Recent advances in the management of clinically significant diabetic macular ede­ma (CSDME) have led to early, effective, and po­tentially more permanent re­stor­ation of vision than in years past, when treatment options were li­mit­ed to macular laser, systemic medical management or observation. Focal CSDME, from discrete, well-defined microaneurysmal leakage, is generally responsive to mac­ular laser when applied by Early Treat­ment Diabetic Retinopathy Study guidelines. The ETDRS found that macular laser re­duced moderate visual loss and persistent CSDME by 50 percent, but was unsuccessful in preventing vision loss in up to 25 percent of eyes.1,2 Eyes that respond poorly to focal or grid macular laser are typically those with diffuse CSDME from widespread blood-retinal barrier dysfunction and increased vascular permeability. Clinical characteristics of these eyes, including retinal thickening, with or without visible microaneurysms, intraretinal cystoid spaces, macular ischemia, submacular detachment, subretinal hard exudates, and pos­sibly an attached and taut posterior hyaloid membrane, may be seen with slit-lamp biomicro­sc­opy and evaluated further with optical coherence tomography. Fluorescein angiography may demonstrate macular is­chemia and a diffuse, nearly arcade vessel to arcade vessel, petalloid pattern of hyperfluorescence (not from distinct microaneurysms) (See Figure 1). Recent di­agnostic, pharmacologic, and surgical ad­vancements have spurred the evolution of alternative treatment methods that can better re­solve refractory CSDME and stabilize or im­­prove vision. Prominent among current man­agement options are the intravitreal injections of corticosteroids or anti-vascular en­do­thelial growth factor (VEGF) agents and vitrectomy.

Figure 1. Fluorescein angiogram demonstrating features of refractory diffuse CSDME: broad, diffuse, petalloid hyperfluorescence with few microaneurysms.


Why Vitrectomy?

The role of the vitreous in the development or progression of macular edema has been de­scribed for over two decades. Vitrectomy has been investigated as a treatment alternative for re­fractory CSDME for approximately 15 years. Initially, Charles Schepens suggested that vitreous traction may play a role in the cystoid macular edema associated with retinitis pigmentosa, aphakia, and uveitis.3

Later, F.P. Nas­ral­lah suggested a possible role for the vitreous in the development of CSDME when he reported that eyes with CSDME were less likely to have a posterior vitreous detachment (PVD) than those without CSDME.4 The spontaneous resolution of CSDME in 55 percent of eyes that de­veloped a PVD versus 25 percent of eyes that did not was also reported.5 Beyond such published re­ports, there has long been anecdotal evi­dence of resolution of CSDME in eyes after vitrectomy for complications of proliferative diabetic retinopathy.

Shortly after the description of the successful manipulation of the vitreomacular interface to close macular holes,6 reports began to suggest that the vit­re­o­macular interface could be surgically ma­nipulated to effectively treat CSDME as well. Visual acuity was reported to improve following vitrectomy and membrane peeling of a visibly taut, opacified posterior hyaloid in eyes with diffuse CSDME.7

Since then, multiple authors have retrospectively reported that vitrectomy and sep­aration of both visibly taut and presumably invisibly taut, at­tached posterior hyaloid membranes resulted in re­solution of CSDME in 43 to 100 per­cent of eyes and VA im­provement of >2 lines in 38 to 92 percent of eyes.8-19 In a small, prospective, controlled trial, researchers de­mon­strated statistically significant VA improvement and decreased macular thickness (by OCT) in vitrectomized eyes compared to a control group of ob­served matched fellow eyes.20 In most eyes, resolution of CSDME has been shown to occur between three and six months postoperatively, though improvement has been seen to begin earlier (See Figures 2 and 3).11,13

Vitrectomy has also been described to benefit eyes with end-stage CSDME. Following vitrectomy and subretinal mechanical removal of massive subfoveal hard exudates, one report showed VA improvement in five of seven eyes while CSDME resolution was seen in all eyes despite macular holes occurring in four of the eyes.21 Long-term results following this procedure were published by another group, showing that VA im­provement was maintained in 54 percent of eyes at one year and 38 percent at three to four years postoperatively.22 In our current series, with a mean follow-up of 16 months, we have seen VA improvement of >2 Snel­len lines in 10 of 16 eyes and CSDME resolution or reduction in all eyes following vitrectomy and submacular irrigation of hard exudates (without mechanical forceps extraction).

Figure 2a. Pre-vitrectomy OCT in an eye with visibly opacified and taut posterior hyaloidal traction, VA = 20/200.
Figure 2b. Three-month post-vitrectomy OCT, VA = 20/60.

Nearly every published series that has evaluated vitrectomy for diffuse, refractory CSDME has demonstrated significant VA improvement when com­pared to observation and macular laser. Most of them are small, single-center, retrospective, and nonrandomized, and have short follow-up periods that include eyes with nonstandardized VAs and variable inclusion criteria. Nonetheless, the outcomes from these studies are consistent: They strongly suggest that for many eyes with refractory diffuse CSDME, vitrectomy offers the potential for im­proved vision and reduced macular edema. Moreover, most series and anecdotal evidence suggest that the VA improvements and reductions in CSDME are long-lasting and require few retreatments.


How Vitrectomy Improves Vision

Several mechanisms have been proposed to explain the beneficial effects of vitrectomy. Separation of the posterior hyaloid relieves vitreomacular traction in both the anteroposterior and tangential dimensions by creating a PVD. The premacular cortical vitreous is known to contain contractile cells such as fibroblasts, astrocytes, and macrophages, and traction on the macula is relieved with removal of this potentially contractile tissue. Vi­tr­e­o­schisis—or the split hyaloid—is frequently seen in eyes with refractory CSDME. One study demonstrated that eyes with early proliferative diabetic retinopathy and macular traction have a high rate of vitreoschisis and histologic evidence of potentially contractile neovascularization into the pos­terior vitreous cortex.23 Others later described a similar high rate of vitreoschisis in PDR eyes with traction.24 Electron microscopy has shown multilayered sheets of potentially contractile vitreous and RPE cells in the epimacular posterior hyaloid tissue removed from CSDME eyes, and OCT studies have shown the reduction of edema following the relief of this tangentially oriented macular traction.25,26

Figure 3a. Pre-vitrectomy OCT in an eye without a visibly opacified posterior hyaloid membrane, VA = 20/400.
Figure 3b. Three-month post-vitrectomy OCT, VA = 20/50.

Several authors have suggested the benefits of removing the internal limiting membrane during vitrectomy; no series has shown deleterious effects. One group reported better VA and an­atomic outcomes, faster CSDME resolution, and fewer recurrences with ILM peeling than all previously published series that evaluated vitrectomy without specific ILM attention.12 In other work, ILM peeling led to resolution of CSDME and VA improvement in 100 percent of eyes that failed previous vitrectomy for CSDME.27

We feel ILM peeling should be safely attempted in all cases of vitrectomy for CSDME. At a minimum, suc­cessful ILM removal insures complete re­moval of the posterior hyaloid from the macula—a surgical endpoint that can at times be unknowingly elusive, particularly in cases of vitreoschisis. Intrinsic pathologic effects of the ILM on the macula have also been suggested. The ILM in diabetic eyes contains increased levels of fi­bro­nec­tin, laminin and collagen.28,29 And peeled ILM specimens from CSDME eyes have been shown to be several times thicker than normal ILM, possibly contributing to altered fluid shifts between the vitreous and retina.30

Vitrectomy may treat CSDME by other mechanisms as well. Higher vitreous levels of VEGF, sICAM-1, IL-6 are seen in diffuse CSDME eyes than in control eyes, and their levels correlate with the severity of diabetic re­ti­nopathy, degree of angiographic fluorescence, and central foveal thick­ness.31,32 Removal of these permeability fac­tors may allow reduction of CSDME. Vitrectomy has been shown to lead to an approximately tenfold in­crease in vitreous cavity oxygenation,33 and this may improve retinal oxygenation and perfusion, potentially contributing to decreased CSDME.

In recent years, treatment regimens for diffuse refractory CSDME have expanded, improved, and become more complex. The use of intravitreally injected triamcinolone acetonide has grown exponentially in the past five years. From the 2001 American So­ciety of Retinal Specialists Pre­fe­rences and Trend Survey, 61 percent of respondents would treat an eye with diffuse refractory CSDME, maximal macular laser, and VA of 20/100 with vitrectomy versus 13 percent that would treat this eye with an intravitreal steroid injection (Mittra RA and Pollack JS, American Society of Retina Specialists, Preferences and Trends Sur­vey). Since then, many published and anecdotal reports have demonstrated the efficacy of intravitreal triamcinolone in the treatment of CSDME, at least in the short term, and this has led to a dramatic shift in treatment preferences.

From the 2004 PAT Survey, only 14 per­cent chose vitrectomy over the 81 percent that preferred intravitreal ste­roid use for an eye with the same re­fractory CSDME characteristics. Post-injection problems with intravitreal steroid use, such as elevated intraocular pressure, cataract formation, and recurrent CSDME several weeks to months after injection, however, have prevented its ubiquitous use as a permanent solution in all such eyes.

Slow-release steroid implants made with fluocinolone (Controlled De­liv­ery Systems, Bausch & Lomb) and dex­amethasone (Posurdex, Al­ler­gan) are being evaluated for the longer-term treatment of CSDME. Anti-VEGF drugs, used largely for the treatment of choroidal neovascularization, are also gaining increasing attention for the treatment of CSDME. In­tra­vitreally-injected pegaptanib (Mac­ugen, OSI Eyetech Phar­ma­ceu­ticals) has been shown to improve or maintain VA, reduce macular volume, and reduce the need for laser compared to control/sham injections,34 though it currently does not have a label indication for this use. Bevacizumab (Avas­tin, Genentech) is now being intravitreally injected off-label to treat CSDME, though no data as to its wide­spread efficacy has been published.

The role of vitrectomy among the increasing treatment options for refractory CSDME needs definition and refinement. Vitrectomy has the potential to lead to long-lasting good outcomes for some eyes and should be in the armamentarium of all vitreoretinal surgeons. More definitive indications for vitrectomy over steroid or anti-VEGF therapy include CSDME associated with clinically and OCT-demonstrated posterior hyaloidal traction and CSDME refractory to multiple attempts at intravitreal pharmacologic treatment or CSDME in eyes with complications of pharmacologic therapy.

The results of larger multi­center, controlled, prospective, randomized trials (e.g. SCORE and, NEI/NIH) are needed to adequately demonstrate the efficacy of both vitrectomy and pharmacologic therapy for all types of refractory CSDME, and importantly, to compare treatment regimens against one another and evaluate the effectiveness of combination therapies. Until then, the judicious use of all available treatments allow vitreoretinal specialists to offer patients with once devastating refractory VA loss, the potential for improved vision with anticipated in­creasing effectiveness.


Dr. Hassan practices at Associated Re­tinal Consultants and William Beau­mont Hospital, in Royal Oak. He is a clinical as­sis­tant professor of bio­med­ical sciences at Oakland Uni­versity, Ro­chester, Mich. Contact him at

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