visual loss and found no difference when comparing eyes with leakage classified as predominantly focal with those classified as intermediate to diffuse. There were too few eyes with predominantly diffuse leakage for analysis.134 Others have suggested that diffuse DME responds better to intravitreal triamcinolone injections, intravitreal bevacizumab injec-

tions, or vitrectomy and focal DME to focal laser photocoagulation.121,123,140–142 The evidence to

support the claims comes from qualitative compar-

isons across studies of different designs and is

weak.140,141

It is possible that a concept of focal and diffuse edema, possibly expressed with a new vocabulary, will prove to be important in explaining baseline variance in visual acuity or in predicting treatment outcomes as has been claimed, but the usefulness of the concept has not yet been established despite its ubiquitous use.137

7.6 Subclinical Diabetic Macular Edema

Diabetic macular edema may be clinically recognized, yet not reach a severity satisfying the definition of CSME (Fig. 7.18). Clinical assessment of macular edema and OCT assessment of macular

edema frequently disagree in this group of patients.143,144 In addition, some eyes do not have

clinically recognized DME, but macular thickening is detectable by OCT.144 The term subclinical DME (SCDME) has been used to define both of these

classes of DME that are less severe than clinically significant DME.144,145

7.7 Refractory Diabetic Macular Edema

Diabetic macular edema that has been treated with

focal/grid photocoagulation and yet persists is defined as refractory.146–148 Different authors use

different criteria for the number of focal/grid treatments that are used before applying the term, but all require at least one. Eyes may be refractory to treatments other than focal/grid photocoagulation, and some eyes have edema refractory to all known treatments for DME. Refractory DME has been reported to produce more rapid visual acuity loss in older patients, and is associated with greater

short-term variability in macular thickness than is seen in eyes without refractory DME.149,150 It is

also associated with higher levels of HbA1c than DME that resolves with focal/grid laser photocoagulation.148

7.8 Regressed Diabetic Macular Edema

Regressed diabetic macular edema is defined as the macular state in which DME was once present, was treated with focal/grid laser or other treatments, and is now absent. It is important to state the method for determining absence of the macular edema, as classifications may disagree using clinical methods and imaging methods such as OCT or fluorescein angiography.

7.9 Recurrent Diabetic Macular Edema

Regardless of the treatment used, cases exist in which DME vanishes after treatment, but subsequently recurs.153 Although DME can resolve spontaneously without treatment, and then recur, the term recurrent DME is generally used with reference to treated eyes with recurrences.

7.10Methods of Detection of Diabetic Macular Edema

Diabetic macular edema is most commonly assessed by stereoscopic slit-lamp examination using a fundus lens.4 Examination with a contact lens is more sensitive, but takes more time and can degrade the view for subsequent photography.154 Noncontact fundus lenses are more commonly used in daily practice, are faster and more compatible with subsequent fundus imaging, but have less sensitivity for detection of DME.79 Direct ophthalmoscopy allows

detection of lipid exudates, which may be a sign of DME, but suffers from lack of stereopsis. Although lipid presence suggests associated macular thickening, the two findings are not synonymous and,

therefore, presence of lipid alone is an unreliable surrogate for DME.155,156

Stereoscopic fundus photographs can be used to

assess presence of DME and grade its severity in clinical trials but not in clinical practice.151,157 Com-

pared to clinical examination with a contact fundus lens, stereo fundus photography with reading by trained nonphysicians is more sensitive for the detection of DME associated hard exudates, equally sensitive for detection of center-involved DME, and less sensitive for the detection of non- center-involved DME.99 Because OCT is more reproducible and is more widely available, grading of DME by stereo fundus photography is a research tool used only in clinical trials, and even in this setting its use is declining.

Fluorescein angiography has been used to detect leakage of fluorescein from microaneurysms and other leakage sources in diabetic retinopathy. In some studies, fluorescein leakage has been used as a surrogate variable for macular thickening.47 Because it does not assess the function of the retinal pigment

epithelial pump, the correlation of fluorescein leakage with macular thickening is modest.158,159 It was

not used in the ETDRS for the detection of DME, but rather for guidance of focal/grid photocoagulation once DME had been diagnosed by slit-lamp stereo fundus biomicroscopy.99

As a practical matter, there appears to be a trend toward decreasing use of fluorescein angiography in management of DME. Immediately after the publication of the first ETDRS report, fluorescein

angiography was considered as a necessary tool to guide focal/grid laser treatment.160 Although no randomized trials have been done comparing focal/grid with and without use of fluorescein angiography for guidance, subsequent uncontrolled case series have reported similar results of focal/grid laser photocoagulation for DME whether fluores-

cein angiography is or is not used to guide the treatment.112,161 The report that similar planned

focal/grid treatment patterns result regardless of whether experienced retinologists use fluorescein angiography may have boosted a trend away from fluorescein angiography use.162 For example, in a 1998 audit of DME management, only 19.5% of British ophthalmologists treating DME with focal laser photocoagulation obtained a fluorescein angiogram before treatment.110 In a 2007 study from the DRCR Network, 50% of eyes were managed without fluorescein angiography.163 In the year of diagnosis of DME, Medicare claims data indicate that a 60% of patients received a fluorescein angiogram over the 2000–2004 period. Despite investigation, there has been no evidence published to support assertions of necessity of fluorescein

angiography for planning treatment or usefulnesss in predicting outcomes.112,134,162 Oral fluorescein

angiography has promise for detecting DME in the setting of a screening program, possibly reducing the numbers of patients requiring referral to ophthalmologists, but has not been adopted outside of a demonstration project. Compared to stereoscopic slit-lamp biomicroscopy, sensitivity of 92% and specificity of 81% have been reported for detection of DME with this technique.164

The importance of OCT in the diagnosis and management of DME can scarcely be overemphasized.165 The clinical diagnosis of DME as practiced in the ETDRS era before OCT was beset by variability among clinicians actually carrying out the principles established in the clinical trial.79 After accounting for the effects of chance, agreement between the clinical diagnosis of CSME by an investigator and the gold standard diagnosis based on stereoscopic viewing of color fundus photographs has been reported to be 31% in a setting representative of community care.96 The importance of inaccuracy in disease detection and staging has been stressed as a factor explaining discrepancies in outcomes within clinical trials as compared to

community settings.166 Because detection and assessment of DME by OCT are more objective and reproducible than by clinical examination, more uniformity in intervention and outcomes of

treatment may be possible than in the pre-OCT era.143,144 Increasingly in both clinical trials and

community care, an OCT component to a definition

of DME is included based on normal databases of OCT values that have been published.135,167 In the

DRCR Network, central subfield mean thickness by Stratus OCT must be 250 mm to qualify for inclusion in DME trials and to be eligible for retreatment at specified reevaluation intervals. From Medicare claims analyses, 2.5% of patients with DME had an OCT ordered in the year after a diagnosis of DME in 2000, increasing to 40% in 2004.11 The penetration of OCT machines into ophthalmic practice has continued to increase since 2004 and that percentage would undoubtedly be higher today.

There is no reproducibility data on clinical

detection of DME, but there is a wealth of reproducibility data on OCT.168–172 Variability in OCT

measurements occur in several forms. Measurement variability is that variability noted between repeat measurements made within minutes of each other. Measurement variability has been found to be dependent on the macular thickness. In general, any change of macular thickness greater than 11% of a previous measurement exceeds OCT measurement variability and can be assumed to be a real change in macular thickness.170 In addition to measurement variability, there is shortterm fluctuation in macular thickness in DME. By this one refers to the variability noted over the course of days to even weeks when there is no trend in the changes.173 Short-term fluctuation in DME is also dependent on macular thickness and is larger than measurement variability.150 It is of particular importance in eyes with refractory DME and of little clinical importance in eyes with diabetic retinopathy but no previous history or present evidence of macular edema (Table 7.1).173 Unpublished data of the author suggest that it is of intermediate magnitude and concern in eyes with regressed DME. Two clinical examples will help make concrete the clinical significance of short-term variation in macular thickness.

7.11 Case Report 1

A 67-year-old female with type 2 diabetes for 28 years had a history of DME in both eyes. She had had argon laser focal/grid photocoagulation of the right eye three times previously as well as vitrectomy and internal limiting membrane peeling when the DME did not resolve after laser treatment. Panretinal photocoagulation of the right eye had been administered for proliferative diabetic retinopathy with regression of the neovascularization. Despite multiple treatments, refractory DME of the right eye persisted (Fig. 7.19), yet her visual acuity was sufficient that she was able to read a newspaper and pass a drivers test. Treatment had been suspended as

futile over the past 2 years, but she was monitored at 3–6-month intervals. The corrected visual acuity in March 2008 was right eye 20/50 and left eye 20/200. The central subfield mean thickness (CSMT) of the right eye was 273 mm. The left eye had chronic, more severe, refractory DME. She returned 6 months later and reported worse blurring of vision. At this time visual acuity was right eye 20/80 and left eye 20/200. The OCT-measured DME of the right eye had worsened with CSMT of 371 mm (Fig. 7.20). The fundus appearance and the fluorescein angiography for the right eye are shown in Figs. 7.21, 7.22, and 7.23. Loss of the ability to drive was feared, and reconsideration was therefore given to further intervention for the refractory DME. In attempting to decide the wisest

Fig. 7.20 OCT images of the right eye of case 1 in September 2008 when the patient had experienced deterioration of visual acuity, more difficulty driving, and was found to have increased diabetic macular edema. The radial line scan is oriented vertically

Fig. 7.21 Red-free photograph of the right eye of case 1 in September 2008 when exacerbation of DME was observed. Two large microaneurysms on the foveal avascular zone border and several others more remote from the border are noted

Fig. 7.22 Mid-phase fluorescein angiogram of the right eye of case 1 in September 2008. The location of two large microaneurysms on the border of the foveal avascular zone is documented

recommendation for this patient, the question arose whether the 98 mm thickening of the CSMT witnessed between the last two visits was within the expected range of short-term OCT variability for eyes with refractory DME. In other words, was she truly worsening – showing increasing macular thickening – or was this compatible with short-term

variability of macular thickening in an eye with refractory DME?

The patient returned 1 month later, and the CSMT and visual acuity of the right eye had improved spontaneously to 178 mm and 20/60, respectively (Fig. 7.24). That is, as this case exemplifies, short-term fluctuation in CSMT in