by the choroid than the RPE, and is associated with more pain for the patient.247–249 Frequency doubled

neodymium YAG and diode micropulse (532 and 810 nm, respectively) laser have been used as well in

case series, again with some evidence of efficacy.250,251 The advantage is an elimination of

photoreceptor damage, reduction in retinal pigment

epithelial scarring, and elimination of paracentral visual field scotomata.252,253 The disadvantage is

that there is no visible endpoint for treatment, making it difficult to determine where treatment has been given; treatment methods and settings have varied from study to study.253 In addition, the treatment response is slower than with conventional laser treatment, and more treatments may be necessary to achieve elimination of edema.252 Neither of these modalities has been widely used.

7.22 Peribulbar Triamcinolone Injection

Peribulbar triamcinolone or methylprednisolone injections have been used to treat DME either as monotherapy or as adjunctive therapy to focal/grid laser, and short-term efficacy in thinning the macula

and improving visual acuity has been demonstrated.102,104,242,260 Evidence exists that peribulbar

triamcinolone is less effective than intravitreal triam-

cinolone in improving visual acuity in DME over a 3-month period.261,262 In a pilot prospective, rando-

mized, multicentered clinical trial, neither peribulbar monotherapy nor combination therapy showed clinically important superiority over modified ETDRS focal/grid photocoagulation, and, therefore, a large-scale clinical trial was not done.242 The complications of peribulbar triamcinolone injection include

intraocular pressure elevation and ptosis in approximately 10 and 20% of cases, respectively.242

7.23 Intravitreal Triamcinolone Injection

Jonas and Sofker were the first to use intravitreal triamcinolone injection in the treatment of DME in 2001.263 In a randomized clinical trial comparing intravitreal triamcinolone injection to observation, the efficacy of triamcinolone injections was established through 2 years of follow-up.264 Many case series and a separate shorter term placebo con-

trolled randomized trial have supported this conclusion.142,150,245,265,266 The benefits of this form of

therapy must be balanced by consideration of the side effects including surgical cataract formation in

51% of phakic eyes at 2 years follow-up and intraocular pressure elevation in 25–40% of eyes.142,267,268

In a randomized clinical trial comparing serial intravitreal triamcinolone injection therapy using 1 or 4 mg to focal/grid photocoagulation, focal/grid photocoagulation showed superior efficacy and fewer side effects; thus, intravitreal triamcinolone therapy is a second line therapy for consideration when focal photocoagulation has failed.227 In this study, the mean visual acuity was four–six ETDRS letters better in the laser group than in the 1 and 4 mg intravitreal triamcinolone groups after 2 years, and the improved visual outcomes persisted after discounting the effects of cataract progression in the triamcinolone groups.227 The mean central subfield mean thickness decreased 53–62 mm more in the focal/grid group compared to the 1- and 4-mg triamcinolone groups at 2 years, respectively.227 The 4-mg triamcinolone group was superior to the focal/grid laser group at the 4-month follow-up visit, but that short-term advantage of triamcinolone had vanished by 1 year follow-up, and at 2 years follow-up the focal/grid group had clearly superior outcomes.227

Many doses of intravitreal triamcinolone have been used, including 1, 2, 4, 5, 8, 13, and 20– 25 mg. In general, there is inconclusive but suggestive evidence that duration of action is longer with

higher doses and that frequency of intraocular pressure rise increases with higher doses.140,238,269,270

There is no consistent evidence that higher doses are more effective for thinning the macula or improving visual acuity than lower doses, and some evidence exists that lower doses have greater efficacy for macular thinning than higher doses.139

In a small pilot randomized trial, intravitreal triamcinolone injection was associated with a higher rate of partial vitreous separation with foveal attachment or traction compared to eyes treated with focal/grid photocoagulation. Eyes with this change had worse visual outcomes.271

7.24Intravitreal Dexamethasone Delivery System

A sustained release drug delivery system for dexamethasone inserted transclerally into the vitreous produced statistically significant visual acuity

improvement for 90 days after insertion and was well tolerated for 180 days.272 For the 700 mg device,

the probability of a 10 letter improvement in visual acuity at 90 days was 2.8 times greater in the device group compared to the observation group. Mean central retinal thickness decreased by more than 160 mm at 90 days, but this figure included pooled results from other causes of macular edema besides DME. Eleven percent of treated patients had an intraocular pressure

rise of 10 mmHg or higher. This device is presently undergoing further clinical trials.272,273

7.25Intravitreal Injections of Anti-VEGF Drugs

Intravitreal injections of anti-VEGF drugs also produce reductions in macular thickening, but on average the magnitudes of the reductions and the durations of responses are less than with intravitreal triamcinolone injections, suggesting that biochem-

ical pathways not involving VEGF are important in the pathogenesis of DME.121,163,274–276 Intravi-

treal pegaptanib, bevacizumab, ranibizumab, and VEGF-trap all fall into this category.109,121,274,277–279

Counterbalancing their lesser efficacy compared to steroids, the anti-VEGF drugs have a more favorable side effect profile, in particular without the tendency to cause cataract and raise intraocular pressure.276 Instances have been reported in which intravitreal pegaptanib injected in one eye has been associated with regression in neovascularization in the fellow eye.280 Similar concerns have been expressed for bevacizumab, but, despite study, no evidence of a fellow eye effect on DME has been found, suggesting that systemic absorption is negligible.120 Limited data suggest that fears that intravitreal anti-VEGF drugs could worsen macular ischemia are unfounded.121 No clinically important differences in effects on

DME of 1.25 vs. 2.5 mg of bevacizumab have been reported in studies comparing the two.163,109,281

Some evidence suggests that these drugs are more effective in treatment of naı¨ve eyes than in eyes previously treated with focal/grid laser.281 Further research will be necessary to better determine the role of these intravitreal injections in the therapy of DME, but they may find a role in phakic patients and patients with glaucoma.275

7.26Combined Intravitreal Anti-VEGF Drugs and Triamcinolone

Combined intravitreal bevacizumab and triamcinolone as an initial injection followed by two intravitreal bevacizumab injections given at 6-week intervals was no more effective in decreasing DME than

three consecutive intravitreal injections of bevacizumab given at 6-week intervals.282,283 As the addi-

tion of triamcinolone would be expected to increase cataract development and intraocular pressure rise, there is little impetus to continue exploring the combination of steroids and anti-VEGF drugs for DME.

7.27Combined Intravitreal and Peribulbar Triamcinolone and Focal Laser Therapy

Visual acuity outcomes are superior with focal laser photocoagulation than with observation alone in managing DME.4 Serial injections of intravitreal triamcinolone therapy are also superior to observation at least over a period of 2 years follow-up.264 A combination of intravitreal triamcinolone injection followed by focal laser photocoagulation is a form of therapy that has a theoretical rationale for being possibly superior to focal laser alone or serial intravitreal triamcinolone injections alone. Preceding the focal/grid photocoagulation by steroid treatment might reduce inflammation associated with the photocoagulation, reduce the macular thickness allowing less powerful laser applications, and thereby reduce unnecessary collateral retinal damage and laserinduced scarring.284,285 The photocoagulation part of the combined regimen theoretically provides sustainability to the treatment effect that an injection alone lacks.174 The preponderance of the evidence suggests that combination therapy may reduce macular thickening somewhat better than serial intravitreal

triamcinolone injections in the short term and have a faster onset of action than focal laser alone.266,285,286

Similar improved results of combined peribulbar

triamcinolone plus focal photocoagulation have been reported.102,122 Not enough patients have been

studied prospectively for a sufficiently long time to make conclusions on this point, but the DRCR

Network is engaged in a clinical trial that should answer whether combination therapy is superior to focal/grid laser alone.

7.28 Vitrectomy

The idea that vitreomacular adhesion might promote DME arose from the observation that eyes with DME have a lower prevalence of posterior vitreous detachment than eyes without DME.47 The subsequent observation that resolution of DME could occur after posterior vitreous detachment strengthened the plausibility that surgical induction

of a vitreomacular separation might improve DME.287,288 Vitrectomy for DME was first reported

by Lewis and colleagues in 1992.289 Since then, many small retrospective and prospective case series, several small clinical trials, one large retrospective case series, but no large, multicentered, randomized, con-

trolled trials of the approach have been pub-

lished.48,74,76,146,147,149,153,229,238,290–301 Vitrectomy

was introduced for eyes with a taut posterior hyaloid adherent to the macula, often associated with shallow

traction macular detachment, which had futile previous focal/grid laser.73,75,153,289,290,302 Later, it was

explored as a therapy for eyes with an attached but nonthickened, nontaut posterior hyaloid or for eyes with persistent DME despite previous focal laser or

intravitreal triamcinolone injection regardless of the status of the posterior hyaloid.147,153,291–293,300,301

Most recently, the treatment has been studied as a potential primary therapy in eyes with more severe edema, greater visual acuity loss at presentation,

and characteristics considered to mitigate against effectiveness of focal/grid.74,294,296,299 The relative

frequencies of the various candidate groups have been reported as follows: refractory DME in eyes with attached but nontaut posterior hyaloid 68%, refractory DME in eyes with posterior vitreous detachment 22%, refractory DME in eyes with a taut posterior hyaloid 5%, and refractory DME in eyes with an epiretinal membrane 5%.237 Other categories for which primary vitrectomy has been applied include eyes with microaneurysms too close to the fovea to receive focal laser, eyes with enlarged foveal avascular zones, and eyes with cystoid edema.121

Although the concept of a taut hyaloid has been widely discussed, the term is not consistently defined in the literature. On biomicroscopy, a taut hyaloid has been defined as a thickened, glistening, posterior hyaloid without stria.237 In addition to a biomicroscopic appearance, others define the term based on an OCTvisualized attachment of the hyaloid layer to the macula with adjacent partial vitreomacular detachment and accompanying submacular fluid. Finally, some define the term based on intraoperative findings

even when preoperative biomicroscopic and OCT examinations are negative.289,303,304 Because subma-

cular fluid has been seen in cases of DME with no macular traction by clinical examination or OCT,

submacular fluid cannot be considered specific for the taut hyaloid syndrome.116,305,306

Some groups distinguish a taut hyaloid with its hypothesized tangential traction in DME from the vitreomacular traction syndrome with its hypothe-

sized anterior–posterior traction, but others do not.146,289,290,292 Diffuse, deep intraretinal fluorescein

leakage has been commonly associated with a taut

hyaloid, but is also not specific for this condition, as it can be seen in eyes after vitrectomy.289,293 Some

authors have required more than simple OCT identification of a vitreomacular point of contact, requiring, for example, that the slope of the elevated macula be

steep and that the OCT-defined posterior hyaloid be thicker than normal and hyperreflective, although a cutpoint for ‘‘thicker’’ and a definition of hyperreflective have not been given.75 Others report an associated large central macular cyst in tractional cases.146 When eyes have been classified by biomicroscopic signs, OCT evidence of partial vitreomacular separation, and OCT evidence of submacular fluid, different groupings of eyes result. Some eyes have all three signs, some any two of the three, and some only one of the three.304 Several groups have reported inability to predict OCT or intraoperative signs of vitreomacu-

lar traction and adhesion based on clinical biomicroscopy.146,290 Eyes with DME in association with a taut

hyaloid are uncommon, with estimates that they comprise 3.1–18.0% of cases of DME.304,306 Lewis has

suggested that the presence of a shallow macular traction detachment on OCT is a conservative way to determine if a suspected taut hyaloid is truly contributory in a specific case of DME and perhaps indicative that vitrectomy surgery might be helpful, but Massin and colleagues report numerous cases of DME with

taut hyaloid yet no traction macular detachment on OCT.48,307 Among reports in which vitrectomy was

effective in thinning the macula, the magnitude of the treatment effect has been greater in eyes with OCT signs of macular traction.146

Fig. 7.40 It is difficult to distinguish OCTs published to exemplify the taut hyaloid syndrome in diabetic macular edema and the vitreomacular traction syndrome. The left panel shows DME with a taut hyaloid and the right from a case of

nondiabetic vitreomacular traction syndrome. The left panel is reproduced with permission from Kaiser et al.73

and right panel is reproduced with permission from Johnson et al.308

It is likely that many cases exist in which vitreous traction on the macula contributes to microvessel hyperpermeability but is not the sole problem. The clinical issue is frequently whether to attempt focal laser treatment or intravitreal injectional therapy alone or in combination first to address the nontractional component of the problem or whether to proceed directly to a treatment involving vitrectomy with peeling of frequently associated epiretinal membranes and the adherent posterior hyaloidal face.309 Although eyes with a taut hyaloid are frequently refractory to focal/grid photocoagulation, it is typical for clinicians to attempt these less invasive treatments first in hopes of substantial improvement without needing to proceed to vitrectomy.289

A controversy exists regarding the effects of vitrectomy for DME. Several groups of investigators have reported that vitrectomy reduces macular

thickening but does not improve visual acuity.297,310,311 Others report improved visual acui-

ties simultaneous with decreases in macular thick-

ening or lagging behind macular thinning by a few months.146,271,294,301,303 Still others report improved

visual acuity in cases with macular traction, but no visual improvement in cases without traction.75,305 Ancillary tests of macular function, such as cone thresholds by fine matrix mapping, have been reported to improve in parallel with macular thinning after vitrectomy surgery.146 Even when investigators report that both morphology and visual acuity improve, the morphologic improvement has consistently been more pronounced than visual acuity improvement, presumably because of permanent damage to the macula due to ischemia, subfoveal exudates and pigment epithelial metaplasia,

damage from previous extensive focal/grid laser, or long duration of edema.89,238

Because the types of eyes chosen for application of vitrectomy could influence the outcomes, it is difficult to compare the results of different series. Table 7.5 lists the characteristics of included eyes in various studies of vitrectomy for DME to assist in the comparison. Some studies report that a history of previous focal/grid laser or presence of subma-

cular fluid at baseline is a negative influence on visual acuity outcome.240,312 Longer duration of

edema has been reported to negatively influence visual outcomes.111 Duration of DME is difficult

to quantitate, however, because of ambiguity

regarding date of onset before clinical diagnosis.75,189

Vitrectomy surgery for DME potentially involves multiple steps that could affect DME. Creating a posterior vitreous separation with or without enzymatic adjuncts, internal limiting membrane peeling with or without staining, supplemental or de novo panretinal laser photocoagulation, supplemental or de novo focal laser photocoagulation, concomitant cataract extraction, and concomitant injection of intravitreal triamcinolone or anti-VEGF drugs could all be important variables affecting the response to the

intervention.299 Different groups have employed different procedures (Table 7.5).302,310 Internal limiting

membrane (ILM) peeling with the use of indocyanine green (ICG) staining has been considered potentially toxic to the macula and optic nerve with loss of visual field after its use in cases of DME.313 Two groups reported no advantage in

outcomes in eyes receiving internal limiting membrane peeling.310,311 The largest study reported an

improved visual outcome in the group with ILM peeling at 6 months and 1 year but not at 5 years.301

Others report improved OCT outcomes but not visual acuity outcomes with ILM peeling.297 Terasaki and colleagues reported that ILM removal was associated with delayed recovery of the focal macular electroretinogram b-wave after surgery.294 In the absence of a randomized clinical trial, it is difficult to determine which steps are important in reducing macular edema.

A consensus on the kinetics of macular thinning after vitrectomy for DME is lacking. In support of slow change, Terasaki and colleagues found that thinning progressively occurred over 12 months of follow-up. For 19 eyes for which posterior hyaloid separation was induced, the reduction in thickening observed was 61, 69, and 82% of the baseline macular thickening at 3, 6, and 12 months, respectively.294 Tachi and Ogino likewise found that progressive macular thinning occurred from 6 to 12 months after vitrectomy.293 Yanyali and colleagues found progressive reduction in thickening over follow-up time

through 6 months. Reduction in thickening observed was 61 and 85% at 1 and 6 months, respectively.296

Yamamoto and colleagues found that macular thinning continues at least through 4 months after vitrectomy.298 In support of faster equilibration, Recchia

and colleagues and the DRCR Network studies reported completion of the macular thinning response by 3 months after surgery153 (DRCR Vitrectomy study submitted for publication).

The reported amplitude of the macular thinning to vitrectomy surgery has been variable, but more

thinning occurs with vitrectomy than single session macular grid laser.237,241 The average macular thin-

ning effect of single session focal laser at 6 months is –69 mm for an eye with CSMT of 410 mm.241 In

contrast, the average thinning produced by vitrectomy surgery in eyes of this baseline thickness was – 144 mm.241 Vitrectomy surgery is rarely done for eyes with macular thickness less than 300 mm. For eyes of 300 mm, the average response to vitrectomy surgery is macular thinning of approximately 60 mm at 6 months (Table 7.5 and Fig. 7.40). For each additional 100 mm of baseline macular thickness, vitrectomy surgery on average yields an additional 70 mm of macular thinning at 6-month follow-up (Fig. 7.41).241 The median change in visual acuity at 6-month follow-up after vitrectomy surgery for DME is eight ETDRS letters, IQR (2,11), based on analysis of the data in Table 7.5. There are no important relationships between the baseline macular thickening and the change in visual acuity at 6 months or between change in macular thickness at 6 months and change in visual acuity at 6 months (data not shown, but based on Table 7.5).

As has been reported for other treatments for DME, recurrence of edema after initial improvement,

incomplete resolution of macular thickening, and failure to respond also occur with vitrectomy. Recchia and colleagues found recurrence of initially improved edema in 18% of eyes by 6-month follow-up and employed intravitreal triamcinolone injection to manage such cases.153 Rosenblatt and colleagues found that macular thickening increased despite vitrectomy in 7% of eyes.147 Massin and colleagues found that macular thickening resolved in all seven patients with vitreomacular traction treated with vitrectomy over a mean follow-up of 19 months, but persistent thickening was present in 75% of eyes without vitreomacular traction.75 Kadonoso and colleagues found that 22% of eyes failed to show macular thinning after vitrectomy for DME.76

Although there is general acceptance that vitrectomy has a role in the management of at least some cases of DME, there is also consensus that it has no role in many cases, including cases of mild edema with minimal visual compromise and in cases with large submacular hard exudates, in which chronic retinal pigment epithelial atrophic changes limit the potential for improvement even after specifically removing these exudates through small retinotomies.89,314 Prospective, multicentered, randomized clinical trials have been published regarding focal/grid photocoagulation and intravitreal triamcinolone injection for DME. A similar large study is needed to define the role of vitrectomy surgery in the management of DME. The many retrospective studies make a case that vitrectomy for DME has a

6 Month Change Macular Thickness ( )

–400

Baseline Macular Thickness ( )

Fig. 7.41 Relationship of macular thinning induced at 6 months by vitrectomy surgery for DME and the baseline macular thickness. The thinning effect increases with increasing baseline macular thickness. Each data point represents

one study in Table 7.5 for which a baseline mean or median central subfield mean thickness and a 6-month change in central subfield mean thickness were reported