Surgical treatment for macular edema.

Seminars in Ophthalmology, 2014; 29(4): 242–256 ! Informa Healthcare USA, Inc. ISSN: 0882-0538 print / 1744-5205 online DOI: 10.3109/08820538.2013.796394

REVIEW

Surgical Treatment for Macular Edema Shani Golan and Anat Loewenstein

Semin Ophthalmol Downloaded from informahealthcare.com by Mcgill University on 10/07/14 For personal use only.

Department of Ophthalmology, Tel Aviv Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

ABSTRACT Objective or Purpose: Macular edema (ME) is secondary to various disease processes. It is most commonly seen following venous occlusive disease, diabetic retinopathy, posterior segment inflammatory disease, and vitreomacular traction syndromes. Treatment varies, depending upon the underlying etiology, and has led to varying degrees of success. Advances in vitreoretinal surgical techniques over the years have expanded the list of indications for vitreoretinal surgical treatment. The purpose of this review is to outline the current use of vitreoretinal surgery and highlight the ever-growing indications for surgery in macular edema. Design: This is a comprehensive review, using Medline, of all literature published on vitreoretinal surgery for macular edema secondary to various conditions. Results: Over 450 abstracts were reviewed, and the articles pertinent to our discussion were selected. The search words were ‘‘macular edema’’ and ‘‘pars plana vitrectomy’’ or ‘‘surgery.’’ Conclusions: The pathology of the vitreous body is associated with ME in several different conditions, and vitreoretinal surgical techniques can be effective in the management of ME in the majority of them. The everexpanding new surgical techniques, as well as the new pharmacologic agents used during surgery, show great promise for the future. Keywords: Macular edema, pars plana viterectomy, surgery, vitreous

MACULAR EDEMA (ME)

intracapsular cataract extraction. Irvine observed that cases with persistent loss in visual acuity (VA) were associated with a vitreous strand. In 1966, Iliff described what was probably the first application of vitreous surgery in the treatment of macular edema.2 He treated cases with Vitreous Tug Syndrome similar to those of Irvine. VA improved postoperatively in the majority of his patients. The indications for surgery in the treatment for ME continue to expand to this day. This review summarizes the current indications for surgical intervention in macular edema, the complications associated with surgery, and the newly developing surgical techniques.

Macular edema (ME) is a common condition usually associated with a number of intraocular disorders. It may be secondary to endogenous uveitis, retinal vascular diseases, and inherited retinal diseases, and can occur after cataract surgery as well. ME may also be secondary to vitreous traction and may develop in association with various systemic disorders, such as drug toxicity. The factors that underlie the pathogenesis of ME are of great importance for management and better understanding the role of vitreoretinal surgery. The observations of Irvine in 1953 were the first to suggest that vitrectomy might have a role in the treatment of macular edema.1 He described a syndrome consisting of conjunctival injection, photophobia, reduced vision, and increased flare in eyes that had undergone cataract extraction complicated by rupture of the anterior hyaloid face. The syndrome appeared from two to three months after

Pathology ME represents an accumulation of excess fluid in the extracellular space of the neurosensory retina. The term ‘‘cystoid macular edema’’ (CME) applies when

Received 11 October 2012; revised 15 March 2013; accepted 11 April 2013; published online 26 November 2013 Correspondence: Shani Golan, MD, Department of Ophthalmology, Tel Aviv Medical Center, 6 Weizman Street, Tel Aviv 64239, Israel. E-mail: [email protected]

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Surgical Treatment for Macular Edema there is evidence of fluid accumulation in cyst-like spaces within the macula on biomicroscopy, fluorescein angiography (FA), and/or optical coherence tomography (OCT). The classic pathology of CME consists of cystoid spaces in the outer plexiform layer, but such fluid-filled spaces can be seen in various layers of the retina, depending in part on the underlying etiology.3 The factors that underlie the pathogenesis of ME are of great importance for management and better understanding the role of vitreoretinal surgery. The blood-retinal barrier (BRB) essentially operates in two ways: (1) the inner barrier is the endothelial membrane of the retinal vessels; and (2) the outer barrier is the retinal pigment epithelium (RPE). Breakdown of the BRB may result from several mechanisms. First, tight junctions of capillary endothelial cells can be damaged from vitreoretinal adhesion and traction on the macula, or from factors secreted into the vitreous which are produced by the retina and other parts of the eye4 that increase vascular permeability. The main factor is vascular endothelial growth factor (VEGF).5,6 Second, there can be damage to the function of the RPE by ischemia and disruption of the BRB tissues.7 Finally, the BRB can be disrupted by inflammation. The inflammatory mediators are prostaglandins, leukotrienes, histamine, bradykinin, platelet-activating factor (PAF), and interleukin (IL)-1.8 Several pathologic conditions may contribute to the development of ME (Table 1). As a final common pathway in numerous prevalent retinal disorders, ME in its various forms can be considered the leading cause of central vision loss in the developed world, and is

TABLE 1. Pathologic conditions causing macular edema. Retinal vascular diseases - systemic/diffuse Diabetic retinopathy Retinal venous obstruction Hypertensive retinopathy Retinal vascular diseases - localized/focal Retinal arterial macroaneurysm Retinal telangiectasis Intraocular inflammatory processes Post-surgery (Irvine Gass syndrome) Uveitis Choroidal vascular diseases Choroidal neovascularization Tractional maculopathies Vitreomacular traction syndrome Epiretinal membrane Retinal detachment Intraocular tumors Inherited retinal diseases Drug reactions Prostaglandins analogues Epinephrine Nicotinic acid Tamoxifen Idiopathic !

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therefore of enormous medical and socioeconomic importance.9–11 Mounting clinical and anatomic evidence suggests that abnormalities in the structure of the vitreoretinal interface may play an important role in the pathogenesis of ME. Several authors have studied pars plana vitrectomy (PPV) for persistent ME, and they have suggested that the release of tractional forces at the vitreomacular interface may improve resolution of the ME and restore VA.12–15 The mechanism by which the release of traction resolves ME is unclear. Some investigators hypothesize that vitrectomy may improve perifoveal retinal microcirculation, while others suggest that the posterior hyaloid may exert tangential tractional forces that are released with surgery.16,17

INDICATIONS FOR SURGERY Irvine Gass Syndrome The first application of vitreous surgery was the treatment of pseudophakic CME (Figure 1a,b and Figure 2), commonly termed ‘‘Irvine Gass syndrome.’’ Although the precise mechanistic details underlying pseudophakic CME remain to be elucidated, two primary hypothetical components have been implicated in its pathogenesis. The first of these is ocular inflammation, as described by Irvine Gass.1 The second influence, which was thought to contribute to the development of CME, at least in some patients, is mechanical forces induced by a modified vitreous; whether they lead to ‘‘rolapse of the vitreous into the anterior chamber with late rupture of the hyaloid face,’’ as originally described by Irvine, or produce vitreomacular traction leading to alterations in the BRB, as described by Schepens and others.1,18 In support of this theory, complete posterior vitreous detachment (PVD) has been found to be protective against the development of pseudophakic CME.19 Ultimately, both of these factors, among others, may lead to an imbalance of macular fluid dynamics. Based on the postulated connection between vitreous changes and the development of pseudophakic CME, surgical alteration of the vitreous has been tried as a therapeutic intervention, particularly in cases where medical treatment has failed. In 1980, Fung reported a series of patients treated with anterior vitrectomy using the Kloti stripper via a limbal approach.20 All patients had angiographically proven CME associated with vitreous to the section, for six months or more following intracapsular cataract extraction. The results were sufficiently encouraging and a large-scale, prospective, multicenter, randomized controlled trial was undertaken.21 A total of 136 aphakic eyes with CME were included from 15 centers in the United States. Sixty-eight eyes


244 S. Golan and A. Loewenstein

FIGURE 1. (a) Early fluorescein angiography of a patient with macular edema secondary to pseudophakic CME; 99 99 mm (300 300 DPI). (b) Late fluorescein angiography of a patient with macular edema secondary to pseudophakic CME; 99 99 mm (300 300 DPI).

were randomized to surgery or control. The rate of improvement (defined as an increase in VA of two or more lines) was 29 of 43 (67%) in the treatment group, compared with 8 of 24 (33%) in the control group. The difference was statistically significant (p50.01). In addition, a very low rate of complications was reported. Unfortunately, there have been no prospective investigations on vitrectomy for pseudophakic CME, but a retrospective series of vitrectomy for chronic, refractory pseudophakic CME showed VA improvement in 24 of 24 eyes, with the mean acuity improving from 20/190 to 20/52.13 In these cases, vitrectomy was undertaken because of either clinical evidence of vitreous adhesions to anterior segment structures (23 eyes) or iris capture of the intraocular lens (IOL). Another retrospective study of patients with recalcitrant pseudophakic CME who underwent PPV showed resolution of clinically visible edema in 23 of 23 eyes, with improvement in the median bestcorrected VA from 20/200 to 20/60.22 The authors noted that vitrectomy might be of value in pseudophakic CME, even without evidence of vitreous abnormalities. Another report showed an improvement in ME and VA in two patients who underwent PPV with peeling of the internal limiting membrane (ILM).23 Updated publications report increasingly promising outcomes of vitrectomy with or without membrane peeling in pseudophakic CME. Still, there is no question that more evidence is needed, not only to prove the efficacy of the procedure, but also to better define at what point and in which patients it should be considered.

Diabetic Macular Edema (DME) In the diabetic population, ME is the principal cause of visual impairment (Figure 3). In the Early Treatment Diabetic Retinopathy Study (ETDRS), the effectiveness of focal laser photocoagulation was proven with regard to the reduction of the incidence of moderate visual losses in eyes with clinically significant ME.24 However, the incidence of visual improvements three years after macular photocoagulation was not greater than 3%. Other treatment options include the injection of intravitreal triamcinolone acetonide (IVTA) or sustained release corticosteroid formulations administered intravitreally.25,26 However, these treatments do not alleviate macular hypoxia, the underlying cause of the disease. Intravitreal injections of anti-VEGF are increasingly being adopted as a new strategy for the treatment of diabetic macular edema (DME). This approach is being investigated in various large-scale studies. AntiVEGF treatment does not, however, alleviate macular hypoxia and it requires repeated injections for an extended period.27–29 Nasrallah and coworkers were the first to suggest that the vitreous might play a role in the pathogenesis of DME.30 They found that diabetic patients who are 60 years of age and who had ME had a significantly higher prevalence of attached posterior vitreous than those without ME. Furthermore, naturally occurring PVD is rare in diabetics who are 50 years of age. PVD in younger diabetic patients results from a diabetes-related vitreous contraction that simultaneously causes traction on the macula and may lead Seminars in Ophthalmology


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FIGURE 2. Time domain stratus optical coheresence tomography (OCT) for the same patient presented in Figure 1 demonstrating pseudophakic CME; 174 166 mm (300 300 DPI).

to ME.31 Moreover, sustained hyperglycemia can affect several biochemical pathways that can lead to liquefaction and destabilization of the vitreous gel.32 Such destabilization of the central vitreous with persistent attachment to the retina could induce traction on the macula (vitreoretinal adhesions in diabetic eyes are stronger than the shear forces of the traction from vitreous shrinkage), and may contribute to the development of ME.32–35 Lopes de Faria and coworkers have shown that the risk for developing diffuse ME in patients with vitreomacular adhesion is 3.4 times greater compared to those with complete PVD or vitreoretinal separation.35 Hikichi and coworkers reported the spontaneous resolution of ME in 55% of eyes with vitreomacular separation, whereas only 25% of eyes with vitreomacular adhesion had spontaneous resolution of ME (p = 0.01).36 !


The results of PPV for DME were first reported in patients with a thickened and taut posterior vitreous membrane.32 Subsequent studies evaluated vitrectomy results in patients with PVD, and patients who had neither a thickened posterior membrane nor PVD.12,37,38 It should be mentioned, however, that most of the surgeries performed for diffuse macular edema without traction were performed before the advent of anti-VEGF treatment. The effectiveness of vitreous surgery for DME involves relief of the posterior hyaloid membrane traction, removal of inflammatory cytokines, such as VEGF, and an increase in preretinal oxygen pressure.12,32,37–39 Surgical approaches are most commonly used for diffuse and non-resolving DME. An analysis of multiple studies involving a variety of inclusion criteria and surgical techniques found that



FIGURE 3. OCT Spectralis, Heidelberg, tomography vertical scan of a patient with macular edema secondary to diabetes; 250 84 mm (300 300 DPI).

PPV resulted in the resolution of DME in 83% of cases, with 56% demonstrating improvements in VA.40 A recent prospective cohort study by the Diabetic Retinopathy Clinical Research (DRCR) Network examined the utility of PPV in treating DME with vitreomacular traction accompanied by at least a moderate loss of vision and central subfield thickening on OCT of 300 microns (mm). Additional procedures used in the study included epiretinal membrane peeling (61%), ILM peeling (54%), and injection of corticosteroids at closing (64%). The 87 eyes that were followed for six months experienced a median reduction of retinal subfield thickness of 160 mm and a mean VA gain of three letters.41 Positive results have also been reported for diffuse non-tractional DME. In a retrospective consecutive case series of 332 patients (496 eyes) with a mean follow-up of 74 months (range: 12–170 months), final VA improved in 53% of eyes, remained unchanged in 31%, and worsened in 16%.42

The Role of ILM Peeling Several authors have postulated a positive effect of additional peeling of the ILM in patients with DME refractory to laser photocoagulation.12,43 Stolba et al. reported a favorable outcome following vitrectomy and ILM peeling compared to the natural course.44 Still, it is unclear whether the ILM needs to be removed or whether PVD alone is sufficient. For example, Stefaniotou et al.’s retrospective study found that ILM peeling was beneficial in patients with diffuse DME,45 while Bahadir and colleagues could not prove any beneficial effect of vitrectomy and ILM removal in comparison to vitrectomy alone.46 The exact pathomechanism of ILM removal on DME is currently unknown. The ILM, which is the basement membrane of the Mu¨ller cells, may act as a diffusion barrier. Recent findings of a comparative histopathological study of surgically removed ILM

showed that the ILMs in patients with DME were significantly thicker (mean thickness: 4.8 1.6 mm), revealing a larger amount of cellular elements on the vitreous side than that seen in patients with macular holes (1.8 0.6 mm).47,48 The thickened ILM may act as a barrier, decreasing transretinal fluid movement. After removal of the diffusion barrier, disturbance of transretinal fluid movement may be partly restored and contribute to a resolution of ME.47 Also, Radetzky et al. speculated about a pseudomembrane formed by the endplates of Mu¨ller cells, exerting a barrier function.49 Intraretinal structural damage in chronic cystoid edema may further influence the diffusion properties. It is also possible that the thickened ILM may reduce the diffusion of oxygen from the vitreous cavity to the retina following vitrectomy. Stefańsson et al. have suggested that fluid currents in the vitreous cavity following vitrectomy of PVD transport oxygen from well-perfused areas of the retina to hypoxic areas, such as those present in DME.39,50 The diffusion of oxygen from the fluid in the vitreous cavity into the retina would be retarded by a thickened ILM. Another theory is that the repair mechanisms of Mu¨ller cells may be activated by delamination of the ILM.51 Also, the absence of the vitreous gel would increase the transport of cytokines, such as VEGF, from the retina into the vitreous cavity. The absence of the ILM would further speed up this clearance of cytokines from the retina.52 The efficacy of ILM delamination may be caused by the removal of a growth factor reservoir, which may have accumulated in the ILM and in cellular elements on its vitreous side. A recent study showed that vitreous remnants could be present after surgical vitreous separation.53 Histopathologic correlations by Gandorfer et al. and Matsunaga et al. support the theory that ILM delamination allows a more complete removal of vitreous elements.48,54 A recent prospective randomized trial evaluated a histological section of a surgically removed ILM from DME patients undergoing PPV, Seminars in Ophthalmology

Surgical Treatment for Macular Edema and demonstrated methylglyoxal advanced glycation end products (AGEs) within the removed ILM specimens.55 The study suggested a role for both substances in the pathogenesis of DME. AGEs have been implicated in the primary pathogenesis of diabetic vascular damage, and can enhance VEGF production, thereby inducing permeability changes.55 CML (N-carboxymethyl lysine) is a glycoxidation product present in a variety of conditions associated with increased oxidative or glycative stress, particularly in the eye.56


Smaller Gauge Vitrectomies for DME The quest to find ways to shorten surgical time and to minimize trauma to the eye has led to considerable improvement in surgical techniques and equipment, and eventually to the development of the first 25gauge (0.51 mm) and 23-gauge (0.61 mm) transconjunctival sutureless vitrectomies for DME.57–59 These smaller-gauge techniques were shown to be safely used for the treatment of vitreoretinal complications in patients with diabetes mellitus.57,58 Further miniaturization of the surgical technique was recently presented by Oshima et al. with the 27gauge sutureless vitrectomy system.60

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vitreous hemorrhage.64 Intravitreally administered VitreosolveÕ (a carbamide derivative) is also currently being evaluated in a phase III randomized controlled trial in patients with non-proliferative diabetic retinopathy (NPDR). Microplasmin (Thrombogenics, NV, Leuven, Belgium), a fragment of plasmin, is being studied as a treatment for DME in a sham-controlled phase II trial. Furthermore, in a 2010 report of another phase II trial (MIVI III) of microplasmin for nonproliferative vitreoretinal disease, the agent proved superior to the placebo both for inducing a PVD and resolving the condition without the need for surgery.64 There has also been one small, prospective case series employing intravitreal injections of autologous plasmin as a treatment for bilateral DME, with improvements in both ME and retinal thickness compared with the non-injected control eyes.65 In conclusion, in a comprehensive review of the relevant peer-reviewed scientific literature published in 2003, the rate of resolution (complete or partial) of persistent ME after vitrectomy with or without ILM peeling ranged from 70% to 100%.66 PPV led to the resolution of ME and improved vision, even among patients in whom DME is not associated with clinically evident posterior hyaloidal thickening or traction. Improvement in VA reportedly occurred in 38–90% of the patients, and improvement or stabilization of VA after vitrectomy ranged from 84.5–100%.66

Combination Therapies Retinal Vascular Occlusion Combination treatment was suggested to enhance the beneficial effects of PPV and to obviate the limitations of the above-mentioned treatment methods.61,62 Kang et al. reported a prospective, interventional case series involving 24 eyes from 24 subjects who were diagnosed with intractable DME of non-tractional origin and who underwent PPV.61 IVTA injection and macular laser photocoagulation were conducted sequentially at 1 and 14 days after PPV. The changes in both best-corrected VA (BCVA) and central macular thickness (CMT) at 3, 6, and 12 months from baseline were significant (p50.003). The major adverse events after triple therapy were the development of nuclear sclerotic cataracts (eight among 12 phakic eyes) and elevation of intraocular pressure (IOP; eight of 24 eyes). Other reports suggested that eyes that received TA-assisted PPV showed significantly less breakdown of the blood-ocular barrier than those that underwent routine PPV.61,62

Vitreolysis in DME Intravitreally administered pharmacological agents are also being investigated as possible options for dissolution of the vitreous and achievement of posterior vitreous detachment or clearance of !


Retinal vein occlusion (RVO) is second only to diabetic retinopathy as a cause of retinal vascular disease. Vision loss from RVO may be associated with multiple causes, including ME (Figure 4), macular ischemia, foveal hemorrhage, vitreous hemorrhage, epiretinal membrane, and retinal detachment. The unsatisfactory results of medical therapy techniques led to the development of novel treatment strategies that focus on the surgical treatment of the occluded retinal vein. Some surgical approaches to RVO are rarely performed today. A brief summary of these approaches and of PPV for RVO is summarized as follows. Radial Optic Neurotomy Increased pressure within the confined scleral outlet was hypothesized to cause thrombus as a result of decreased lumen size and increased turbulence. Radial optic neurotomy (RON) was thought to release the pressure, increase the lumen size and venous blood outflow of the central retinal vein (CRV), and thus allow thrombosis clearance.67 Moreover, RON was thought to induce the postoperative development of optociliary venous anastomosis or retinochoroidal shunts, leading to increased retinal venous outflow.67–73 When RON was combined with IVTA



FIGURE 4. OCT Spectralis, Heidelberg, tomography horizontal scan of a patient with macular edema secondary to branch retinal vein occlusion; 250 84 mm (300 300 DPI).

injections in patients with central retinal vein occlusion (CRVO), anatomic resolution was observed in more than 77% of patients.68,69,74 The synergetic effects of RON, PPV, ILM peeling, and IVTA injection in patients with CRVO were also evaluated.75 After five months of follow-up, mean VA improved in 87.5% of eyes, and there was anatomic resolution in all eyes. Although RON has been proposed as safe by some authors, the possibility of serious complications should be considered.67,68 The procedure carries a potential risk of laceration of the central retinal artery (CRA) or CRV, optic nerve fiber damage with visual field loss, globe perforation, retinal detachment, choroidal neovascularization (CNV) at the neurotomy site, and anterior segment neovascularization.67,76–78 In a biomechanical model that was constructed to simulate the potential therapeutic effect of this surgical procedure, it was found that the increase in the lumen area of the central retinal vein lumen after RON remained trivial, ranging from only 1% to a maximum of 5%.79 As a result, the benefits of RON appear to be controversial, and most vitreoretinal surgeons have abandoned this procedure.68,69,80 Efficacy remains to be proven in prospective randomized clinical studies. Chorioretinal Venous Anastomosis Chorioretinal venous anastomosis, in which a shunt is created between a retinal vein and the choroids, aims to bypass the occluded vein by an alternative route, improve retinal outflow, and relieve the venous obstruction.81–83 The procedure can be performed by laser or by surgery. A success rate of 33% has been reported for a laser-induced anastomosis.82 However, this treatment is frequently associated with serious complications.67,81,82 A recent report by McAllister et al. evaluated the effectiveness of a laser-induced chorioretinal venous anastomosis as a treatment for nonischemic CRVO and found that the eyes that developed an anastomosis (76.4%) had a significant

improvement (11.7 letters) in final VA after 18 months.83 Complications of the laser approach were progression to ischemic CRVO, CNV, macular traction, and vitreous hemorrhage. Surgically induced chorioretinal venous anastomosis has been described by several authors using several techniques.84–86 Visual improvement was reported in 60–80% of patients.84,86 These studies, however, included small sample sizes. One study reported that 30% of patients experienced complications, such as retinal detachment, vitreous hemorrhage, and cataract.84 Direct Injection of Tissue Plasminogen Activator via Retinal Vein Cannulation Direct injection of tissue plasminogen activator (t-PA) includes PPV with posterior hyaloid removal, followed by cannulation of a peripapillary retinal vein branch and injection of a bolus of 200-mg/ml t-PA towards the optic nerve head (ONH). Visual improvement was observed in 15 of 28 eyes with CRVO with this technique.87 In another study, the visual outcome of this technique was disappointing and the complication rates were high.88 While direct injection of t-PA via retinal vein cannulation is feasible, it can lead to serious ocular complications, including vitreous hemorrhage, retinal tear formation, retinal detachment, neovascular glaucoma, endophthalmitis, and phthisis bulbi. Arteriovenous Sheathotomy The arteriovenous sheathotomy surgical procedure was first described by Osterloh et al. in 1988, and included PPV with posterior hyaloid detachment (PHD).89 The endpoint of surgery was elevation and separation of the arteriole from the underlying venule, which was confirmed using a subretinal spatula. More recently, a bimanual technique of arteriovenous sheathotomy followed by intravitreal recombinant t-PA had reportedly favorable results.90 Until now, most studies on arteriovenous sheathotomy have been Seminars in Ophthalmology



uncontrolled and they failed to show a convincing improvement in outcomes of branched retinal vein occlusions (BRVO) that would justify the risks of this surgical procedure.91–93 Vitrectomy with or without Internal Limiting Membrane Peeling Persistent ME may lead to irreversible visual loss as a result of apoptosis of the photoreceptors. Rapid resolution of ME is mandatory for the preservation of VA.14 PPV with ILM peeling has been suggested as beneficial for the rapid resolution of retinal damage and ME in patients with CRVO.78,94,95 Decreased retinal thickness and increased VA were observed postoperatively in more than 70% of cases of ME caused by CRVO or BRVO.94,95 These effects persisted for up to five years.96 Comparatively successful results have also been reported in vitrectomy without ILM peeling. Vitrectomy itself can provide resolution of ME by removing VEGF and other cytokines within the vitreous cavity and enhancing oxygen transport to the hypoxic retina.12,97 There are some reports of a significant improvement in patients after vitrectomy with gas/air tamponade for ME caused by BRVO, but others did not confirm any benefits from PPV in eyes with CRVO.98,99 Vitrectomy showed an initial positive effect for the resolution of ME, but no beneficial effect in the long-term.49 The authors hypothesized that vitrectomy and ILM peeling might be beneficial in the reduction of intraretinal edema, although they failed to identify the underlying the pathophysiological mechanisms, such as growth factor expression or altered fluid dynamics.

Uveitis CME is the most common cause of blindness and visual impairment in uveitic patients. It is usually the sequel of chronic intraocular inflammation, and its incidence varies according to the underlying clinical syndrome. Uveitic CME results in significant reduction of VA in 21–52% of patients.100 Despite rigorous treatment with steroids and other immunomodulators, long-term results indicate that ME may persist in a substantial number of cases.101 There are many indications for vitrectomy in such cases, including biopsy for diagnosis, media opacity, and epiretinal membranes. Most studies have reported visual improvement following surgery.49,102–106 The majority of these studies also reported a beneficial effect of surgery on CME. Gutfleisch et al. performed a PPV with ILM peeling and injection of 4 mg triamcinolone in 19 patients with refractory ME and found a decrease of ME on FA in 44% of the eyes, but a worsening of VA in 22% of the eyes.104 Schaal et al. reported a positive effect of a surgical PVD on retinal thickness and VA.105 Those authors indicated that !


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even the presence of a Weiss ring does not ensure the absence of adherent vitreous to the macula. Also, it has been suggested that PPV might improve ME and lead to a decrease of systemic immunosuppressive therapies in pediatric uveitis.103 In a randomized controlled study of 23 patients with CME secondary to chronic refractory uveitis, vision improved by two or more lines in 50% of the eyes that received vitrectomy compared to only 18% of the eyes in the control group.106 In addition, 33% of the vitrectomized eyes had angiographic improvement of CME compared to 14% in the medically treated group. The effect of PPV on the angiographic outcome of CME appeared to be modest with 66% of the eyes showing no improvement after six months of follow-up. A possible explanation for this finding is that removal of the vitreous may improve vision because of improvement in media clarity rather than specifically inducing changes in the pre-existing CME. The possible mechanisms of regression of ME after PPV remain uncertain. There is some evidence that removal of inflammatory mediators from the vitreous gel may have a therapeutic effect on CME since it may result in reduced antigen presentation and increased responsiveness to systemic treatment.107–109 Mechanical factors may also have a role in the pathogenesis of uveitic CME. Previous reports on eyes with peripheral uveitis and posterior vitreous adhesion documented a higher incidence and more refractory ME compared to eyes with complete vitreoretinal separation.36 In addition, enhanced fibrosis of the vitreoretinal interface often occurs and may result in the formation of epiretinal membranes and subsequent ME. The presence of an epiretinal membrane has been proven to be a significant factor associated with medical treatment failure, and its removal can help to reduce ME.110 A large-scale trial is needed to more clearly define the role of vitrectomy in uveitic ME.

Tractional Maculopathies Vitreomacular Traction Syndrome As the vitreous detaches from the macula and liquefies due to age, a natural progression can be demonstrated by OCT in normal eyes.111 An abnormally strong adhesion is present between the vitreous and macula in some individuals, however, and the vitreous continues to pull on areas of the macula as it detaches peripherally. Tractional forces on the macula may cause different pathologies, including formation of full- and partial-thickness macular holes (Figure 5) and formation of CME (Figure 6) and submacular fluid. Macular thickening caused by continued pathologic adherence of the vitreous to the retina in the setting of a peripheral vitreous detachment has been termed vitreomacular traction syndrome (VMT).112 VMT may lead to a decline in VA, metamorphopsia,



FIGURE 5. OCT Spectralis, Heidelberg, tomography vertical scan of a patient with macular edema secondary to macular hole; 249 84 mm (300 300 DPI).

FIGURE 6. OCT Spectralis, Heidelberg, tomography vertical scan of a patient with macular edema secondary to vitreomacular traction; 250 84 mm (300 300 DPI).

or both. The vitreous eventually separates from the macula on its own in some of the affected eyes, leading to subsequent resolution of intraretinal and subretinal fluid and restoration of more normal vision, but it is more common for vitreomacular traction to persist.113 Vitrectomy may be an effective treatment option for patients with persistent and symptomatic VMT diagnosed biomicroscopically.114,115 The question of how often or which cases progress to full-thickness macular hole formation has not yet been answered and, therefore, the indications for and timing of surgical intervention remain controversial.42,116,117 Many reports have implied or assumed that vitreofoveal traction syndrome is a macular hole precursor – what had previously been called stage 1 or impending macular hole – and authors have based the rationale for undertaking surgery as taking measures to avoid the formation of a macular hole.118,119 With the advent of OCT, the posterior hyaloid could be seen as a thin line anterior to the retina in patients with vitreomacular traction.120 The VMT that

is evident on OCT is often not visible on biomicroscopic examination of the fundus120,121; therefore, OCT has become especially useful in diagnosing VMT and subsequently determining treatment for it. However, since the commercialization of OCT, there have been few reports on the surgical results of vitrectomy for vitreomacular traction syndrome.117,122 A recent case series described 20 eyes with vitreomacular traction syndrome diagnosed preoperatively by OCT that underwent PPV and detachment of the posterior hyaloids from the fovea.123 The authors found a significant improvement in VA, from 20/122 preoperatively to 20/68 postoperatively (p = 0.005). Nine of the 20 eyes (45%) had two or more lines of improvement in Snellen VA, and seven eyes (35%) had an improvement of three or more lines. There was also a significant decrease in central macular thickness on OCT, from 404 mm preoperatively to 250 mm postoperatively (p = 0.001). As noted earlier, intravitreally administered pharmacological agents are also being investigated as possible options for dissolution of the vitreous and achievement of PVD or clearance of Seminars in Ophthalmology



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FIGURE 7. OCT Spectralis, Heidelberg, tomography horizontal scan of a patient with macular edema secondary to epiretinal membrane; 250 84 mm (300 300 DPI).

vitreous hemorrhage.63 Microplasmin, a fragment of plasmin, was studied in porcine eyes and it was shown capable of consistently producing a posterior vitreous separation, leaving a smooth retinal surface at doses of approximately 125 mg.124 The MIVI I trial was the first to report the use of recombinant microplasmin (Thrombogenics, NV, Leuven, Belgium) for intravitreal injection in human patients.125 The primary aim of the trial was to determine the safety of the compound and to obtain preliminary data on its efficacy. The investigators evaluated the safety and preliminary efficacy of four doses (25, 50, 75, or 125 mg in 100 ml) of intravitreal microplasmin and several exposure times (either one to two hours, 24 hours, or seven days) given before PPV for vitreomacular traction maculopathy in 60 patients. Ultrasonographic imaging demonstrated that the use of microplasmin led to a progressively higher incidence of PVD induction with increasing time exposure. Increasing the dose of microplasmin apparently facilitated the separation of the posterior hyaloid, particularly when the assessment was by B-scan ultrasonography. Since the MIVI I trial, reports from subsequent MIVI II and III trials have shown similar results with microplasmin proving to be superior to the placebo both for inducing a PVD and resolving the condition without the need for surgery.126 The results warrant further evaluation of microplasmin in larger, controlled trials. Epiretinal Membrane Idiopathic epiretinal membranes (ERMs) are associated with symptoms of distortion and visual loss. Edema can often be demonstrated in ERMs (Figure 7) and it is thought to contribute to visual impairment. Treatment of ERM is mainly surgical, including PPV and peeling of the ERM after dye application. After surgery, vision is improved in most eyes, but complete normalization of VA is rare.127 Similarly, the appearance of the retina tends to return to normal but not completely with 60% to 87% of eyes improving by two !


Snellen lines.128 The improvement continues for more than six months, and the mean time to achieve best final vision is about one year.128 Among many prognostic factors associated with the visual outcome, the presence of CME generally suggests a worse prognosis for any visual improvement following surgery.129 However, a recent study retrospectively reviewed 75 eyes that underwent primary PPV with membrane peeling and evaluated whether morphologic differences in idiopathic ERMs seen on OCT may help predict surgical outcomes.130 The eyes were categorized into four types: 42 eyes were included in the diffuse type, 12 in the CME type, 14 in the pseudolamellar hole type, and seven in the vitreomacular traction type. The surgical procedure significantly improved vision in all types except for the pseudolamellar hole type.

COMPLICATIONS OF VITRECTOMIES Complications after PPV, as described in the literature, include cataract formation (10%–57.5%), corneal decompensation (8%), development of an ERM (8%–13.8%), fibrinoid syndrome (8%), glaucoma (1.7%–8%), increased hard exudates (3%–4.6%), development of a macular hole (1.5%), macular ischemia (10%), neovascular glaucoma (3%–8%), retinal detachment (5%–10%), rubeosis iridis (4.6%), retinal tear (4.6%–20.7%), traction-rhegmatogenous retinal detachment (1.5%–1.7%), and vitreous hemorrhage (1.5%–16%).12–14,22,34,37,38,40,41,131

NEW SURGICAL TECHNIQUES Several innovations propelled vitreoretinal surgery forward over the past several years, including endoscopic light amplification by stimulated emission of radiation (endoLASER), perfluorocarbon liquid, widefield viewing systems, and improved illuminating


252 S. Golan and A. Loewenstein systems (e.g., Xenon). Each of these advances made it easier to treat diseases that were previously difficult or impossible to treat. Moreover, there has been a major shift in how vitreoretinal surgery is performed with the introduction of the 25-gauge vitrectomy by Au Eong et al. in 2002.132 Although early 25-gauge instrumentation was limited by excessive flexibility, subsequent generations became more rigid, thereby increasing utility. In 2003, Eckhart promoted the 23-gauge vitrectomy, which combined some of the benefits of both 25- and 20-gauge instrumentation. Like the 25-gauge, the 23-gauge was relatively small and enabled the performance of a transconjunctival, sutureless vitrectomy. Like the 20-gauge, the 23-gauge was rigid and facilitated the use of the endoLASER and the shaving of the peripheral vitreous gel. Thanks to these advances, vitreoretinal surgeons now have multiple operative approaches from which to choose. As is true in other fields of medicine, however, when multiple treatments or methods exist, it is typically because no single treatment or method is ideal. For example, although certain aspects of 25-gauge instrumentation are clearly advantageous, other aspects of 23-gauge and 20-gauge techniques are actually preferable.

CONCLUSION The pathology of the vitreous body is associated with ME in several different conditions, and vitreoretinal surgical techniques can be effective in the management of the majority of ME. The ever-expanding new surgical techniques, as well as the new pharmacologic agents used during surgery, show great promise for the future.

METHOD OF LITERATURE SEARCH The literature searched was performed using Medline (1993 to March 2012) with preference given to manuscripts relevant to our topic and published in Englishlanguage peer-reviewed journals. Clinical studies were selected if they were randomized controlled trials. Also included were especially relevant case series, single case reports, and editorials. Four hundred and fifty abstracts were reviewed, and the articles pertinent to the authors’ discussion were selected. The search words were ‘‘macular edema’’ and ‘‘pars plana vitrectomy’’ or ‘‘surgery."

DECLARATION OF INTEREST Anat Loewenstein, MD, is Consultant to Allergan, Inc., Consultant to Alcon, Inc., Consultant to Lumenis, Ltd., Consultant to Forsightlabs, Consultant to Notal

Vision, Ltd., Consultant to Orabio, Ltd. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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Uveitic Macular Edema: Treatment Update.

Corticosteroid Treatment in Diabetic Macular Edema.

Drilling Deeper for Treatment Choices in Diabetic Macular Edema.

Intravitreal pegaptanib for the treatment of ischemic diabetic macular edema.

Effect of macular ischemia on intravitreal ranibizumab treatment for diabetic macular edema.

Relation between macular morphology and treatment frequency during twelve months with ranibizumab for diabetic macular edema.

Strategy for the management of diabetic macular edema: the European vitreo-retinal society macular edema study.

Combined therapy for diabetic macular edema.

Anti-VEGF therapy for diabetic macular edema.

Vitrectomy for center-involved diabetic macular edema.

Emerging drugs for diabetic macular edema.

Intravitreal aflibercept for diabetic macular edema.

Update on corticosteroids for diabetic macular edema.

Diabetic macular edema.

Uveitic macular edema.

Macular Edema after Gabapentin.

Diabetic Macular Edema.

Diabetic macular edema: new concepts in patho-physiology and treatment.

Is laser photocoagulation treatment currently useful in diabetic macular edema?

Revolution to a new standard treatment of diabetic macular edema.

Dexamethasone intravitreal implant in the treatment of diabetic macular edema.

Interdigitation Zone Band Restoration After Treatment of Diabetic Macular Edema.

Anti-vascular endothelial growth factor treatment in diabetic macular edema.

Topical indomethacin in the treatment of chronic cystoid macular edema.