role, but a large-scale clinical trial is necessary to clarify what that role is. Such a trial has been frequently advocated in the past, although not unanimously.237 A multicentered, randomized clinical trial (the TIME Study) comparing observation vs. vitrectomy with internal limiting membrane peeling vs. intravitreal injection(s) of triamcinolone 4 mg once is underway.244

7.29Supplemental Oxygen and Hyperbaric Oxygenation

Hyperbaric oxygenation reduced breakdown of the blood–retinal barrier in a rat model of diabetic retinopathy.315 In a small clinical series, 10–30 hyperbaric oxygen treatments resulted in no morphologic change in DME.316 Three months of supplemental oxygen therapy by nasal cannula improved macular thickness in nine eyes of five patients with DME refractory to conventional focal/grid laser treatment.317 Three eyes showed 2 lines improvement in visual acuity and five of nine eyes worsened after cessation of supplemental oxygen. More experience is needed with these therapies before any recommendations for use can be considered.

7.30Resection of Subfoveal Hard Exudates

Lipid exudates in DME primarily occur in the outer plexiform layer, often in a perivascular distribution.69 However, in advanced and chronic cases of DME, large plaques of hard exudates can accumu-

late in the subfoveal space and stimulate formation of fibrotic scars.197,318 Several case series have exam-

ined whether surgical removal of these plaques is beneficial. The conclusions of the series are inconsistent with some series reporting improvements compared to nonrandomly selected comparison groups

not undergoing surgery and others suggesting improvements over the natural course.314,319 Because

the effect size of the surgery based on these case series is modest, a randomized controlled trial of a large number of patients would be needed to decide

whether this type of surgery is worthwhile, an unlikely prospect given the relative infrequency of such cases in practice.

7.31 Subclinical Diabetic Macular Edema

The ETDRS included several groups of patients that provided useful estimates of the rate of development of CSME in patients without DME at baseline. In eyes with severe NPDR or early PDR and no macular edema, an estimate of the rate of development of CSME was 4% per year over a follow-up period of 7 years.320 For eyes with severe NPDR or early PDR and macular edema, but not CSME, an estimate for the rate of development of CSME was 12% per year over 5 years of follow-up.320 A similar estimate for the eyes with mild to moderate nonproliferative diabetic retinopathy and macular edema,

but not CSME, was 14% per year over 5 years of follow-up.320

With known effective treatments for DME, the clinical problem of following patients with macular

edema insufficient to lead to a recommendation for focal/grid laser treatment is important.4,79,135 The

management of patients with less than clinically significant DME was investigated in the ETDRS

in an era without the assistance of retinal thickness measurements by OCT.4,320 Studies have shown

that clinical assessment of macular edema and

OCT assessment of macular edema frequently disagree in this group of patients.143,144 The macular

status of such patients as followed in the OCT era is not well understood.143,144 Subclinical DME refers

to eyes with macular edema recognized clinically, but of severity less than the threshold characterized

by the term clinically significant, as well as edema not detected clinically but detected by OCT.144,145

Clinically important questions concerning these patients include the following: Are there factors that predict rates of progression of patients with subclinical DME to reach CSME? And, how frequently should patients be followed with subclinical DME in order to promptly detect conversion to CSME and institute treatment?

In one study of a cohort of eyes with SCDME followed over a median duration of 14 months, 31.4% of the eyes reached clinically significant

DME and received treatment.145 An analysis looking for any patient characteristics or eye characteristics that predicted the eventual need for treatment revealed none. In particular, no OCT indices were predictive of progression. The median time to treatment for the eyes eventually receiving treatment was 13 months, and only 11% needed treatment within 4 months of the baseline visit.145 Thus, the generally observed slow change in OCT values and delayed time to treatment suggest that a 4–6 month follow-up interval would be unlikely to miss progression from SCDME to clinically significant DME. Figure 7.42 shows an example of an eye

that progressed from SCDME to CSME over a period of 28 months of periodic observation.

Patients with subclinical DME merit periodic examination with stereoscopic slit-lamp biomicroscopy to determine when the threshold for intervention is reached. This threshold continues to be defined by the concept of CSME proposed by the ETDRS. Where OCT is available, it should be used in the care of these patients, because of evidence that stereoscopic slit-lamp biomicroscopy alone results in

errors of both underdiagnosis and overdiagnosis of DME.143,144 Subclinical DME does not inexorably

progress, and when it progresses, tends to do so

Fig. 7.42 (a) Red-free fundus photograph of the left macula manifesting CSME on 24 August 2008. Microaneurysms are present temporal to the macula with a lipid ring superotemporal to the center of the macula. (b) Late-phase fluorescein angiogram shows leakage of fluorescein from the microaneurysms temporal to the macula. (c) OCT map images of the left eye over time. In 2006, the central subfield mean thickness is at the upper limit of normal and the inner paracentral fields are more than two standard deviations

above normal, but there was no clinically recognized edema (i.e., the eye manifests SCDME). Over the ensuing 28 months, all subfields increased in thickness and edema became clinically apparent. (d) Horizontally oriented OCT line scans of the left eye of a patient with SCDME. The morphology is initially normal, with a preserved foveal depression. Over the ensuing 28 months of follow-up cystoid thickening developed

slowly. A substantial fraction of eyes with subclinical DME show spontaneous improvement in macular edema over time.145 There is no rationale to push intervention earlier than the present standard of clinically significant DME.145

7.32Cases with Simultaneous Indications for Focal and Scatter Laser Photocoagulation

In some cases of diabetic retinopathy, both clinically significant diabetic macular edema and a level of retinopathy equal to or more severe than severe nonproliferative retinopathy are present (Fig. 7.43). In these eyes, there are indications to begin both focal and panretinal laser photocoagulation, giving rise to the question of how the two types of treatments should be administered. Should therapy be sequential, and if so, in what order? Should therapy be combined in some cases?

No large randomized clinical trials have been performed that give evidence favoring the best management approach in every clinical scenario, but evidence does exist that suggests reasonable approaches in many situations. The ETDRS compared five treatment approaches in eyes with macular edema and either severe nonproliferative or early proliferative retinopathy: deferral of photocoagulation, immediate focal/immediate mild scatter, immediate mild

scatter/delayed focal, immediate focal/immediate full scatter, and immediate full scatter/delayed focal.320 The approach with the lowest rates of 15 ETDRS letters visual acuity loss (moderate visual loss) was immediate focal/immediate mild scatter. Approximately, 5% of patients with this approach will have moderate visual loss shortly after treatment, a greater percentage than with deferral, but this shortterm inferior outcome is effaced by 4 months compared to deferral, and thereafter the intervention is superior to deferral.320 For eyes with high-risk PDR and macular edema, Maia and colleagues reported a small randomized trial of 22 patients with symmetric disease in which both eyes received focal/grid plus three sitting scatter laser treatments separated by 1 week. One eye of the two in each patient was randomized to receive a 4 mg intravitreal triamcinolone injection after the third sitting. Both macular thickness and visual acuity were better in the intravitreal triamcinolone group at 12 months.321 Other case series and reasoning based on pathophysiology suggest that simultaneous focal/grid with panretinal photocoagulation supplemented in some cases by a preparatory intravitreal injection of an anti-VEGF drug is a reasonable treatment alternative.224,322 A DRCR Network randomized trial comparing focal/ grid plus panretinal laser, adjunctive intravitreal ranibizumab followed by focal/grid plus panretinal laser and repeat ranibizumab at 4 weeks, and adjunctive intravitreal triamcinolone followed by focal/grid plus panretinal laser is underway.

Fig. 7.43 (a) Red-free photograph of a pseudophakic eye with high-risk proliferative diabetic retinopathy (new vessels along the superior arcade plus preretinal hemorrhage inferiorly) and concomitant clinically significant diabetic macular edema. (b) Frame from the mid-phase fluorescein angiogram

showing mid-peripheral capillary nonperfusion and rather many leaky microaneurysms and capillary segments. (c) Frame from the late-phase fluorescein angiogram showing widespread fluorescein leakage

7.33Exacerbation of Diabetic Macular Edema by Scatter Photocoagulation

Scatter photocoagulation can induce DME in eyes

without preexisting DME and can exacerbate DME in eyes with concomitant DME.320,323,324 Hydrogen

peroxide increases in the vitreous after scatter laser photocoagulation which is in turn associated with increased adhesion molecules in the vascular endothelium. Leukocytes therefore stagnate in the macular microcirculation and reduce blood flow leading to release of oxygen-free radicals, proteoly-

tic enzymes, nitric oxide, and inflammatory cytokines.325,326 The risk of scatter photocoagulation-

induced DME increases for eyes with subclinical

DME compared to eyes with normal macular thickness.327,328 Because these are eyes for which clinical

examination alone is frequently unreliable for detecting increased thickening, it is worthwhile to

obtain a macular OCT study for any eye for which scatter photocoagulation is being considered.328,329

If thickening is detected, consideration should be given to pretreating the eye with a peribulbar or

intravitreal injection of triamcinolone or an intravitreal injection of an anti-VEGF drug.328,330,331 If the

indications for scatter photocoagulation are not so pressing, dividing the treatment into smaller sessions separated over time may decrease the treatmentassociated inflammation and reduce the chance of induced DME.327 Some evidence exists that panretinal laser that emphasizes more peripheral treatment and avoids treatment closer to the perimacular vascular arcades may reduce the chance of exacerbating concomitant DME.332 There is no good evidence that dividing sessions of scatter laser in eyes without increased macular thickening is useful in preventing induction of new DME.333

7.34Factors Influencing Treatment of Diabetic Macular Edema

Increasing duration of DME with cell death has been hypothesized as a negative influence on treatments for

DME, but because of inability to determine duration, its effects have not been adequately assessed.30,151

Increased macular ischemia has been reported to negatively influence results of vitrectomy and intravitreal bevacizumab therapy for DME and has been sus-

pected as a negative influence in other therapies for DME.121,238,334 These studies suggest that if vitrect-

omy and intravitreal bevacizumab therapy were applied to cases with less macular ischemia, the visual outcomes might be better. Macular ischemia is difficult to quantitate, gradable with only modest reproducibility, and associated with low rates of interpretable fluorescein angiograms in eyes with DME which often have concomitant cataract. Macular ischemia has been infrequent in most cases with DME making it difficult to assess the modifying effects of macular ischemia on treatments for DME. Presence of subretinal fluid and subretinal hard lipid exudates have both

been reported as negative prognostic factors for cases treated with vitrectomy.306,335

7.35 Sequence of Therapy

Four different interventions for DME are in current use by ophthalmologists: focal laser photocoagulation, intravitreal injection of triamcinolone acetonide

(IVTA), injection of anti-VEGF drugs, and vitrectomy surgery.4,163,267,289 In general, focal laser is

applied initially, followed by intravitreal triamcinolone or anti-VEGF drug injection if response is suboptimal or transitory, and vitrectomy surgery is reserved for the worst cases in which less invasive techniques have failed or for which intravitreal triamcinolone injections are contraindicated.147 This paradigm has evolved by the historical development of treatments and their relative risks, and not by conscious design. As these treatments improve and risks change with modification of techniques, it is possible that the conventionally accepted sequence of interventions may change, with factors affecting the surgical decisions depending on particulars of anatomy, visual acuity, lens status, and other clinical variables. The targeted abnormalities for all of these treatments are the thickening of the macula anatomically and decreased visual acuity ultimately. Reconsidering the rationale underpinning the optimal sequence of intervention in diabetic macular edema has been suggested.241 Groups of investigators have already begun to study alternative sequences of intervention, including intravitreal triamcinolone

therapy and vitrectomy surgery as initial treatments.75,227,310 When traction of the vitreous on the

macula has been judged to be important, vitrectomy surgery is sometimes chosen as the initial treatment, although the criteria are often subjective and unstated for deciding that vitreous traction is of primary importance.75,300 One articulated rationale has been that visual outcomes in cases undergoing vitrectomy without previous focal/grid photocoagulation have, in some series, been superior to those in eyes with previous focal/grid photocoagulation.238,292

The four interventions for DME are not currently applied to comparable groups of eyes. The best seeing eyes with the least macular thickening generally receive focal laser treatment. More severely affected eyes, with thicker maculas and often having failed focal laser, receive intravitreal triamcinolone injection. The most severely affected eyes, with the thickest maculas and often having failed the first two treatments, receive vitrectomy surgery or combined treatments.336 For example, in the DRCR Network studies of focal/grid laser therapy, intravitreal triamcinolone injections, and vitrectomy surgery for DME, the median CSMTs were 327, 398, and 491 mm, respectively227 (DRCR vitrectomy study submitted for publication, DRCR protocol K submitted for publication).

For the purpose of considering an optimal sequence of intervention, treatments for DME can be characterized by their effect sizes with respect to macular thickening and visual acuity at specific times after treatment, the slope of the effect with respect to time, and rates of paradoxical thickening. Table 7.6 shows such a comparison using 6 months as the reference interval after treatment.

Differences in effect size, stability, and duration of effect, and rates of paradoxical thickening

associated with the three interventions have been reported.241 Focal/grid laser has a modest, stable effect. IVTA has a more pronounced early effect, but it wears off, and the same is true of intravitreal anti-VEGF therapy. Vitrectomy surgery has an early effect midway between focal laser and IVTA, but the effect appears to increase to a stable ceiling over time.241 Prospective studies are needed to put these provisional observations in truer context.

The observed differences in treatment effects have to do in part with the differences in baseline characteristics of the groups to which the interventions are applied. Thus, the effect size of IVTA and vitrectomy may in part reflect the opportunity in these groups for the macula to thin more after an intervention because these groups typically have thicker maculas. For example, the macular thinning effects of focal laser, IVTA, and vitrectomy all vary directly with the baseline CSMT (Fig. 7.41).241 In addition, the treatments work by different mechanisms, which makes the concept of combined therapy more attractive for severe cases.

In mild cases of DME, focal/grid laser remains the gold standard treatment. In more severe cases, this approach is also worth an initial trial, understanding that persistent thickening of the center of the macula may be seen in approximately 35% of cases after 1 year of repetitive treatments at 4-month intervals.4 Because persistent DME is associated with progressive loss of visual acuity, which is faster the more severe the edema, at some point an alternative combined treatment may be prudent.151

In view of the small effect size and 25.4% rate of paradoxical thickening induced by focal laser, and the consistent, but transient thinning induced by peribulbar or intravitreal triamcinolone, a combined approach with initial steroid adjunct followed by