Systemic factors

Macular edema manifests clinically as retinal thickening that results from chronic breakdown of the blood–retinal barrier. Extracellular fluid accumulates in the outer plexiform layer and extends into the inner retina with increasing severity. The pathophysiologic factors that govern the formation of edema in the macula are similar to those that contribute to edema elsewhere, such as in the brain. That is, tissue edema occurs when the ability of the blood vessels and the surrounding tissue to regulate leakage are overcome either by increased intralumenal hydrostatic pressure or increased extravascular (tissue) concentration of albumin. This relationship is classically described in Starling’s Law of the Capillary, which states that fluid filtration is related to the forces that drive fluid across the vessel wall (blood pressure, intravascular fluid volume, and interstitial fluid osmotic pressure) minus the forces that promote fluid reabsorption (plasma oncotic pressure). The importance of this concept has been related to macular edema in diabetes by Kristinsson and co-workers¹. This physiologic principle is useful to guide investigations into macular edema and the evaluation and treatment of patients.

The primary systemic factor that contributes to disruption of the normal autoregulatory process of the retinal vasculature is systemic arterial hypertension. Epidemiologic studie have confirmed that hypertension aggravates existing retinopathy and increases the risk of developing retinopathy ². This point is illustrated in Figure 62.1. The patient whose eye is illustrated is a 65-year-old woman with 10 years of type 2 diabetes, and her blood pressure was 150/105 mmHg. The eye has diffusely narrowed retinal arterioles, cotton wool spots, and hemorrhages. The macula is thickened, and lipid exudates threaten the fovea, and visual acuity was 20/40. The other eye had a similar appearance.

Fig. 62.1 Effect of uncontrolled hypertension on diabetic macular edema. The right eye of a 65-year-old female with 10 years of type II diabetes whose blood pressure was 150/105 mmHg. Note the diffusely narrowed retinal arterioles, the nerve fiber layer infarcts and hemorrhages. Her right macula is thickened with lipid exudates threatening the fovea, and her visual acuity was 20/40. The macular edema did not respond well to focal laser because her blood pressure remained elevated.

In addition to hypertension, intravascular fluid overload from congestive heart failure or renal failure increases the hydrostatic pressure across the vascular wall and the propensity to edema formation. The ophthalmologist should ask patients with diabetic macular edema about symptoms of fluid overload, such as orthopnea and dyspnea, and should observe whether those patients have pitting edema of their ankles.

Patients with hyperlipidemia may also have an increased tendency for macular edema formation when serum lipoproteins accumulate in the retina and exert the osmotic influences that draw water out of retinal vessels and cause retinal thickening. Data from the Early Treatment Diabetic Retinopathy Study (ETDRS) showed a twofold increase in risk of macular edema in visual loss in patients with total serum cholesterol greater than 240 mg/dl³.

The issue of glycemic control as an isolated factor in the development of macular edema is difficult to determine because insulin affects numerous aspects of cellular metabolism. However, in the Diabetes Control and Complications Trial (DCCT), the risk of macular edema was approximately 50% greater in the group that received conventional treatment than in the group under intensive treatment. The overall risk of developing macular edema in the intensively treated patients in the secondary intervention group (those patients who had mild to moderate retinopathy at the beginning of the study) was 27%⁴.

Diabetic nephropathy is also associated with increased incidence and progression of retinopathy in general and macular edema in particular. This correlation of diabetic nephropathy and retinopathy is known as the diabetic ‘renal–retinal syndrome’. The risk of macular edema is greatest in patients with overt proteinuria⁵, and systolic hypertension and higher glycosylated hemoglobin are also important factors in the Wisconsin Epidemiologic Study of Diabetes⁶. Nephropathy may aggravate macular edema via hypertension, fluid overload, hypoproteinemia, hyperlipidemia, or increased difficulty with metabolic control. Diabetic macular edema is a risk factor for increased mortality from heart disease⁷.

Several reports have suggested that thiazolidinedione (glitazone) drugs that are used widely as effective agents for type 2 diabetes may increase the risk of diabetic macular edema^8,9. Therefore, patients should be questioned about the use of these medications if they have a recent onset of DME associated with systemic edema but without cardiac or renal failure.

Taken together, poor metabolic (glycemic) control, increased blood pressure and serum lipids, nephropathy, and some medications contribute to the development of retinopathy and macular edema.

Ocular risk factors

In addition to systemic influences on the retinal circulation, several ocular conditions may also increase the risk of macular edema.

The combination of cataract and diabetic retinopathy is a common and clinically challenging problem. Cataract extraction, even with an intact posterior capsule and a posterior chamber intraocular lens, frequently increases the severity of retinopathy and macular edema⁷

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