity were associated with greater visual acuity improvement after vitrectomy surgery | ||
To help identify the patient characteristics as factors that would maximize anatomic and functional outcomes, a separate analysis of the composite 241 eyes was undertaken.47 Multivariate correlation analysis was performed on 20 pre- and intraoperative factors associated with visual and anatomic outcomes at 6 months postsurgery.47 The factors significantly associated with reduction of fluid on OCT included worse baseline vision and greater central subfoveal thickness, the presence of vitreoretinal abnormalities, and removal of the ILM.47 However, the VA improvement was associated only with worse preoperative visual acuity and ERM peeling.47 Neither ILM peeling nor physician assessment of posterior vitreous anatomy were associated with VA outcomes.
Overall, Protocol D of the DRCRnet suggests that the presence of vitreomacular interface abnormalities and specifically the presence of ERM are important determinants of visual outcomes in vitrectomy surgery for DME. In addition, ILM peeling may help augment at least the OCT-defined anatomic outcomes, but the visual outcomes appear variable.
The strengths of this study were multiple and included: 1) the large sample size of patients recruited over a large collaborative network; 2) well-defined inclusion and follow-up criteria; and 3) an attempt to simulate the real-world challenges of complex DME management.
The weaknesses included: 1) the lack of a control group; 2) case selection that was, at least in part, based on the individual physician’s criteria; and 3) varied surgical techniques employed based on individual surgeon preferences (eg, ILM peeling vs none, use of steroids vs none, peripheral laser vs none).
Perhaps most importantly, this study predated the anti-VEGF era and included patients who failed macular laser therapy but had unknown potential responses to anti-VEGF agents. Considering that anti-VEGFs are currently the first-line treatment for the vast majority of eyes with DME, this fact may limit applicability of this study to the present-day patient with DME.
Nevertheless, the results of protocol D represent important empirical evidence supporting the use of vitrectomy in selected patients with tractional DME, and this approach is gaining acceptance among the broader retina community.
Internal Limiting Membrane: To Peel or Not To Peel?
Does ILM peeling improve anatomic and visual outcomes in vitrectomy for DME? Since its introduction in 2000, peeling of the ILM has become a critical part of macular surgery.
Small-gauge surgery (Figure 1) with 23-, 25-, and most recently 27-gauge instrumentation, combined with advanced visualization systems and indocyanine green and brilliant blue staining, are increasingly making ILM peeling safer and less traumatic to the underlying retina.48-50
Figure. Patient with poorly controlled diabetes mellitus presented with 20/60 visual acuity and DME with diffuse leakage pattern on fluorescein angiography. Her macular OCT showed cystic changes with taut posterior hyaloid. She was previously treated with macular laser and anti-VEGF injections, all of which failed to improve intra-retinal fluid. She underwent 25G pars plana vitrectomy, removal of posterior hyaloid and ILM peeling (A). There was release of all traction (B), with significantly improved anatomy and 20/40 visual acuity that is stable at 1 year of follow up (C).
In diabetic patients, the ILM is thicker and may appear to be more taut, thus contributing to the tangential traction in DME.51,52 Furthermore, the higher content of collagen, fibronectin and laminin not only results in a thicker ILM, but it may also produce some degree of toxic effect to neurosensory retina.53,54
Surgical removal of the ILM may significantly decrease the recurrence of ERMs in eyes with macular pucker.55 Most importantly, ILM peeling ensures complete removal of the posterior hyaloid and its remnants, which may be critical in diabetic eyes with high incidences of sticky cortical vitreous and vitreoschisis.56
In one small series of 12 eyes with diffuse DME that underwent PPV and ILM peeling, six of the eyes previously underwent prior macular laser, and two were previously vitrectomized.43
Within 12 weeks of follow-up, 11 of 12 eyes experienced improved vision of 2 lines or better, and there was no recurrence of macular edema or ERM at 16 months of follow-up.43
In another prospective, comparative study involving clinically significant macular edema refractory to macular laser, 18 patients underwent vitrectomy with removal of the posterior hyaloid with or without ILM peeling.32 At 12 months of follow-up, there was significant improvement in foveal thickness and macular volume but no significant change in mean VA.32
Visualization and Surgical Techniques
In general clinical experience, complete removal of the posterior hyaloid and relief of all traction are critical to the success of vitrectomy surgery for tractional DME (Figure 1). Because of the firm adherence of the vitreous to the macula and the high incidence of vitreoschisis, complete removal can be difficult to achieve in some cases of DME.
If initial attempts of inducing a PVD with the vitreous cutter are unsuccessful, a lighted pick can be used to engage the posterior hyaloid over the optic nerve and safely elevate it toward the midvitreous cavity.
Staining with dilute triamcinolone acetonide can be particularly helpful in this setting to visualize remnants of cortical vitreous, yet in our experience, the only way to ensure the removal of all vitreous remnants from the macular surface is to perform ILM peeling.
Staining with ICG to visualize the ILM makes it easier and more efficient, and it ensures complete peeling of the ILM over the macular area. Negative staining can demonstrate a sheet of ERM or remaining portions of posterior hyaloid that can be readily removed as well.
Significant ischemic changes may be present in some eyes, in which the underlying retina is thin and atrophic. Even when ILM peeling is performed delicately and with great care, complications may include hemorrhages in the macula and unroofing one of the cystic spaces, causing iatrogenic macular holes.
Current and future technology using intraoperative OCT may help guide peeling techniques to avoid such complications. Various techniques have been employed to engage the ILM, including “pinch and peel” with ILM forceps, creating an edge with a Tano scraper, followed by ILM forceps, and most recently, employing the FINESSE flex loop (Alcon, Fort Worth, TX) to create a large flap, followed by forceps peel.
Although each technique has its theoretical advantages and drawbacks, all work reasonably well, and the decision regarding which technique to use should be based on individual surgeon preference and comfort level.
Finally, we take advantage of “being in the eye” as a means to administer additional peripheral laser in eyes with active proliferative DR or significant peripheral capillary nonperfusion, or we leave a steroid depot, which can facilitate long-term management of chronic DME.
Vitrectomy for Nontractional DME
The efficacy of PPV for DME not associated with vitreomacular interface abnormalities is much less clear. The nonmechanical benefits of PPV include removal of cytokine and chemokine depot from the posterior cortical vitreous, improved oxygenation of the macula, and removal of VEGF and other proangiogenic factors that promote instability of the BRB.
In one study, oxygen tension in the vitreous cavity following vitrectomy surgery increased 10-fold,57 which alone could lessen ischemic drive and decrease overall VEGF burden.
Stolba and colleagues conducted a small prospective trial involving 56 eyes with diffuse, nontractional DME with attached posterior hyaloid, who previously failed macular laser photocoagulation.58 The patients were randomized to either vitrectomy with ILM peeling or observation.
At six months, vitrectomized eyes demonstrated improved macular thickness and VA, suggesting the superiority of PPV with ILM peeling for chronic diffuse DME to observation alone.58
Despite the apparent success of this trial, which favored vitrectomy over observation, several other studies have failed to identify a benefit of PPV for nontractional DME.59-68 It is difficult to reconcile these studies, considering their varied designs, surgical approaches, heterogeneous patient populations, and differing chronicities of DME.
A meta-analysis published in 2014 included 11 studies with varied patient populations and heterogeneous designs and reported only a modest benefit of vitrectomy on anatomical and functional outcomes in DME eyes. Further prospective studies are clearly warranted to clarify this issue.
SURGICAL CONSIDERATIONS AND PATIENT SELECTION
When it comes to DME and vitrectomy surgery, we have learned a great deal. Over the last two decades, significant improvements in vitreoretinal techniques have included the introduction of small-gauge vitreous surgery in 2002, application of valved cannulas, advanced contact and noncontact visualization systems, and vital dyes for visualization of macular pathology.
These innovations have optimized fluidics and intraoperative visualization and have made vitrectomy surgery much safer and more efficient, offering potentially reduced operative time, faster recovery, and improved patient outcomes.
High-resolution OCT imaging helps to define vitreomacular interface pathology, and most recently, integration of OCT into operating room microscopes will allow for histology-level imaging of the macula during surgery and perhaps even real-time OCT-guided surgery in the near future.
Such feedback may allow the surgeon to perform minimal sufficient surgery to achieve a desired anatomical outcome while allowing for minimal collateral tissue damage (eg, iatrogenic breaks, macular hole formation) during surgical maneuvers, such as membrane peels.
Although modern vitrectomy surgery techniques have improved, vitrectomy is associated with definitive risks, such as the risk of cataract progression, a low but not insignificant rate of endophthalmitis, retinal detachment, vitreous hemorrhage, and postoperative intraocular pressure spikes, all of which need to be weighed against the potential benefits of PPV.
Furthermore, increasing use of anti-VEGF agents and of steroids, including sustained-release intravitreal implants of dexamethasone (Ozurdex, Allergan, Irvine, CA) and fluocinolone acetonide (Iluvien, Alimera, Alpharetta, CA), and their use in combination treatment algorithms are making treatment decisions increasingly complex.
CONCLUSION
Despite these advancements in pharmacotherapy, it is our belief that vitrectomy still has a role in treatment of DME. Careful patient selection is key to optimizing treatment outcomes, and further, well-designed prospective studies are needed to clarify which DME patients would benefit from vitrectomy after they have failed pharmacotherapy, as well as when in their disease process is the optimal time for surgical intervention to maximize visual outcomes.
Ultimately, predictive measures to detect those eyes refractory to intravitreal pharmacotherapy and the evaluation of early vitrectomy and its potential impact on anatomical and functional improvement in such cases are needed. RP
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