Vitreous fluorometry has been used in research centers to assess permeability of the blood–retina barrier and has great appeal because it assesses a

pathophysiologic variable directly responsible for DME.192,193 Using this technique, it has been deter-

mined that the blood–retina barrier permeability increases 9–26% per 6 months in patients with nonproliferative diabetic retinopathy and no DME and

that daily variation in permeability is approximately 20%.50,193 The technique has been used to show that

angiotensin converting enzyme inhibitor therapy (captopril) for 6 months in hypertensive diabetics and 18 months in normotensive diabetics with nonproliferative retinopathy can blunt this rise in permeability.50,194 Limited evidence suggests that it has prognostic significance for visual loss in DME, but because it is not a clinically relevant ancillary study, and because interpretation of results is confounded by vitreous liquefaction, a common finding in patients with diabetic retinopathy, it currently has little impact in clinical care.158 Fluorescein angiography does not provide equivalent information, because it is graded subjectively rather than objectively.

7.13Other Ancillary Studies in Diabetic Macular Edema

Studies of multifocal electroretinography (mfERG) show that response density is decreased in eyes with DME, especially in the subclass of eyes with cystoid macular edema.119 Full field cone b-wave amplitudes are also decreased in eyes with DME compared to normal controls. Microperimetry shows that DME can lead to unstable central fixation, that fixation may

remain predominantly central, but can also become eccentric.195,196 One study suggested that eyes with

DME and eccentric fixation run the risk of treating the new area of fixation with supplemental focal/grid photocoagulation.196 None of these ancillary studies is regularly used in clinical care of patients.119

7.14 Natural History

ETDRS chart) was 8% per year, such that by 3 years 24% of untreated eyes had suffered moderate visual loss.4 Rates of visual loss increased according to the baseline visual acuity with worse-seeing eyes losing vision at a higher rate.4 Rates of visual loss also increased according to baseline retinopathy severity with eyes having more severe retinopathy losing vision at higher rates than eyes with less severe retinopathy.4 The median rate of visual loss in eyes with severe DME and baseline visual acuity of 20/40 was 0.63 ETDRS letters per month.151 Rates of visual acuity gain of at least six ETDRS letters (at least one line on the ETDRS chart) in untreated eyes with DME and visual acuity of 20/40 (and thus capable of visual acuity improvement) over 3 years of follow-up were stable at 20–25%.4 In the ETDRS, of eyes with DME less severe than CSME (one subset of what has been termed subclinical DME) and observed without treatment, 22 and 25% progress to DME with the center of the macula involved at 1 and 3 years of follow-up, respectively.4 In the OCT era, in a retrospective case series, 31% of eyes with SCDME and serially observed progressed to CSME over a median follow-up of 14 months.145

Chronic, untreated DME and refractory DME can be associated with subretinal fibrosis, particularly if hard exudates are present, and by more

subtle retinal pigment epithelial pigmentary changes (Fig. 7.30).87,197

The ETDRS provided natural history data on a large number of eyes with DME. Over 3 years of followup, the rate of moderate visual loss (15 letters on the

Fig. 7.30 Chronic extracellular fluid and subretinal fluid accumulation in the macula can trigger reactive retinal pigment epithelial hyperplasia manifested clinically as the stellate lesion in the center of the macula