Fig. 7.35 This eye shows subfoveal retinal pigment epithelial metaplasia after focal photocoagulation for diabetic macular edema

Fig. 7.36 A gray subretinal neovascular membrane with surrounding subretinal hemorrhage is shown arising from the site of a focal laser burn in the inferior perifoveal zone

7.17Evolution in Focal/Grid Laser Treatment Since the ETDRS

The style of focal/grid argon laser treatment applied in the ETDRS has been modified over time. The most significant changes are embodied in the Diabetic Retinopathy Clinical Research Network (DRCR Network) protocols that employ focal/grid

photocoagulation. Table 7.3 lists the major changes. Rather than burns that can vary from 50 to 200 mm, contemporary burns are 50 mm. The burns are lighter – light gray – rather than heavier intensity burns illustrated in ETDRS publications (Fig. 7.31).222 The yellow wavelength (561–589 nm) laser is acceptable in addition to green (514–532 nm); blue-green (488 nm) is not used now because of the theoretical concern of absorption by macular luteal pigment, although it was allowed in the ETDRS. It is not necessary to darken microaneurysms as long as the subjacent retinal pigment epithelium is lightly blanched. The use of a fluorescein angiogram is now optional rather than required. Approximately 50% of eyes in DRCR Network studies, and up to 80% of eyes in other Western hemisphere countries, are treated without fluorescein angiography, and probably even higher percentages

of eyes are treated without guiding fluorescein angiograms in less developed countries.79,110,163 In eyes

treated without fluorescein angiography, grid laser is applied to areas of thickening without focal lesions within 2 disk diameters of the center of the macula, and there is no provision for treating zones of capillary nonperfusion. The goal of these changes is to reduce the incidence of laser scar expansion and paracentral scotomata that have been reported to occur after ETDRS style focal/grid photocoagulation.229 Figure 7.37 shows the type of post laser scarring intensity that could be seen with more intense laser technique 20 years after application compared with contemporary technique.

A continual problem with focal/grid laser photocoagulation for DME has been the decision regarding what constitutes maximal treatment. The decision is intrinsically subjective and makes it difficult to standardize.235 For example, one study defines maximal focal laser treatment as ‘‘a point at which the investigator felt that additional laser treatment would be of no benefit based on clinical judgment and flurescein

angiogram.’’236 Other studies have graded focal/grid photocoagulation based on number of burns.237,238

Heavy laser is defined as >300 burns, moderate as 126–300 burns, and light as <126 burns.237,238 Unfor-

tunately, these numerical definitions fail to capture the reality that spot sizes used in focal/grid laser vary from 50 to 200 mm, such that a specified number of burns may produce large differences in the area of photocoagulated macula.

Fig. 7.37 The left panel shows the pigmentary pattern seen after contemporary focal/grid laser photocoagulation. The right panel shows the effects of more intense laser burns from

an earlier era with laser scar expansion, retinal pigment epithelial hyperplastic scar formation, and paracentral scotoma induction

The interval for retreatment specified in the ETDRS has also been reevaluated. There is evidence that the macular thinning response to focal/ grid laser takes longer than 4 months to reach an asymptote, which implies that a retreatment interval of 4 months for persistent edema could result in unnecessary overtreatment with the attendant side effects. A DRCR Network study showed that further reductions in macular thickness beyond 4 months occur in 42% of eyes with improved but persistent DME after a single session of focal/grid laser for DME (DRCR protocol K manuscript submitted for publication). This group amounted to 10% of all eyes (11 of 115) with DME receiving focal/grid laser in the study and evaluable at 32 weeks after laser. It is not known whether visual acuity outcomes would be improved by observation until OCT improvement stops or by retreatment for persistent DME 4 months after initial treatment as is the current convention in DRCR Network studies involving a laser arm for DME. A randomized trial would be necessary to answer this question.

A semiautomated patterned scanning laser has been developed that uses the argon green wavelength, shortens the pulse duration from the

historically conventional 100–200 to 10–20 ms, and applies automatic patterns of laser with physician control of focusing.239 Histologically, burns with this technology are indistinguishable from conventional argon green laser burns.239 The advantage in the treatment of DME is faster treatment. A potential disadvantage of using patterned laser is that burn characteristics may change depending on the variable retinal thickness seen in DME such that a pattern of uniform powered spots applied to regionally varying retinal thickness may give varying thermal uptake over these regions. For scatter photocoagulation, an additional advantage is decreased pain associated with shorter pulse duration, but this advantage does not apply to focal/grid laser, which is painless using conventional laser machines.239

7.18Macular Thickness Outcomes After Focal/Grid Photocoagulation

At the time the ETDRS was performed, there was no way to objectively measure macular thickness, but with OCT, this outcome has become important

in following treatment. There is little information published on comparability of outcomes among different ophthalmologists performing ostensibly similar treatment, but what is available suggests rough comparability.240 The biggest determinant of macular thinning effect after focal/grid laser treatment is the baseline macular thickness.241 Table 7.4 shows a sample of the range of reported thinning effects as a function of baseline macular thickness. It is apparent that the greater the macular thickening before laser treatment, the greater the thinning response after focal/grid laser.

In general, the threshold for performing focal/ grid laser photocoagulation occurs when the central subfield mean thickness attains 250 mm, and on average, for this threshold level of edema, one can expect approximately 25 mm of macular thinning after focal/grid laser at the usual first follow-up interval of 3–4 months. For every 100 mm of additional baseline macular thickening above this

250 mm threshold, one can expect that focal/grid laser will yield approximately 10 mm of additional macular thinning at the 3–4-month follow-up visit

(Fig. 7.38). Visual acuity at this follow-up time is, on average, unchanged from baseline.163,227,241,242

7.19Resolution of Lipid Exudates After Focal/Grid Laser Photocoagulation

The natural history of lipid exudates associated with DME is to spontaneously resolve over 2 years or longer.243 Macrophages clear the exudates by phagocytosis.69 Both serum lipid control and focal/grid photocoagulation can independently accelerate the clearance of lipid exudates in DME (Fig. 7.39).87 A potential clinical problem is the subfoveal migration of hard lipid after focal/grid laser treatment,

Fig. 7.38 Relationship of macular thinning at 12–17 weeks of follow-up induced by a single session of focal/ grid laser photocoagulation for DME as a function of macular thickness. Each data point represents a row of data from Table 7.4

Change in Thickness at 12 – 17 ( )

–20

–30

–30

–35

–40

–45

Baseline Macular Thickness ( )

Fig. 7.39 Although spontaneous resolution of intraretinal lipid in DME can take 2 years, interventions can speed the process. (a) Lipid exudates present in the macula of an eye with DME before any treatment. (b) Five months after focal/

grid laser treatment, a large fraction of the lipid has resolved, much faster than the natural history of lipid resolution. Faint gray focal laser scars are seen

particularly in patients with heavy lipid exudates before treatment. Adjunctive oral statin therapy in such patients has been reported to eliminate this problem in a small clinical trial.87

7.20Inconsistency in Defining Refractory Diabetic Macular Edema

Focal/grid laser photocoagulation is the standard treatment for DME after optimization of metabolic control fails to eliminate DME. It is the only form of treatment that has been proven through a large, multicentered, randomized controlled trial. Moreover, it has been proven to be superior to serial intravitreal triamcinolone injections in a large, multicentered, randomized controlled clinical trial.227 Thus, it becomes important to decide when an eye meets criteria for refractoriness to focal laser. This decision is linked to the clinician’s sense of what constitutes maximal focal/grid laser photocoagulation, a conundrum already discussed. The mean number of focal/grid laser treatments in the ETDRS was 3.8. Yet, in some studies, investigators have labeled eyes as refractory to focal/grid laser after one or two sessions of laser, and used this term

to justify moving on to alternative forms of therapy.139,146,147,236 Some have termed eyes with per-

sistent edema after three focal/grid treatments to be refractory and have used them in an observational

control arm in testing other forms of therapy.149 A recently initiated randomized clinical trial for refractory DME does not define how many laser treatments are required to qualify as refractory, and the same is true of another published randomized

trial of intravitreal triamcinolone injection vs. placebo.244,245 It is the norm for multiple focal/grid

laser treatments to be necessary in the treatment of DME, and yet despite multiple treatments it is common for DME to persist. Of eyes with CSME at baseline and randomized to immediate focal photocoagulation, 35 and 24% of eyes continued to have DME with the center of the macula involved at 1 and 3 years, respectively.246 In WESDR, 35 of 109 older onset diabetics with baseline DME returned for reexamination 10 years later. Of these 35, 5 (14.3%) had persistent DME and of these 5, 2 had refractory DME having received focal/grid laser photocoagulation after the baseline examination.1

7.21Alternative Forms of Laser Treatment for Diabetic Macular Edema

Krypton red laser (647–670 nm) has been used in some clinical series and appears to have efficacy in DME; however, it is not the preferred wavelength, because it is poorly absorbed by red microaneurysms and other focal leaking sites, is absorbed more