Overview
Diabetic macular edema (DME) can cause structural retinal changes severe enough to make it the most common cause of visual loss in patients with diabetes. DME is defined by retinal thickening involving or threatening the center of the macula, secondary to the intraretinal accumulation of fluid in the macular area. Although the pathogenesis of DME is still not fully understood, it is mainly caused by the breakdown of the inner blood–retinal barrier. DME can develop at all stages of diabetic retinopathy (DR), but appears to occur more frequently as the severity of DR increases. Risk factors for DME include duration of diabetes, poor glycemic control, hypertension, proteinuria, and hypercholesterolemia. Combined with laser photocoagulation, therapy is therefore directed at controlling these factors. However, other therapies directed at the causative mechanisms of DME are currently being investigated in clinical trials.
Clinical background
Key symptoms and signs
DME is usually diagnosed by stereoscopic slit-lamp biomicroscopy, which may reveal signs such as intraretinal cysts (defining cystoid macular edema) and/or retinal hard exudates ( Figures 67.1 and 67.2 ). Hard exudates are intraretinal lipid deposits that usually accumulate at the border of the thickened retina. They probably result from lipid precipitation due to a differential reabsorption of water-soluble molecules and lipids.
Visual deterioration due to macular edema is usually slow, and only occurs when retinal thickening involves the center of the fovea. In the Early Treatment Diabetic Retinopathy Study (ETDRS), the 3-year risk of moderate visual loss was 33% when thickening initially involved the center of the fovea, and 22% when it did not. Severe visual loss usually results from longstanding DME resulting in degeneration of the photoreceptor–retinal pigment epithelial (RPE) complex and/or combined severe macular capillary closure. Lastly, retinal degeneration may also result from the presence of large plaque of hard exudates under the central fovea. Spontaneous fluctuations of DME during the day as well as long-term variations have been reported in several studies.
Classifications of diabetic maculopathy ( Table 67.1 )
Several classifications of diabetic maculopathy have been proposed, based on the risk of vision loss.
| Bresnick classification of DME | |
| Focal DME | Localized retinal thickening often surrounded by exudates |
| Diffuse DME | Generalized thickening of the central macula |
| Ischemc maculopathy | Extended macular capillary occlusion |
| ETDRS classification of DME | |
| Macular edema | Retinal thickening and/or exudates within one disc diameter of the center of the macula |
| Clinically significant DME | Any of the following features:
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| International classification | |
| Macular edema | Any apparent retinal thickening or exudates in posterior pole |
| Mild DME | Some retinal thickening or exudates in posterior pole, but distant from the center of the macula |
| Moderate DME | Retinal thickening or exudates approaching the center of the macula, but not involving the center |
| Severe DME | Retinal thickening or exudates involving the center of the macula |
In 1983, focal and diffuse DME was distinguished, as well as ischemic maculopathy. Focal DME is defined by localized retinal thickening, often surrounded by exudate rings, resulting from leakage from microaneurysms, and/or intraretinal microvascular abnormalities. The prognosis of focal DME is generally good, as it responds well to laser photocoagulation. Diffuse DME consists of generalized thickening of the central macula caused by widespread leakage from dilated capillaries in this area. The effect of laser treatment on diffuse DME is limited. Finally ischemic maculopathy is secondary to extended occlusion of macular capillaries. Frequently, there is combined pathology of focal and diffuse edema as well as ischemia. Nevertheless, classifying the maculopathy according to its predominant features is useful from a therapeutic and prognostic point of view.
In the ETDRS classification, the severity of DME is based according to its distance from the center of the macula. Clinically significant macular edema (CSME) is defined as retinal thickening and/or adjacent hard exudates that either involve or threaten the center of the macula to spread into it. Patients with CSME should be considered for focal laser photocoagulation.
In an attempt to improve communication worldwide between ophthalmologists and primary care physicians caring for patients with diabetes, an international clinical disease severity scale was developed for DR and macular edema.
Epidemiology ( Box 67.1 )
Diabetic maculopathy is the main cause of vision loss in diabetic patients, occurring in 7–10% of the diabetic population.
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Duration of diabetes
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Diabetic retinopathy severity level
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Hyperglycemia
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Hypertension
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Dyslipidemia
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Nephropathy
Macular edema incidence has been studied in the Wisconsin Epidemiologic Diabetic Retinopathy Study. The results of this study demonstrated a higher 4- and 10-year DME incidence in diabetic patients with early onset (8.2% and 20% respectively) and in those with late onset and taking insulin (8.4% and 26% respectively) compared to those not taking insulin (2.9% and 14% respectively). Risk factors that contribute to the progression of DME include increasing levels of hyperglycemia, diabetes duration, severity of DR at baseline, diastolic blood pressure, and the presence of gross proteinuria. The UK Prospective Diabetes Study Group clearly demonstrated the beneficial effect of tight blood pressure control on DME in type 2 diabetic patients as it showed, at 9 years of follow-up, a 47% reduced risk of visual loss due to reduced incidence of macular edema. Lastly, several studies found a correlation between elevated rate of serum lipids and the amount of lipid exudates.
Diagnostic workup ( Box 67.2 )
Until recently, the clinical detection and evaluation methods currently used have been limited to slit-lamp biomicroscopy and stereoscopic photography. However, both methods are subjective and insensitive to small changes in retinal thickness.
Fluorescein angiography facilitates the visualization of the breakdown of the inner blood–retinal barrier, demonstrating leakage of fluorescein from the macular capillaries or microaneurysms into the retinal tissue; it may also show its accumulation within cystoid spaces. However, fluorescein leakage alone does not necessarily indicate the presence of macular edema. Fluorescein angiography is also useful to identify macular capillary nonperfusion, which may be combined with DME.
Profound change in the diagnosis and management of DME has occurred since the advent of OCT in the late 1990s ( Box 67.3 ). OCT was first described by Huang et al in 1991. Since it became commercially available in 1995, there has been tremendous progress in this technology. OCT provides both cross-sectional imaging of the retina and reliable quantitative measurement of macular thickness. First OCT devices were based on the principle of low-coherence interferometry, which measures the time-of-flight delay of light reflected from ocular structures. To date, time domain OCT using the Stratus OCT instrument (Carl Zeiss Meditec, Dublin, CA) has been the most widely used tool. This instrument acquires images at a rate of 400 axial scans per second, with an axial resolution of 10 µm. Recently, a new class of OCT instruments employing spectral (Fourier) domain technology has been developed, with a scan rate of at least 20 000 axial scans per second and an improved axial resolution of 5 µm.
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Accurate measurement of macular thickness
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Detection of intraretinal cysts and serous retinal detachment
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Analysis of the vitreomacular relationship:
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Tractional DME with thickening of the posterior hyaloid
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Early posterior vitreous detachment
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Neuronal remodeling, including loss of outer-segment reflectance
In the case of DME, OCT demonstrates increased retinal thickness with areas of low intraretinal reflectivity prevailing in the outer retinal layers, and loss of foveal depression. Hard exudates are detected as spots of high reflectivity, and are found primarily in the outer retinal layers ( Figure 67.1 ); intraretinal cysts appear as small round intraretinal hyporeflective lacunae ( Figure 67.2 ). OCT seems particularly useful to detect a feature combined with macular edema that is not easily seen on biomicroscopy – serous retinal detachment ( Figure 67.3 ). It is seen in 15% of eyes with DME. The pathogenesis and prognostic value of serous retinal detachment are not clearly established, but it does not appear to have any negative prognostic value. OCT may also show a disruption in the line of the inner/outer-segment photoreceptors, which is an indicator of poor visual prognosis ( Figure 67.4 ).
