Basic Science of Diabetic Macular Edema

Einar Stefánsson, MD, PhD

Most discussions of the basic science of diabetic macular edema (DME) begin with a discussion of the molecular mechanisms that lead to retinal tissue damage and clinical signs and symptoms of the disease. Not this time: Dr Stefánsson’s iconoclastic talk could easily have been retitled “Essentials of Fluid Biomechanics for the Retinal Surgeon,” and provides a new rationale for various routine diagnostic and therapeutic interventions in DME.

Starling’s Law, shown in Figure 1, is the fundamental equation of interest in developing a deeper understanding of the pathogenesis of DME. Starling’s Law states that the net flux (Φ) of fluid across a permeable membrane is equal to the difference between the capillary pressure (P_c) minus the interstitial pressure (P_i) and the capillary osmotic pressure (Q_c) minus the interstitial osmotic pressure (Q_i). Starling’s Law thus has 2 arms: ΔP is the hydrostatic arm of the equation, while ΔQ is the osmotic arm. When Φ = 0, there is no net movement of fluid between the vasculature and tissue.

Figure 1. Starling’s Law for Fluid Exchange Between Vessels and Tissue

Φ = (P_c – P_i) – (Q_c – Q_i) = ΔP – ΔQ

Dr Stefánsson reminded the subspecialists in attendance that retinal capillaries are always permeable to water; “they are not lead pipes.” Fluorescein does not exert the same osmotic pressure on the retinal capillaries as plasma, thus fluorescein leakage is not necessarily a good marker for the plasma leakage that occurs in DME.

Hypoxia plays a central role in the pathogenesis of DME triggering several autoregulatory mechanisms that change the net flux of fluid across retinal capillaries according to Starling’s Law (see Figure 2). Among other things, hypoxia induces vascular endothelial growth factor (VEGF), which increases vascular permeability, which increases Q_i. Vasodilation, a hallmark of diabetic retinopathy, is reversed with increased oxygen availability (Stefánsson E. Ocular oxygenation and the treatment of diabetic retinopathy. Surv Ophthalmol. 2006;51:364-380). Retinal hypoxia can be reversed by breathing oxygen, laser photocoagulation, or vitrectomy.

Figure 2. The role of hypoxia in the pathogenesis of DME

   ↓Oxygen for inner retina

↓                                      ↓

     ↑VEGF                   Autoregulatory vasodilation

↓                                      ↓

↑Permeability                  ↑Hydrostatic pressure

                        ↓                      ↓                                  ↓

                        ↓             ↑H2O flux                 Venule vasodilation

                        ↓          (Starling’s law)                (Laplace’s law)

↓                      ↓                                  ↓

    ↑Edema             ↑Edema                        ↑Edema

The interrelationship between hypoxia, hydrostatic effects, and permeability shown in Figure 2 suggest several rational therapeutic strategies for DME. Therapeutically, hydrostatic effects can be addressed by antihypertensive agents, treatments that increase oxygen (laser, vitrectomy), and treatments that relieve retinal traction and decrease vitreous viscosity (vitrectomy). Increased permeability suggests that decreasing VEGF is a rational therapeutic strategy. Clinically, this can be achieved by increasing oxygen (laser, vitrectomy), administering anti-VEGF agents, or administering corticosteroids.