Diabetic macular edema.

Management of Specific Diseases Oh H, Oshima Y (eds): Microincision Vitrectomy Surgery. Emerging Techniques and Technology. Dev Ophthalmol. Basel, Karger, 2014, vol 54, pp 164–173 (DOI: 10.1159/000360463)

Diabetic Macular Edema Fabio Patelli a · Paolo Radice b · Enrico Giacomotti a

a Vitreoretina Surgery, Department of Ophthalmology, Igea Clinic, and b Department of Vitreoretina Surgery, Fatebenefratelli Ophthalmic Hospital, Milan, Italy

Abstract Diabetic macular edema (DME) is one of the most common causes of visual loss in patients with diabetes mellitus. Many patients continue to lose vision despite laser photocoagulation and medical therapies. The two major categories of medications currently used to treat DME are corticosteroids and anti-VEGF agents. The vitreous has been implicated as a cause of macular edema in people with diabetes via several mechanical and physiologic mechanisms, all of which are postulated to lead to increased vascular permeability. Vitrectomy can release the mechanical traction on the macula and increase oxygenation with subsequent reduction in DME. Early vitrectomy even in nontractional DME results in significant macular thinning and may lead to rapid improvement in vision with long-term stabilization. Unfortunately, a randomized trial pitting vitrectomy against the methods currently employed has not yet been performed.

croaneurysms, and loss of pericytes, with eventual impairment of the blood-retinal barrier [2]. Breakdown of the blood-retinal barrier results in fluid leakage into the extracellular space, which disrupts macular structure and function on a cellular level [3, 4]. The pathogenesis of DME is at this time poorly defined, but is believed to involve angiogenesis, inflammation, and oxidative stress [5]. Hyperglycemia is reported to lead to capillary endothelial damage and alterations in leukocyte function [6]. In addition, hyperglycemia has been reported to activate oxidative stress agents, such as advanced glycation end-products and the protein kinase C pathway [7]. Various inflammatory mediators appear to play a role in promoting DME, including vascular endothelial growth factor (VEGF) [8], placental growth factor [9], and hepatocyte factor [10].

© 2014 S. Karger AG, Basel

Diabetic Macular Edema Classification

The Early Treatment Diabetic Retinopathy Study Research Group (ETDRS) defined clinically significant DME as any one of the following: Downloaded by: Université Laval, Bibliothèque 198.143.38.97 - 7/3/2015 7:03:04 AM

Diabetic macular edema (DME) is one of the most common causes of visual loss in patients with diabetes mellitus [1]. The pathophysiology of DME involves dilated capillaries, retinal mi-

Fig. 1. OCT demonstrating diffuse retinal thickening. Diffuse retinal thickening appears as increased retinal thickness with areas of reduced intraretinal reflectivity.

Fig. 2. OCT demonstrating diabetic cystoid macular edema. The scan highlights the large, ovoid areas of low reflectivity, separated by highly reflective septae that represent intraretinal cystoid-like cavities.

• Diffuse retinal thickening (fig. 1) • Cystoid macular edema (fig. 2) • Serous retinal detachment without posterior hyaloidal traction (PHT; fig. 3) • PHT without traction retinal detachment (TRD; fig. 4) • PHT with TRD (fig. 5) Medical Therapies for Diabetic Macular Edema

Focal/grid photocoagulation has demonstrated efficacy in a large, prospective, randomized clinical trial [16]. Nevertheless, many patients con-

Diabetic Macular Edema Oh H, Oshima Y (eds): Microincision Vitrectomy Surgery. Emerging Techniques and Technology. Dev Ophthalmol. Basel, Karger, 2014, vol 54, pp 164–173 (DOI: 10.1159/000360463)

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Downloaded by: Université Laval, Bibliothèque 198.143.38.97 - 7/3/2015 7:03:04 AM

• Retinal edema located at or within 500 μm of the center of the macula • Hard exudates at or within 500 μm of the center, associated with thickening of adjacent retina • A zone of thickening larger than one disc area if located within 1 disc diameter of the center of the macula Optical coherence tomography (OCT) has also been shown to be effective in both the qualitative and quantitative description of DME [11–14]. The widely accepted classification was proposed by Kim et al. [15] who described and classified five patterns of DME according to OCT:

Fig. 3. OCT of a serous retinal detachment not associated with PHT. A dark accumulation of subretinal fluid is seen beneath the highly reflective and dome-like elevation of detached retina.

Fig. 4. OCT demonstrating PHT. Tangential traction exerted by the PHT is identified on OCT as a highly reflective band over the retinal surface.

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Patelli · Radice · Giacomotti Oh H, Oshima Y (eds): Microincision Vitrectomy Surgery. Emerging Techniques and Technology. Dev Ophthalmol. Basel, Karger, 2014, vol 54, pp 164–173 (DOI: 10.1159/000360463)


Fig. 5. OCT demonstrating PHT and TRD. PHT is seen as the highly reflective signal arising from the inner retinal surface. The TRD is identified as the area of low signal underlying the highly reflective border of detached retina.

DME. The Ranibizumab for Edema of the Macula in Diabetes (READ-2) study randomized 126 eyes with DME to three groups: ranibizumab only (injection at baseline and months 1, 3, and 5), photocoagulation (at baseline and at 3 months if needed), and combined ranibizumab and photocoagulation (photocoagulation and ranibizumab at baseline, and ranibizumab at 3 months if needed) [31]. Patients randomized to ranibizumab only showed a significantly better visual outcome at 6 months compared with the other two groups. At 24 months, the study reported that intravitreal ranibizumab provided persistent treatment benefits [26]. Two-year visual outcomes were similar to 1-year results and reinforced the conclusion that ranibizumab with prompt or deferred photocoagulation should be considered for patients with vision impairment worse than 20/32 secondary to DME [32]. The RESTORE phase 3 study reported that ranibizumab monotherapy or combined with laser photocoagulation provided superior visual acuity gain over standard photocoagulation in the treatment of DME [33]. In contrast to intravitreal corticosteroids, cataract progression associated with intravitreal VEGF antagonists has not been identified. Some patients do have sustained intraocular pressure elevation following repeated injections of VEGF antagonists [34], but this effect does not appear to be as strong as that associated with intravitreal corticosteroids. Aflibercept, or VEGF trap-eye (Eylea, Regeneron, Tarrytown, N.Y., USA), is a recombinant fusion protein with activity against all VEGF-A isoforms and placental growth factor that is approved by the FDA for the treatment of neovascular age-related macular degeneration and has been shown to have short-term efficacy in the treatment of DME [35]. The DA VINCI study assessed the efficacy and safety of intravitreal aflibercept versus laser photocoagulation in the treatment of DME. In this study population, in-


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tinue to lose vision despite these interventions [17], which has led to the investigation of pharmacologic therapies for DME [18]. The two major categories of medications currently used to treat DME are corticosteroids and anti-VEGF agents. The two most commonly used anti-VEGF agents are bevacizumab (Avastin; Genentech, South San Francisco, Calif., USA) and ranibizumab (Lucentis, Genentech). Off-label intravitreal bevacizumab has been reported to have short-term efficacy in the treatment of DME in multiple randomized clinical trials [19, 20]. Ranibizumab has been approved by the FDA for the intravitreal treatment of exudative age-related macular degeneration [21, 22], macular edema secondary to retinal vein occlusion at a 0.5-mg dose [23, 24], and DME at a 0.3-mg dose [25, 26]. Corticosteroids may have multiple mechanisms of action in the treatment of DME. In addition to their anti-inflammatory properties, corticosteroids have been reported to reduce the activity of VEGF [27]. Intravitreal triamcinolone acetonide has been reported as being effective in the treatment of DME [28]. The dexamethasone drug delivery system (Ozurdex; Allergan, Irvine, Calif., USA) is a biodegradable, sustained-release device approved by the FDA for the treatment of macular edema associated with retinal vein occlusion and noninfectious posterior segment uveitis. A phase 2 randomized clinical trial in patients with persistent macular edema, secondary to various etiologies, including DME, showed that the dexamethasone drug delivery system produced improvements in visual acuity, macular thickness, and fluorescein leakage that were sustained for up to 6 months [29]. A more recent study reported that the dexamethasone drug delivery system improved visual acuity and macular edema in previously vitrectomized eyes with diffuse DME [30]. Several randomized clinical trials have shown the efficacy of ranibizumab in the treatment of

The Role of the Vitreous and Vitrectomy in Diabetic Macular Edema

The vitreous has been implicated as a cause of macular edema in people with diabetes via several mechanical and physiologic mechanisms, all of which are postulated to lead to increased vascular permeability [36–45]. Suggested mechanisms include the following: • Destabilization of the vitreous by abnormal glycation and cross-linking of vitreal collagen, leading to traction on the macula • Accumulation and concentration of factors causing vasopermeability in the premacular vitreous gel • Accumulation of chemoattractant factors in the vitreous, leading to the cellular migration to the posterior hyaloid, contraction, and macular traction [37–39, 42, 44] The observation that release of mechanical traction on the macula with subsequent reduction in DME, either by spontaneous posterior vitreous detachment or with vitrectomy, lends support to this line of reasoning [38, 40, 41, 43, 45]. Furthermore, the evidence that increased oxygenation can reduce DME [46] suggests an additional physiologic advantage, potentially conferred by vitrectomy. Increased oxygen tension counteracts the diabetes-induced retinal hypoxia responsible for VEGF upregulation and blood-retinal barrier breakdown, decreasing exudation from the retinal capillaries and resolving DME. Vitrectomy increases the oxygen concentration at the inner retinal surface by improving bulk flow of

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oxygen-rich aqueous from the highly vascularized iris and ciliary body to the posterior pole [47]. Hence, improved oxygen tension in the inner retina is a potent way to decrease macular edema by downregulating VEGF production [48]. The perifoveal microcirculation in eyes with diabetic cystoid macula edema was significantly increased after vitrectomy, as compared with that before surgery, and a significant correlation was found between the increase in perifoveal microcirculation and the improvement in visual acuity [49]. Kim et al. [15] noticed a significant association between decreased visual acuity and the presence of PHT without TRD. The traction produced by the vitreomacular interface alone has been postulated to play a role in the development of DME. This vitreomacular interface has been thought to cause tangential traction, which could lead to macular edema. However, it is impossible to determine whether the premacular vitreous changes cause the macular traction and edema, or whether the diabetic retinopathy leads to the vitreous changes and, thus, the macular traction and edema. Whatever the cause, identifying the structural changes in patients with DME using OCT may allow more effective management of these patients. Surgical Procedure

In patients affected by diabetic macula edema, the following surgical procedure is employed: (1) Cataract surgery in phakic patients is performed at the same time as vitrectomy. (2) A three-port pars plana vitrectomy using a 25-gauge system is carried out. After removal of the anterior and central vitreous, a vitreous detachment is performed, when not present, using the vitrectome probe aspiration only. If the vitreous is not easily visible or it is not sure that all the vitreous has been removed,



travitreal aflibercept produced significant improvements in visual acuity and retinal thickness, as compared to laser photocoagulation at both 24 and 52 weeks. Presently, aflibercept has not been approved by the FDA or EU for the treatment of DME.

Vitrectomy: When?

It is well accepted that in the presence of an evident traction over the macula (detected biomicroscopically and/or by the OCT), vitrectomy is considered the first therapeutic approach. In eyes with traction to the macula, the mechanical removal of the traction by pars plana vitrectomy seems to be effective [37, 42, 50, 51]. Removal of the ILM at time of vitrectomy has been associated with somewhat greater reduction

in retinal thickness, but no association has been found with visual acuity improvement. Few previous reports in the literature have evaluated factors associated with visual acuity or anatomic outcomes after vitrectomy for DME. In a retrospective study of 486 eyes that underwent vitrectomy and lensectomy for diffuse nontractional DME, Kumagai et al. [52] found that visual outcomes with ILM peeling were better than those associated with preservation of the ILM in a univariate analysis. In diffuse DME, the ILM is thickened and a variety of cellular elements, especially numerous kinds of inflammatory cells, adhere to the inner surface of the ILM. To attenuate diffuse DME, vitrectomy combined with ILM peeling to remove the inflammatory cells and the physical barrier might be effective. Several papers have underlined the advantages of ILM removal in these eyes, but the main problem of these studies is that it is very difficult to standardize preoperative DME characteristics because some eyes had been subject to prior laser treatments, treatment with various steroids, or anti-VEGF injections. The role of vitrectomy compared with other approaches in the management of DME remains uncertain because the potential benefits and risks have not been clearly defined in the context of long-term, adequately sized, randomized clinical trials. Several studies have shown limited efficacy in vitrectomy for diffuse DME without evident traction [53, 54]. Other clinical studies have, however, shown that vitrectomy for diffuse DME without evident traction leads to visual improvement of two or more lines in 38–100% of eyes. In a larger series (>50 cases) [34, 40, 55–60], visual improvement in approximately 50% of the cases was described. Proposed reasons for poor visual acuity after complete resolution of DME were macular ischemia [61, 62], photoreceptor dysfunction [54, 63], and accumulated subfoveal hard exudates


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triamcinolone acetonide is injected to better visualize the residual vitreous. All the peripheral vitreous is removed without base shaving, only a small residual vitreous skirt is left. (3) Once all of the posterior hyaloid has been removed, the internal limiting membrane (ILM) is stained. Different dyes can be used, typically blue dyes like triphenylmethane or green dyes like indocyanine green. The blue dye is injected under balanced salt solution (better with the infusion closed and washed out after 2 min). Diluted indocyanine green at a concentration of 0.1% is injected over the macula under balanced salt solution and immediately washed out in order to avoid dye toxicity. Usually, indocyanine green staining of the ILM is more visible than blue dye staining. ILM staining is more important in diabetic patients whose ILM is often more difficult to remove completely because it breaks and is strongly adherent to the retina. When possible, ILM should be removed throughout the macula. (4) After ILM peeling, the peripheral retina is checked in order to see if retinal breaks are present. (5) Panretinal photocoagulation is performed when necessary, and once the trocar’s cannulas are removed dexamethasone (2 mg) is injected subconjunctivally.

Fig. 6. OCT after vitrectomy for DME. The edema is not present. The ELM is well evident near the fovea as a hyperreflective layer (arrow), but is not evident in the fovea area (arrowhead).

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Conclusions

The goal of vitrectomy in DME patients should be to dry the retina as quickly and completely as possible. The posterior hyaloid should be removed as completely as possible, and the ILM should be peeled with the assistance of staining substances to prevent postsurgical proliferation of ERMs, to minimize preretinal sequestration of VEGF, and to maximize diffusion of oxygen into the retina. Accurate spectral domain OCT evaluation of the ELM and the inner and outer segment layer should be performed before and after surgery to predict visual acuity in these patients, even if further studies are required to better define their role. Early vitrectomy results in significant macular thinning and may lead to rapid improvement in vision with long-term stabilization. Unfortunately, a randomized trial pitting vitrectomy against the methods currently employed has not yet been performed. As medical budgets become tighter and alternative therapies, including antiVEGF injections, become more expensive, vitrectomy may emerge as the preferred low-cost, longer-duration therapy.



[64]. Improvements in photoreceptor layer visualization, as assessed by spectral domain OCT, may provide a better opportunity to understand poor visual outcome. In particular, the integrity of the external limiting membrane (ELM) and the inner and outer segments of the photoreceptor junction seems to correlate with good visual acuity in patients with DME. Recently, several studies have shown that ELM interruptions visible on spectral domain OCT are associated with lower visual acuity outcome in patients with clinically significant DME [65–68] (fig. 6). This is possibly because the integrity of the ELM has a critical role in restoration of the photoreceptor microstructures and alignment. Earlier reported approaches [69–71] relied on manual tracing of the corresponding surface or on detecting ELM on 2D B-scans. However, such studies rely on manual interpretation of the state of the ELM, and high intra- and interobserver variabilities are likely. Automated 3D analysis of the ELM is of great interest because of its potential to elucidate structural abnormalities with minimal variability and to possibly predict visual outcomes in DME.

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Fabio Patelli, MD Head Vitreoretina Service Igea Clinic, Director Milano Retina Center Carones Ophthalmology Center Via Pietro Mascagni 20 IT–20122 Milan (Italy) E-Mail [email protected]

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Diabetic Retinopathy and Diabetic Macular Edema.

Diabetic Macular Edema Pathophysiology: Vasogenic versus Inflammatory.

Current status in diabetic macular edema treatments.

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.

Role of inflammation in diabetic macular edema.

Pharmacological approach to diabetic macular edema.

Update on corticosteroids for diabetic macular edema.

Corticosteroid Treatment in Diabetic Macular Edema.

Classification of diabetic retinopathy and diabetic macular edema.

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

Ascorbic acid repletion: A possible therapy for diabetic macular edema?

Intraretinal fibrosis in exudative diabetic macular edema after ranibizumab treatments.

Diabetic Macular Edema: From Old Concepts to New Therapeutic Avenues.

The clinical utility of aflibercept for diabetic macular edema.

Intravitreal pegaptanib for the treatment of ischemic diabetic macular edema.

Is laser photocoagulation treatment currently useful in diabetic macular edema?

Topical nepafenec in eyes with noncentral diabetic macular edema.

Repeated intravitreal dexamethasone implant (Ozurdex) for diabetic macular edema.

Long-term effectiveness of vitrectomy in diabetic cystoid macular edema.