reduced through their use, although visual acuity was not improved, possibly because of advanced

disease and irreversible damage of the maculas at

baseline.204,208,209

Pharmacologically induced diuresis, peritoneal dialysis, hemodialysis, and renal transplantation can

all beneficially influence DME in patients with renal failure.210–212 In a case report, plasmapheresis has

been used in severe cases to lower serum lipids with improvement in macular edema and visual acuity.69 Certain drugs have been associated with induction of new DME or exacerbation of existing DME. Others have been associated with amelioration of DME. Thiazolidinediones are oral agents used to treat type 2 diabetes, often as adjuncts to other drugs. They are peroxisome proliferator-activated receptor g agonists that work by enhancing insulin sensitivity. Pioglitazone and rosiglitazone are members of this class of drugs in common use. They have been associated with peripheral edema, pulmonary edema, and/or congestive heart failure, especially when used in combination with insulin. Plasma VEGF levels are higher in patients on thiazolidinediones than in patients not on these drugs.213 Case reports and series suggest that

they can be associated with new or worsened diabetic macular edema as well.214–216 Although the reported

association is controversial, it is worthwhile for ophthalmologists to monitor their patients using these drugs and to raise the possibility of a regimen change with the supervising internist if ocular intervention is being considered.

Ruboxistaurin is a protein kinase C-b antagonist that ameliorates diabetes-induced retinal circulatory abnormalities and suppresses VEGF-induced retinal vascular hyperpermeability in animal models.217 In a clinical trial, treatment with ruboxistaurin for 36–46 months reduced the risk of moderate visual loss by 63% primarily affecting eyes with DME at baseline. In eyes with moderately severe to severe nonproliferative diabetic retinopathy, ruboxistaurin 32 mg/ day reduced the risk of progression of DME to within 100 mm of the center of the macula in patients with CSME at baseline. In addition, compared to placebo, ruboxistaurin reduced the need for focal/ grid photocoagulation for DME by 26%.218 In a separate randomized, placebo-controlled clinical trial of varying doses of ruboxistaurin orally for 30 months in patients with DME >300 mm from the center of the macula, progression to sight-

threatening DME or focal laser treatment was no different among groups.219 Suggestive evidence for a beneficial neuroprotective effect of the 32-mg dose on secondary outcomes such as rate of visual decline

in the presence of severe DME has led to further planned studies of this drug for DME.152,219

Improved metabolic control of diabetes, hypertension, and serum lipids is frequently underemphasized by the ophthalmologist because changes in management are made by the internist, yet there is an intimate connection between these changes and retinal effects. A multifactorial intervention aimed at reducing glycosylated hemoglobin, elevated blood pressure, and elevated serum lipids can produce measurable effects in OCT-measured macular thickness in as little as 6 weeks, and allows lower power laser treatment to be used when focal/grid photocoagulation is applied. Further collaborative studies taking this approach are needed as the published results involve small numbers of patients.220

There is a small subset of diabetic patients who undergo pancreas transplantation, sometimes in combination with kidney transplantation. Approximately 70% of such surgeries are successful in rendering patients euglycemic.221 Approximately 20% of such patients have had focal laser photocoagulation for DME by the time they undergo transplantation. At an average follow-up of 14 months after surgery, 11.4% of eyes show progression of DME, a fraction similar to that in patients undergoing kidney transplantation alone and who remain insulin dependent.221 In addition, other markers of retinopathy severity do not manifest improvements compared to similar patients who undergo isolated kidney transplantation and remain insulin dependent.221 Thus in these patients who typically have advanced diabetic retinopathy and a significant prevalence of DME, normalization of glycemia via pancreas transplantation does not affect the retinopathy.

7.16 Focal/Grid Laser Photocoagulation

7.16.1 ETDRS Treatment of CSME

In the ETDRS model of treatment, a fluorescein angiogram was obtained to guide focal/grid argon laser treatment using either the argon blue-green or green wavelengths.4 Initial focal treatment of

microaneurysms, intraretinal microvascular abnormalities (IRMA), and other discrete leakage sites could extend from 500 mm of the center of the macula out as far as 2 disk diameters from the center of the macula. Fifty to hundred micrometers burns were used for this type of treatment. Fifty to two hundred micrometers burns could be used in a grid pattern to areas of diffuse fluorescein leakage and capillary nonperfusion. Burns were specified to be light to moderate in intensity, and photographs were published as examples of what this level of intensity meant (Fig. 7.32). In cases with CSME persisting at 4 months follow-up despite initial treatment and if visual acuity was less than 20/40, repeat treatments could extend to within 300 mm of the center of the macula if perifoveal capillary nonperfusion was not present.222 Treatments were repeated at 4-month intervals if CSME persisted and treatable lesions or untreated, thickened, and nonperfused retina remained. It is important to conceive of ETDRS treatment as a

Fig. 7.32 This photograph of exemplary focal laser treatment from the ETDRS era would be considered too intense by contemporary standards

regimen of repeated treatments, as the average patient in that study received between three and four focal/grid laser treatments.

The ETDRS showed that at 3 years follow-up, untreated eyes did worse than treated eyes by several different measures. For example, 24% of eyes in the untreated group had a doubling of the visual angle, compared to 12% in the treated group, and 12% of untreated eyes were legally blind compared to 7% of the treated group.4 Obversely, more treated eyes had improved outcomes, again by several measures. For example, in patients with a presenting acuity of 20/40 or worse, visual acuity improved in 40% of treated eyes compared to 20% of

untreated eyes at 3 years follow-up, and 36% of treated patients reported subjective improvement, compared to 14% of untreated patients at 1 year follow-up.4 In general, these conclusions hold for different lengths of follow-up and across all baseline visual acuity levels, but the relative magnitude of the benefit conferred by focal laser treatment is smaller for better baseline visual acuities.4 There is evidence from retrospective studies that increasing age has a negative influence on visual acuity outcomes after focal/grid laser for DME, but the prospective data

Fig. 7.33 (a) Example of an eye with persistent CSME despite previous focal/grid laser treatment. Microaneurysms within 300 mm of the center of the macula are present. (b) The mid-phase fluorescein angiogram shows many more laser spots than were visible on the red-free photograph which makes it difficult to assess the border of the foveal avascular zone. Some of the microaneurysms are perfused and some are nonperfused. (c) A horizontal radial line scan through the fovea shows loss of the foveal pit and presence of cystoid macular edema

c

contained in the ETDRS has not been explored in

this regard to determine if this relationship is

true.224,225

It has been commonly taught that focal/grid

photocoagulation for DME rarely improves visual acuity.54,222,226 To quote one of many sources,

‘‘Although clearly effective in saving many patients from blindness and severe visual impairment, photocoagulation cannot improve vision.’’54 In fact, this was neither true in the ETDRS among eyes with subnormal baseline visual acuities nor has it been true in cohorts with DME treated with

modified ETDRS focal/grid photocoagulation.227 In the DRCR Network trial of intravitreal triamcinolone vs. focal/grid laser photocoagulation for DME, 31% of eyes in the focal/grid group gained 10 or more ETDRS letters at 2 years follow-up, and similar results were true of eyes with vision 20/40 in the ETDRS 20 years earlier.227 A false impression of no visual acuity benefit conferred by focal laser treatment arose because most of the eyes in the ETDRS started with good vision, making any improvement difficult to achieve.

Focal/grid photocoagulation for DME has potential side effects. Macular visual fields show elevated thresholds after focal/grid laser treatment

and cone thresholds increase using fine matrix mapping.175,229 Laser scars can enlarge over time and

paracentral scotomata from enlarging scars have been reported (Fig. 7.34).230,231 Multifocal ERGs

show prolonged implicit times and decreased

amplitudes after focal/grid laser photocoagulation.130 Some eyes develop subretinal fibrosis, but

the relationship to the laser treatment as opposed to the edema is controversial (Fig. 7.35).197,232,233

Some eyes develop secondary choroidal neovascularization, which has been associated with more intense, smaller burns (Fig. 7.36).234

Fig. 7.34 (a) This eye was treated with a nonconfluent grid of laser spots that over 10 years expanded to produce a confluent zone of geographic retinal pigment epithelial atrophy. Smaller, lighter intensity laser burns are used now compared to the burns described as optimal at the time of the publication of ETDRS results, but evidence is lacking that

these changes have resulted in avoidance of laser scar expansion. (b) Example of a laser scar on the superonasal border of the foveal avascular zone that expanded over 2 years of observation. (c) Note the larger diameter of the superonasal macular laser scar. Less obvious expansion of laser scars is seen in the inferotemporal macula by comparing b and c