Diabetic macular edema

Abstract

A variety of treatment options are available for the treatment of diabetic macular edema. They include laser photocoagulation, anti-VEGF drugs, intravitreal steroids, and vitrectomy with or without release of vitreoretinal traction. A full understanding of the physiological mechanisms of these treatment modalities allows sensible combination of treatment options.

Retinal photocoagulation has repeatedly been shown to improve retinal oxygenation, as does vitrectomy. Oxygen naturally reduces VEGF production and thereby decreases leakage of plasma proteins from capillaries into the tissue. In addition, vitrectomy allows faster clearance of cytokines, such as VEGF, from the retina into the vitreous cavity. The VEGF-lowering effect of photocoagulation and vitrectomy can be augmented with anti-VEGF drugs and corticosteroids reduce the effect of VEGF on capillary permeability.

Starling’s law explains vasogenic edema, which is controlled by osmotic and hydrostatic gradients between vessel and tissue. It explains how VEGF-induced vascular permeability causes plasma protein to leak into the tissue interstitial space, thus decreasing the osmotic pressure gradient between vessel and tissue, resulting in water accumulation, i.e. edema. This is reversed by reducing VEGF production, which is achieved with laser treatment; or by removing VEGF with antibodies or vitrectomy; or by reducing the permeability effect with steroids.

At the same time, Starling’s law takes into account hemodynamic changes that affect the hydrostatic gradient. High arterial blood pressure and hypoxic vasodilatation increase the hydrostatic pressure in the microcirculation, which increases water flux from vessel to tissue and induce edema. Treatment of arterial hypertension or reversal of retinal hypoxia with laser reverses this pathophysiology and reduces edema.

Newton’s third law explains, that vitreoretinal traction decreases hydrostatic tissue pressure in the retina, increases the pressure gradient between vessel and tissue, and stimulates water fluxes from vessel into tissue, leading to edema. Release of vitreoretinal traction reverses this mechanism and reduces edema.

1. Introduction

Diabetic macular edema (DME) remains the most common cause of reduced vision in diabetic patients. About one diabetic patient in four can be expected to develop diabetic macular edema in a lifetime (Klein et al., 2009; Kristinsson, 1997; Stefansson et al., 2000), and this puts the visual acuity at risk.

The treatment of diabetic macular edema has developed over the last 30 years or so. Focal or grid macular photocoagulation was established as an effective treatment in the 1980s and remains the gold standard and the treatment of first choice (O’Doherty et al., 2008). Additional treatment modalities have emerged in recent years and have shown themselves to be effective. These include intravitreal steroids (Gomez-Ulla et al., 2006; Kim et al., 2009), and intravitreal antibodies for vascular endothelial growth factor (VEGF) (Fang et al., 2008; Kook et al., 2008; Soliman et al., 2008), vitrectomy (Kim et al., 2009; Figueroa et al., 2008; Hartley et al., 2008) and release of vitreoretinal traction (Lewis et al., 1992).

Treatment of arterial hypertension has been shown to play a role in reducing diabetic macular edema (Klein et al., 2009; Wong et al., 2008). With several effective treatment options available for DME the question becomes how best to combine these to maximize effect and minimize adverse side effects (Kang et al., 2007; Faghihi et al., 2008; Margolis et al., 2008). It is a daunting task to perform the entire permutation of clinical trials to optimize the combination of the various treatment modalities, such as laser, vitrectomy, anti-VEGF and steroids. Another way to approach this issue is to try to understand the pathophysiology of diabetic macular edema and how this is influenced by the various treatment methods and thus make sense of the various combinations in treatment. This issue has been extensively discussed in a recent article (Stefansson, 2009) and will be briefly reviewed here.

2. Physiology of diabetic macular edema

Edema is defined as an abnormal accumulation of water in a tissue. In vasogenic edema the water accumulates in the interstitial space, whereas water accumulates within cells in cytotoxic or ischemic edema. The physiology of vasogenic edema is based on the water exchange between the blood in the vasculature and the water in the interstitial space in the tissue.

We will focus on vasogenic edema in this discussion.

The physiology of vasogenic edema has been understood in medicine for more than a century. Starling in 1896 defined the forces that transport water between the vascular space (blood) and tissue interstitial space. The forces are hydrostatic and osmotic. The hydrostatic pressure in the blood is established by the pumping activity of the heart. The difference in hydrostatic pressure between the blood in the vasculature and the hydrostatic pressure in the tissue (in the eye the intraocular pressure) defines the hydrostatic pressure gradient which pushes water from the vasculature into the tissue interstitial space and induces edema.

The opposite force is the osmotic gradient which is based on the osmotic activity of the macromolecules, mostly albumin, in the blood, versus osmotically active molecules in the tissue interstitial space. Due to the concentration of albumin, the osmotic pressure in the blood is higher than that in the tissue interstitial space and this pulls water back from the tissue interstitial space into the blood circulation and reduces edema.

In the normal situation the hydrostatic pressure gradient and the osmotic pressure gradients between blood vessel and tissue are equal and opposite and there is no net movement of water between these compartments. This balance can be upset if either pressure gradient is altered. Either an increase in the hydrostatic pressure gradient or a decrease in the osmotic pressure gradient induces edema. Starling’s law is the foundation on which we can understand the pathophysiology of edema formation in any tissue including the retina, and also how this is influenced by treatment (Stefansson, 2009).

Diabetic macular edema is always associated with increased leakage of the macular capillaries as is seen on fluorescein angiography and fluorophotometry (Soliman et al., 2008). The physiological importance of capillary leakage is the leakage of macromolecules, predominantly albumin, from the blood into the tissue interstitial space. The accumulation of albumin in the tissue interstitial space increases the osmotic pressure in the tissue and reduces the osmotic pressure difference between the tissue interstitial space and blood. The smaller osmotic pressure gradient is less effective in pulling water back to the blood stream from the tissue interstitial space and consequently water accumulates in the tissue interstitial space and edema develops.

Vascular endothelial growth factor is very effective in increasing the permeability or leakage of retinal capillaries and may be primarily responsible for the increased leakage of retinal capillaries in diabetic retinopathy (Shimada et al., 2008). Therefore, an essential aim in the treatment of diabetic macular edema is to reduce the concentration of VEGF. This can be done by either decreasing VEGF production or increasing the removal of VEGF.

3. Laser photocoagulation

Vascular endothelial growth factor production is controlled by oxygen tension in the tissue; the production of VEGF is induced by hypoxia. Perhaps the simplest way to increase the oxygen tension in the retina is to breathe oxygen-enriched air and Nguyen et al. (2004) have shown that breathing pure oxygen reduces diabetic macular edema. What may be more relevant for ophthalmologists is that retinal laser photocoagulation also raises the oxygen tension in the retina and reduces hypoxia. This has been demonstrated by four different laboratories in more than 10 publications in a variety of experimental animals and in humans (Stefansson, 2001, 2006, 2009; Alder et al., 1987; Budzynski et al., 2008; Diddie and Ernest, 1977; Funatsu et al., 1997; Landers et al., 1982; Molnar et al., 1985; Novack et al., 1990; Pournaras et al., 1985, 1990; Stefansson et al., 1986, 1981, 1992; Yu et al., 2005).

The laser energy is absorbed by the melanin in the retinal pigment epithelium and transformed into heat which coagulates the retinal pigment epithelium and the adjacent photoreceptors. The destruction of the photoreceptors reduces the oxygen consumption of the retina and allows an oxygen flux to diffuse from the choroid through the glial laser scar into the inner retina without being consumed by the photoreceptors. This increases the oxygen tension in the inner retina and decreases VEGF production (Alder et al., 1987; Budzynski et al., 2008; Diddie and Ernest, 1977; Funatsu et al., 1997; Landers et al., 1982; Molnar et al., 1985; Novack et al., 1990; Pournaras et al., 1985, 1990; Stefansson, 2006; Stefansson et al., 1986, 1981, 1992; Yu et al., 2005).

4. Vitrectomy

In vitrectomy the viscous vitreous gel is replaced by low viscosity saline, resulting in increased transport of any molecule within the vitreous cavity by either diffusion or convection (Stefansson, 2009). For this reason oxygen can be transported from well-perfused areas to non-perfused and hypoxic areas, thus reducing retinal hypoxia in these areas. Stefansson et al. (1990), Maeda and Tano (1996) and Holekamp et al. (2005) have established that vitrectomy reduces retinal hypoxia in experimental animals and humans. Removal of the vitreous gel also allows faster transport of other molecules, such as vascular endothelial growth factor, which can diffuse more readily from the retina into the vitreous cavity, thus reducing the VEGF concentration in the retina (Shimada et al., 2008).

Vitrectomy reduces VEGF concentration both by reducing hypoxia and VEGF production and through increased clearance of cytokines from the retina into the vitreous cavity.

5. Intravitreal VEGF antibodies

The injection of VEGF antibodies, such as bevacizumab and ranibizumab, into the vitreous cavity may have a similar consequence as vitrectomy as far as VEGF clearance goes. Free VEGF in the vitreous gel is bound by the antibody, thus lowering the concentration of free VEGF in the vitreous cavity and increasing the diffusion and clearance of VEGF from the retina, thus lowering the VEGF concentration in the retina. In addition, ranibizumab penetrates the retina and also binds VEGF in the retina itself.

Laser treatment, vitrectomy and intravitreal injection of anti VEGF antibodies may be seen as different ways to reduce the VEGF concentration in the retina and therefore to reduce the leakage of plasma proteins from the blood into the tissue interstitial space.

6. Steroids

Corticosteroids such as triamcinolone and dexamethasone stabilize capillaries and tend to reduce capillary leakage of plasma proteins (Audren et al., 2006; Edelman et al., 2005; Jonas, 2005; Sorensen et al., 2005). These treatment modalities will decrease the leakage of proteins into the interstitial tissue compartment and help to restore the osmotic gradient between blood and tissue compartments. This will resolve edema formation according to Starling’s law (Margolis et al., 2008; Sivaprasad et al., 2006; Wang and Song, 2008).

7. Hydrostatic forces

7.1. Arterial blood pressure

Arterial hypertension is a risk factor for diabetic macular edema (Klein et al., 2009; Wong et al., 2008). Increased arterial blood pressure increases the hydrostatic pressure in the microcirculation, steepens the pressure gradient between the vasculature and tissue interstitial space and stimulates edema formation according to Starling’s law. Treatment of arterial hypertension will lower the hydrostatic pressure gradient and thus reduce the stimulus for edema formation and this is of course well established clinically (Klein et al., 2009; Wong et al., 2008).

7.2. Laser photocoagulation and vitrectomy

Retinal laser photocoagulation and vitrectomy increase the oxygen tension in the inner retina (Stefansson, 2009). Increased oxygen tension results in an autoregulatory vasoconstriction, where arterioles constrict and their resistance increases. This results in a decrease in hydrostatic pressure in capillaries and a decrease in the hydrostatic gradient between the vascular compartment and tissue interstitial space, thus reducing water flux from vessel to tissue and decreasing edema. It is of interest that vasoconstriction in the retina is seen not only following laser treatment but also following intravitreal triamcinolone and bevacizumab injections, even though the hydrodynamic effects of the latter are not fully understood (Soliman et al., 2008).

7.3. Vitreoretinal traction

Vitreoretinal traction will decrease the tissue pressure in the retina according to Newton’s third law. With lower hydrostatic pressure in the tissue, the hydrostatic pressure gradient between the vascular and tissue compartments increases and this stimulates water flux from vessel to tissue and edema formation, much in the same way as can be seen in severe ocular hypotony (Fig. 1). Release of the vitreoretinal traction increases the hydrostatic tissue pressure again and reduces the hydrostatic pressure gradient between the vascular and tissue compartments, thus decreasing edema. A more detailed description of this hypothesis of these mechanisms can be seen in Stefansson (2009).

Figure 1.

This figure indicates several ways in which diabetic macular edema may be treated. Releasing vitreoretinal traction increases the tissue pressure, reduces hydrostatic pressure gradient between vessel and tissue and reduces edema according to Starling’s law (central arrows). Vitrectomy (or posterior vitreous detachment) increases oxygen delivery to the retina and reduces hypoxia and VEGF production (upper right-hand arrow). Vitrectomy (or posterior vitreous detachment) clears VEGF and other cytokines from the retina, due to increased diffusion and convection currents (upper left-hand arrow). VEGF antibodies in the vitreous cavity similarly increases VEGF clearance from the retina. Retinal photocoagulation decreases outer retinal oxygen consumption, increases oxygen delivery to the inner retina and reduces hypoxia and VEGF production (lower arrow). Steroids reduce permeability of retinal blood vessels, reduce leakage of proteins into the tissue and help to restore the osmotic gradient between blood and tissue, thus reducing edema (left horizontal arrow). Lowering of arterial blood pressure or constriction of retinal arterioles (oxygen, photocoagulation, vitrectomy) reduces the hydrostatic pressure in the microcirculation, reduces hydrostatic pressure gradient between vessel and tissue and reduces edema according to Starling’s law (right horizontal arrow).

8. Conclusion

Through understanding of the mechanisms of the various treatment modalities, which are discussed briefly above and in more detail in a recent review (Stefansson, 2009), it becomes possible to understand how these treatment options work in synergy and how they can supplement each other. This is shown graphically in Fig. 2 and explained in the figure legend.

Figure 2.

Principles of physiology and physics help to explain the combination of various treatment options for diabetic macular edema and edema in other ischemic retinopathies, such as vein occlusions. Starling’s law governs the formation of vasogenic edema, based on osmotic and hydrostatic gradients between microcirculation and tissue. The osmotic gradient is influenced by vascular endothelial growth factor (VEGF), which controls the leakage of osmotically active proteins into the tissue compartment (blue balloon). VEGF is controlled by oxygen tension. Laser treatment, vitrectomy and oxygen breathing can increase retinal oxygen tension and thereby reduce VEGF production (green arrows). Vitrectomy and posterior vitreous detachment (purple arrows) increase diffusion and convection in the vitreous cavity and increase clearance of VEGF (and other cytokines) from the retina, thus reducing VEFG concentration in the retina. VEGF antibodies in the vitreous cavity also remove VEGF from the retinal surface and decrease VEFG concentration in the retina by clearance (red arrows). The permeability effect of VEGF can be reduced by the administration of steroids (grey bar). The hydrostatic arm of Starling’s law is indicated by the brownish-red arrows. The hydrostatic gradient between microcirculation and tissue may be reduced through several mechanisms. Releasing vitreoretinal traction will increase the tissue pressure, reduce hydrostatic pressure gradient between vessel and tissue and reduce edema according to Starling’s law. Treating ocular hypotony by raising intraocular pressure will do the same. Reduction of arterial blood pressure will reduce hydrostatic pressure in the microcirculation, and thus reduce the hydrostatic gradient between vessel and tissue and reduce edema. Improved retinal oxygenation through laser treatment or vitrectomy constricts the retinal arterioles, increases their resistance and reduces hydrostatic pressure in the microcirculation, thus reducing the hydrostatic gradient between vessel and tissue and edema.