Mechanisms of Macular Edema and Therapeutic Approaches

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Chapter 28 Mechanisms of Macular Edema and Therapeutic Approaches

Antonia M. Joussen, Thomas J. Wolfensberger

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Introduction

Macular edema is a common phenomenon in various diseases where fluid accumulates in between the retinal cells. The fluid originates from the intravascular compartment. The focal, diffuse, and cystic forms are all characterized by extracellular accumulation of fluid, specifically in Henle’s layer and the inner nuclear layer of the retina. The compartmentalization of the accumulated fluid is likely to be due in part to the relative barrier properties of the inner and outer plexiform layers.

The breakdown of the blood–retinal barrier (BRB), modulated via different growth factors, results from a disturbance of the integrity of the tight junctions.¹ Starling’s law predicts that macular edema will develop if the hydrostatic pressure gradient between capillary and retinal tissue is increased. That can occur, for example, in the presence of elevated blood pressure, or if the osmotic pressure gradient is decreased by excessive protein accumulation in the extracellular space within the retina.²

Macular edema as A result of various disease mechanisms

Causes of macular edema

The classic pattern of cystoid macular edema (CME) with the petaloid appearance originating from the fluorescein leakage from perifoveal capillaries may be seen in cases of advanced edema of various origins (Fig. 28.1, panel B online). This includes postsurgical CME as well as CME associated with one of the following conditions: diabetes, vascular occlusion, hypertensive retinopathy, epiretinal membranes, intraocular tumors (e.g., melanoma, choroidal hemangioma), intraocular inflammation (e.g., pars planitis), macroaneurysm, retinitis pigmentosa, choroidal neovascularization, and radiation retinopathy.

Fig. 28.1 Cystoid macular edema. (A) Histological section of the fovea area demonstrating cystoid macular edema with large cystic spaces in the outer nuclear and plexiform layer as well as in the inner nuclear layer. Panel B, online.

Fig. 28.1, online (B) Schematic drawing of the central retina with large cysts (top), finally resulting in a pseudohole formation (bottom).

Given the heterogeneous etiology of macular edema, its effective treatment depends upon a better understanding of its pathogenesis. In general, formation of macular edema is related to metabolic changes, ischemia, hydrostatic forces, inflammatory and toxic mechanisms, or mechanical forces that occur to various degrees in different conditions (Table 28.1).

Table 28.1 Causes of macular edema in relation to underlying disorders

Disease group	Disorder	Pathogenesis
Metabolic alterations	Diabetes	Abnormal glucose metabolism Aldose reductase
	Retinitis pigmentosa	CME: leakage at the level of RPE
	Inherited CME (autosomal-dominant)	Müller cell disease: leakage from perifoveolar capillaries
Ischemia	Vein occlusion Diabetic retinopathy	Inner BRB (retinal capillary hypoperfusion)
Ischemia	Severe hypertensive retinopathy HELLP syndrome Vasculitis, collagenosis	Outer BRB (ischemic hypoperfusion of the choroid: serous detachment)
Hydrostatic forces	Retinal vascular occlusions Venous occlusion Arterial hypertension Low IOP	Increased intravascular pressure Failure of the BRB
Mechanical forces	Vitreous traction on the macula	Epiretinal membranes with tangential traction Vitreomacular traction syndrome
Inflammation	Intermediate uveitis	Mediated by prostaglandins CME is considered an indication for treatment
	Postoperative CME	Perivascular leukocytic infiltrates
	DME	Diabetic leukostasis mediates vascular leakage by endothelial cell apoptosis
	Choroidal inflammatory diseases	Vogt–Koyanagi–Harada syndrome Birdshot retinochoroidopathy
Pharmacotoxic effects	e.g., Epinephrine (in aphakia) Betaxolol Latanoprost	Mostly via prostaglandins

CME, cystoid macular edema; RPE, retinal pigment epithelium; BRB, blood–retinal barrier; HELLP syndrome, hemolytic anemia, elevated liver enzymes, and low platelet count; IOP, intraocular pressure; DME, diabetic macular edema.

Metabolic alterations have a causal role in diabetic maculopathy, but also in inherited diseases such as the autosomal dominant form of macular edema or macular edema in retinitis pigmentosa. Furthermore, ischemia of the inner or outer BRB leads to formation of a macular edema. Decreased perfusion of the retinal capillaries is seen, e.g., in vein occlusion and diabetic retinopathy, whereas ischemia plus decreased perfusion of the choroid with associated serous retinal detachment occurs in severe hypertensive retinopathy, in eclampsia, or in rheumatoid disorders. Following retinal vascular occlusion the intravascular pressure increases and leads to dysfunction of the BRB. Similarly, hydrostatic forces are effective in arterial hypertension or in eyes with low intraocular pressure and may cause fluid accumulation in the macula.

Mechanical traction such as in epiretinal membranes or in vitreomacular traction syndrome promotes macular edema by physical forces.

Inflammation is important in the pathogenesis of macular edema in conditions such as intermediate uveitis, postoperative CME (Irvine–Gass syndrome), diabetic macular edema (DME) and various forms of choroidal inflammatory disease, including Vogt–Koyanagi–Harada syndrome and birdshot retinochoroidopathy. All prostaglandin-like pharmacological agents, even if applied topically, can induce macular edema via a cytokine response similar to inflammatory conditions.

The knowledge of the basic mechanisms involved in vascular leakage is essential for the development of an effective clinical treatment. Development of optimal strategies for treating retinal edema may depend on determining the ratio of the contribution of intra- and extracellular mechanisms to edema and measuring how this ratio changes between patients, between different retinopathies, and during disease progression.

With the growing understanding of the pathophysiology of the macular edema, the therapeutic thinking is likely to change from a merely symptomatic treatment (either surgical or medical) to a treatment that targets specifically the causal factors involved in its formation (e.g., cytokine or growth factor inhibition).

Molecular and cellular alterations leading to macular edema

Much of the knowledge on the pathophysiology of macular edema has been determined from extensive experimental studies on diabetic retinopathy and diabetic vascular leakage. A variety of techniques measuring accumulation of material from plasma in the neural retina have been investigated to assess permeability. Such accumulation seems diffuse in nature and focal defects have not been reproducibly described in diabetic mice; as well, interpretations of techniques involving tracer accumulation have not been validated in terms of “gold standard” permeability surface area product.³ Interestingly, edema has not been demonstrated in the retina of diabetic mice based on retinal thickness measurements despite the indication of increased permeability.

The BRB consists of the retinal pigment epithelium (RPE) layer (outer BRB), and the vascular endothelium (inner BRB), that prohibit the passage of macromolecules and circulating cells from the vascular compartment to the extracellular compartment and therefore intraretinal space.⁴ Intracellular edema (or cytotoxic edema) is defined as cellular swelling that occurs without opening of the BRB. Extracellular (or vasogenic) edema is characterized by retinal thickening in association with loss of BRB integrity (Fig. 28.2). While for diabetes and ischemic retinopathies the inner BRB was found to play a dominant role in vascular leakage, the importance of the outer BRB has recently been supported.⁵ The outer BRB separates the neural retina from the choroidal vasculature, which is responsible for approximately 80% of the blood supply in the eye. The outer BRB-specific leakage of fluorescent macromolecules can be visualized in diabetic and ischemic rodents and substantial leakage of macromolecules through the outer BRB can be detected.

Fig. 28.2 Blood–retinal barrier (BRB) and breakdown in vascular disease. (A) Normal retinal tissue: dotted blue line marks the outer BRB at the level of the retinal pigment epithelial cells. The inner BRB is at the level of the endothelial cells of retinal vessels (dashed red line). Further structural guidance is given by Müller cells. (B) Diabetic retinopathy: note the large caveolae of fluid and accumulation of blood cells in the retinal tissue, resulting from a breakdown of the inner BRB.

(Courtesy of Sarah Coupland, MD, Liverpool.)

The breakdown of the inner BRB may occur to a variable extent via dysfunction of intercellular junctions, increased transcellular transport, or increased endothelial cell destruction, and result in an increase in vascular permeability (Fig. 28.3B, online).

Fig. 28.3 Pathogenesis of macular edema and vascular leakage. (B) Vascular leakage is increased by a variety of factors, including growth factors and inflammatory cytokines. Leakage in turn is decreased by steroids, inhibition of tight junction formation, or antibodies to factors inducing leakage. ILM, inner limiting membrane; ELM, external limiting membrane; RPE, retinal pigment epithelium; VEGF, vascular endothelial growth factor; TGF-β, transforming growth factor-beta; TNF-α, tumor necrosis factor-alpha; IGF-1, insulin-like growth factor-1; TJAPs, tight junction proteins; NSAIDs, nonsteroidal anti-inflammatory drugs. Panel A, online.

Fig. 28.3, online (A) In general, water outflow through vessels is possible via three major routes: paracellular via dysfunction of tight junctions, transcellular via increased transport, e.g., mediated via growth factors, and finally directly via endothelial gaps after cell death.

The initial site of damage that results in the increased vascular permeability is controversial to date. Although impairment of the perivascular supporting cells such as pericytes and glial cells might play a role, endothelial cell dysfunction and injury seems more likely to be the first pathogenetic step towards the breakdown of the BRB early in the course of the disease. In order to dissect the molecular and pathophysiologic mechanisms that lead to the accumulation of fluid in the macular area, we have chosen DME as a model.

Cell-to-cell junctions and vascular permeability

Fluid homeostasis and endothelial permeability are mostly regulated by intercellular junctions in the nondiseased retina. Intercellular junctions are complex structures formed by the assembly of a transmembrane and cytoplasmic/cytoskeletal protein components. At least four different types of endothelial junctions have been described: tight junctions, gap junctions, adherence junctions, and syndesmos. Tight junctions are the most apical component of the intercellular cleft (Fig. 28.4, online).

Fig. 28.4, online Intercellular junctions in endothelial cells. Endothelial cells are connected and communicate with each other by tight junctions and adherens junctions. Tight junctions resemble a major part of the inner blood–retinal barrier. They are built by different proteins, including occludin, ZO-1, and the claudin family.

Although the molecular structure of tight junctions generally appears to be similar in all barrier systems, there are some differences between epithelial and endothelial tight junctions, and between tight junctions of peripheral and retinal endothelial cells.⁶ Expression of selected endothelial cell tight junction genes and particularly that of occludin and claudin-5 is reduced in the diabetic retina.⁷ In contrast to tight junctions in epithelial systems, structural and functional characteristics of tight junctions in endothelial cells respond promptly to ambient factors. It is likely that inflammatory agents increase permeability by binding to specific receptors that transduce intercellular signals, which in turn cause cytoskeletal reorganization and widening of the interendothelial clefts. For example, tumor necrosis factor-alpha (TNF-α) signals through protein kinase C (PKC)ζ/nuclear factor-kappa B (NF-κB) to alter the tight junction complex and increase retinal endothelial cell permeability.⁸ Endothelial junctions also regulate leukocyte extravasation. Once leukocytes have adhered to the endothelium, a coordinated opening of interendothelial cell junctions occurs.

Inflammation and vascular permeability

Leukocytic infiltration of the retinal tissue characterizes many inflammatory diseases such as diabetes, pars planitis, or choroidal inflammatory diseases.

In diabetes, activated leukocytes adhere to the retinal vascular endothelium.^9,¹⁰ Increased leukostasis is one of the first histologic changes in diabetic retinopathy and occurs prior to any apparent clinical pathology.

Adherent leukocytes play a crucial role in diabetic retinopathy by directly inducing endothelial cell death in capillaries,¹¹ causing vascular obstruction and vascular leakage. Endothelial cell death precedes the formation of acellular capillaries.¹⁰ With time, however, acellular capillaries prevail and become widespread. Although the mechanism of this destructive process remains elusive, it is clear that the interaction between the altered leukocytes and the endothelial cells and the subsequent endothelial damage represents a crucial pathogenic step^9,^11,¹² (Fig. 28.5).

Fig. 28.5 Inhibition of retinal pathology in long-term hyperhexosemic intercellular adhesion molecule-1 (ICAM-1) and CD18-deficient mice. Trypsin digests demonstrating a large destruction of the capillary network comparable to nonproliferative diabetic retinopathy with acellular capillaries and microaneurysms in 24-month hyperhexosemic mice. The capillary network in mice with a “noninflammatory” phenotype (CD-18- or ICAM-1-deficient) demonstrates almost normal capillaries.

(Reproduced with permission from Joussen AM, Poulaki V, Le ML, et al. A central role for inflammation in the pathogenesis of diabetic retinopathy. FASEB J 2004;18:1450–2.)

Inflammatory cytokines such as TNF-α decrease the protein and mRNA content of the tight junction proteins zonula occludens (ZO)-1 and claudin-5.⁸ TNF-α and interleukin-1 beta (IL-1β) are elevated in the vitreous of diabetic patients and in the retina of diabetic rats associated with increased retinal vascular permeability and leukostasis^13,¹⁴ (Fig. 28.6, online). Furthermore, TNF-α is involved in ischemic vascular changes.¹⁵

Fig. 28.6, online Inflammatory mediators are involved in leukocyte–endothelial interaction that, via reduction of tight junction protein expression and induction of apoptosis, results in vascular leakage. MCP-1, monocyte chemoattractant protein; Il-8, interleukin-8; MIB-1, macrophage-inhibitory factor; TNF-a, tumor necrosis factor-alpha; ZO-1, zona occludens-1.

Growth factors, vasoactive factors, and vascular permeability

The disruption of endothelial integrity leads to retinal ischemia and vascular endothelial growth factor (VEGF)-mediated iris and retinal neovascularization.^9,^16,¹⁷ VEGF is 50 000 times more potent than histamine in causing vascular permeability.¹⁸^–²⁰ Previous work has shown that retinal VEGF levels correlate with diabetic BRB breakdown in rodents²¹ and humans.²² Flt-1(1–3 Ig)Fc, a soluble VEGF receptor, reverses early diabetic BRB breakdown and diabetic leukostasis in a dose-dependent manner.¹⁷ Early BRB breakdown localizes, in part, to retinal venules and capillaries of the superficial inner retinal circulation²³ and can be sufficiently reduced by VEGF inhibition (Fig. 28.7, online). Although VEGF is only one of the cytokines involved in the pathogenesis of the vascular leakage, it is likely to be one of the most effective therapeutic targets.

Fig. 28.7, online Vascular endothelial growth factor (VEGF) is the key mediator of vascular damage and finally proliferation in the diabetic retina. AGE, advanced glycation end-products; IGF, insulin-like growth factor.

On a cellular level, VEGF has been implicated in many different mechanisms, which lead to macular edema. VEGF has, for example, been shown to decrease the proteins responsible for the tightness of the intercellular junctions and induces rapid phosphorylation of the tight junction proteins occludin and ZO-1, resulting in breakdown of the BRB.²⁴ VEGF-induced BRB breakdown appears to be effected via nitric oxide.¹⁷ VEGF also increases paracellular transport without altering the solvent drag reflection coefficient.²⁵ Furthermore, VEGF activation of PKC stimulates occludin phosphorylation and contributes to endothelial permeability.²⁶

There are tight connections between inflammation and VEGF expression.¹⁷ Recently, Müller-cell-derived VEGF was shown to be essential for diabetes-induced retinal inflammation and vascular leakage.²⁷

To determine the significance of Müller-cell-derived VEGF in diabetic retinopathy, VEGF expression in Müller cells was disrupted with an inducible Cre/lox system and diabetes-induced retinal inflammation and vascular leakage was examined in these conditional VEGF knockout (KO) mice. Diabetic conditional VEGF KO mice exhibited significantly reduced leukostasis, reduced expression of inflammatory biomarkers, depletion of tight junction proteins, reduced numbers of acellular capillaries, and reduced vascular leakage compared to diabetic control mice.

Investigations on cell–cell interactions by D’Amore and coworkers demonstrated an inhibitory effect of TGF-β secreted by pericytes on endothelial cell growth. In diabetic retinopathy formation of sorbitol via aldose reductase leads to PKC activation, resulting in a loss of the inhibitory balance ²⁸ (Fig. 28.8).

Fig. 28.8 Transforming growth factor-β (TGF-β) is involved in an inhibitory balance between pericytes and endothelial cells.

There are several other vasoactive factors and biochemical pathways affected by sustained hyperglycemia and known to be involved in DME, which are discussed in more detail in other chapters.

High glucose concentration leads to increased diacylglycerol (DAG) by two pathways: de novo synthesis and through dehydrogenation of phosphatidylcholine. Increased levels of DAG mediate PKC activation. Several studies have shown that a decrease in retinal blood flow occurs with PKC activation. Conversely, inhibition of PKC with LY333531 (Eli Lilly, Indianapolis, IN) normalized decreased retinal blood flow in diabetic rats.^29,³⁰

PKC activation causes vasoconstriction by increasing the expression of endothelins (ET), especially ET-1. The expression of ETs can be induced by a variety of growth factors and cytokines, including thrombin, TNF-α, TGF-β, insulin, and vasoactive substances including: angiotensin II, vasopressin, and bradykinin.

Furthermore, retinal vascular endothelial cells are very sensitive to histamine. Several studies have documented increased vascular histamine synthesis in diabetic rats and humans.³¹^–³³ The administration of histamine reduces ZO-1 protein expression and thus correlates with vascular permeability. The H1 receptor stimulates PKC that has been implicated in increased retinal vascular permeability.³⁴ Interestingly, Aiello and coworkers showed that administration of LY333531, a PKC-β isoform-selective inhibitor, does not significantly decrease histamine-induced permeability but instead VEGF-induced permeability. In contrast, administration of nonisoform-selective PKC inhibitors did significantly suppress histamine-induced permeability.³⁵

Furthermore, in vascular endothelial cells, advanced glycation end-products (AGE) may affect the gene expression of ET-1 and modify VEGF expression. The AGE-stimulated increased VEGF expression is dose- and time-dependent and additive to hypoxia.^36,³⁷

Endothelial cell death and vascular permeability

Where intraluminal pressure falls below a critical closing pressure the tone of the arteriolar wall cannot be maintained and the downstream capillary bed collapses and endothelial cells become “fibrin-locked.” Endothelial cells deprived of their circulation and nutrition die and only acellular basement membranes persists. A reduction in intraocular pressure may cause macular edema with cystoid degenerative changes and secondary atrophic alterations at the outer retina. Similarly, a reduction in retinal perfusion pressure, often linked to carotid/ophthalmic artery insufficiency, can have similar retinal manifestations and in extreme circumstances there may be retrograde filling of arteries from fellow veins. Stasis of the blood flow in capillaries after venous or arterial occlusions results in rapid apoptosis of endothelial cells.³⁸

Similarly, in diabetes, retinal barrier breakdown is at least in part due to endothelial cell damage and apoptosis. The proapoptotic molecule Fas-ligand (FasL) induces apoptosis in cells that carry its receptor Fas (CD 95).³⁹ There is evidence that FasL is expressed on vascular endothelium where it functions to inhibit leukocyte extravasation. The expression of FasL on vascular endothelial cells might thus prevent detrimental inflammation by inducing apoptosis in leukocytes as they attempt to enter the vessel. In fact, during inflammation and ensuing TNF-α release, the retinal endothelium upregulates several adhesion molecules⁴⁰ that mediate the adherence of the leukocytes, but also downregulates FasL thus allowing leukocyte survival and migration to active sites of inflammation. In experimental diabetic retinopathy, inhibition of Fas-mediated apoptotic cell death reduces vascular leakage.⁴¹ The cumulative endothelial cell death during the course of diabetes plays a causal role in the pathogenesis of the diabetic vascular leakage and maculopathy.

Extracellular matrix alterations and vascular permeability

Degradation of the extracellular matrix affects endothelial cell function at many levels causing endothelial cell lability which is required for cellular invasion and proliferation, or influencing the cellular resistance and therefore the vascular permeability. The degradation and modulation of the extracellular matrix are exerted by matrix metalloproteinases (MMPs), a family of zinc-binding, calcium-dependent enzymes.⁴² Elevation of MMP-9 and MMP-2 expression has been shown in diabetic neovascular membranes,^43,⁴⁴ although a direct effect of glucose on MMP-9 expression in vascular endothelial cells could not be shown.⁴⁵ It is probable that MMPs participate at various stages during the course of the BRB dysfunction and breakdown. Their actions include early changes of the endothelial cell resistance with influence on intercellular junction formation and function⁴⁶ to active participation in endothelial and pericyte cell death⁴⁷ that occurs late in the course of the disease.

Transcellular transport and vascular permeability

Disruption of the BRB is an early phenomenon in preclinical diabetic retinopathy. Two vascular permeability pathways may be affected, the paracellular pathway involving endothelial cell tight junctions, and the endothelial transcellular pathway mediated by endocytotic vesicles (caveolae). Despite the fact that pinocytic transport is critically involved in the transepithelial fluid exchange, its role in the pathogenesis of increased vascular leakage in diabetes is just emerging.^48,⁴⁹ The importance of the regulation of fluid homeostasis by active cellular transport of nutrients and fluid via pinocytosis is underlined by recent data suggesting a transient induction of the paracellular pathway and prolonged involvement of transcellular endothelial transport mechanisms in the increased permeability of retinal capillaries in diabetes.⁷

It is currently known that one of the factors involved in the regulation of pinocytic transport is VEGF. VEGF increases vascular permeability not only by disrupting the intercellular tight junctions between the retinal endothelial cells but also by inducing the formation of fenestrations and vesiculovacuolar organelles. The role of VEGF in the disruption of the pinocytic transport that is translated into increased vascular permeability in disease states is still controversial.⁵⁰ Whereas, in higly permeable blood vessels the number of pinocytotic vesicles at the endothelial luminal membrane transporting plasma immunoglobulin G is significantly increased, no fenestrations or vesicles were found in the endothelial cells of the VEGF-affected eyes when examined by electron microscopy.

Neuronal involvement in the formation of macular edema

Recent research on DME emphasizes the role of neuronal cells in the diabetic retinal damage. The retina consists of a network of neurons and glia (astrocytes, Müller cells, and microglial cells) that comprise approximately 95% of the tissue, with blood vessels representing less than 5% of the retinal mass.⁵¹ As the network of retinal neurons and glia is intimately linked, there is no doubt that the neural (photoreceptors, bipolar cells, horizontal cells, amacrine cells, and ganglion cells) and vascular components of the retina are closely associated by metabolic synergy and paracrine communication.^52,⁵³ Neuroglial cells are involved in vision, and blood vessels provide nutrients to facilitate the process.⁵⁴

The functional integration of blood vessels with the neurosensory retina is clinically evident during autoregulation in which retinal arterioles and venules constrict in response to hypertension and hyperoxia and dilate in response to hypercapnia. Likewise, disorders of the neurosensory retina and retinal vasculature are integrally linked, and understanding of the neurodegenerative component of retinal damage is of importance for treatments of macular edema.

In the inner retina, metabolic substrates, such as glucose, flow from vascular endothelium to astrocytes to neurons. In the outer retina, substrates reach Müller cells and photoreceptors from the choroid via the RPE.⁵² Microglia associate intimately with neurons that express molecules, such as CX3CL1 (fractalkine) and CD20, that negatively regulate microglial activation through their respective receptors. As such, perturbation of expression of ligand or receptor during stress would activate microglia to produce proinflammatory cytokines and acquire an activated morphology. Activated microglia produce chemokines such as monocyte chemoattractant protein-1, inducing expression of adhesion molecules, which can promote the leukostasis of neutrophils on endothelium, and potentially inducing the extravasation of inflammatory macrophages.^52,⁵⁴ Induction of glial fibrillary acidic protein (GFAP) is a marker of glial activation and increased expression of this protein occurs in Müller cells from the retinas of diabetic patients, but also after ischemic injury.

Mechanical factors involved in the formation of macular edema

Clinical and anatomic evidence indicates that abnormalities in the structure of the vitreoretinal interface may play an important role in the pathogenesis of DME.⁵⁵^–⁵⁷ It was suggested that vitreoretinal adhesions in diabetic eyes are stronger than the shear forces of traction from vitreous shrinkage and this in turn may lead to the development of vitreomacular traction and subsequently to macular edema.⁵⁸ Nevertheless, the risk of developing diffuse macular edema was 3.4-fold lower in the group of eyes with complete posterior vitreous attachment or complete vitreoretinal separation compared to the eyes with vitreomacular adhesion.⁵⁹

The vitreous humor is a gel-like structure composed mostly of water (99%), hyaluronic acid, and collagen. A structural barrier between the vitreous cavity and the retina is formed by the inner limiting membrane (ILM), which is localized between the innermost layer of the retina and the outer boundary of the vitreous. The ILM shows typical ultrastructural characteristics of a basal lamina, is found in close contact with the foot processes of Müller cells, and contains proteins that are typically found in basal laminae such as collagen type IV and laminin.⁶⁰ Striated collagen fibrils of the vitreous cortex insert into the inner portion of the ILM,⁶¹ which is also known as the hyaloid membrane of the vitreous. Detachment of the posterior hyaloid membrane with aging or pathology results in a condensation of the posterior vitreous surface (membrana hyaloidea posterior). In youth, there is adhesion between the vitreous cortex and the ILM that is stronger than Müller cells themselves and Müller cell foot processes become separated from their main cell body and remain connected to the posterior aspect of the ILM when this is separated from the retinal surface.⁶²

There has been a controversial discussion regarding the embryonic origin of the ILM, which can be demonstrated as early as 4 weeks after gestation in the human eye.^63,⁶⁴ Traditionally, the ILM has been considered to be synthesized by Müller cells. This concept has been challenged by data presented from Sarthy, who investigated the expression of collagen type IV during development of the mouse eye.⁶⁵ ILM proteins appear to originate largely from lens and ciliary body, although a contribution of retinal glial cells in ILM synthesis cannot be excluded. In support of this are data which show that also other ILM proteins such as perlecan, laminin-1, nidogen, and collagen XVIII are expressed predominantly in lens and ciliary body, but are not detected in the retina.⁶⁶

Diffuse DME has been found in association with an attached, thickened, and taut posterior hyaloid.⁶⁷ As immunocytochemical staining for cytokeratin (found in RPE) and GFAP protein (found in astrocytes and Müller cells) demonstrated the existence of cells in the premacular posterior hyaloids, suggesting a possible role for cell infiltration in the development or maintenance of macular edema. It remains to be elucidated whether these cells in the posterior vitreous cause macular edema physiologically rather than mechanically through the production of cytokines.

Treatment of macular edema

The current therapy for macular edema targets conditions where mechanical traction, hydrostatic force, or inflammation, plays a pathogenetic role. Laser coagulation, pharmacological approaches, and surgical measures are the most frequently used therapies.

Laser treatment

Many studies have demonstrated a beneficial effect of photocoagulation therapy for DME.⁶⁸^–⁷³ The exact mechanism of action of laser photocoagulation-induced resolution of DME is unknown. In short, a laser-induced destruction of oxygen-consuming photoreceptors has been discussed as well as cell death and scarring (involving gliosis and RPE hyperplasia) induced by the temporary rise in tissue temperature. Oxygen that normally diffuses from the choriocapillaris into the outer retina can now diffuse through the laser scar to the inner retina, thus relieving inner retinal hypoxia.^74,⁷⁵ There are contrasting data whether an increased preretinal oxygen partial pressure is involved and allows for microvascular repair in the treated areas.^76,⁷⁷

When studying the diameter of retinal arterioles, venules, and their macular branches before and after macular laser photocoagulation in eyes with DME, the macular arteriolar branches were found to be constricted by 20.2% and the venular branches 13.8%. This was attributed to an improved retinal oxygenation caused by the laser treatment leading to autoregulatory vasoconstriction, improving the DME.⁷⁸

According to another theory, the beneficial effect of laser photocoagulation is due to an enhanced proliferation of RPE and endothelial cells leading to repair and restoration of the BRB.⁷⁹ The RPE cells may respond to the injury in several ways: if the lesion is relatively small, the RPE defect can be filled by cell spreading; if the defect is relatively large, the cells can proliferate to resurface the area, and the RPE can produce cytokines (e.g., TGF-β) that antagonize the permeabilizing effects of VEGF.^80,⁸¹

Laser therapy is well established in diabetic retinopathy as well as in diseases with peripheral retinal ischemia. The Early Treatment Diabetic Retinopathy Study (ETDRS) was designed to evaluate the effects of argon laser photocoagulation for DME in a prospective, randomized, multicenter clinical trial. Among the subgroup of eyes with mild to moderate nonproliferative diabetic retinopathy with DME, visual acuity improved in 16%, remained unchanged in 77%, and worsened in 7% of treated eyes, whereas visual acuity improved in 11%, remained unchanged in 73%, and worsened in 16% of untreated eyes after 2 years of follow-up. After 3 years of follow-up, vision worsened in 12% of treated eyes compared to 24% of untreated eyes. There was a statistically significant benefit of laser photocoagulation in this group of eyes. Nevertheless, a current literature review indicates that, at least in selected groups, a beneficial effect of panretinal photocoagulation with respect to DME can be identified. The exact relationship between peripheral ischemia and DME and thus the relevance of peripheral panretinal photocoagulation in these patients as a treatment for DME still remains to be determined.

While focal laser coagulation reduces hypoxic areas and directly occludes leaky microaneurysms, the rationale for grid laser treatment in DME is not yet well established. Potentially, grid laser may have its beneficial effect by thinning the retina, bringing retinal vessels closer to choroidal vessels, permitting the retinal vessels to constrict by autoregulation, thereby decreasing retinal blood flow and consequently decreasing edema formation.⁸²

Potential side-effects are choroidal neovascularization induction (Fig. 28.9) or lack of effect in cases of diffuse edema (Fig. 28.10).

Fig. 28.9 Complications after grid laser coagulation. (A) Enlarged central retinal pigment epithelial scars of the left eye, no obvious macula edema. (B) Early-phase fluorescein angiography demonstrates choroidal neovascularization lesion growing from earlier photocoagulation scars at the right eye. (C) Late phase with increased leakage of fluorescein.

Fig. 28.10 (A, B) Grid laser treatment in persistent diffuse diabetic macular edema has limited effects. The optical coherence tomography imaging demonstrates no difference in retinal thickness prior to and 3 months after grid laser treatment.

Medical treatment

General aspects of systemic and topical medical therapy

In many cases, macular edema is caused by a generalized health problem such as diabetes, high blood pressure, or inflammatory conditions.⁸³ These generalized diseases need to be treated prior to any other measures. There have been several reports in the literature that such treatments – particularly in diabetes, high blood pressure, and inflammatory diseases – can cure macular edema without any additional specific ocular treatment.⁸⁴

Modification of the systemic blood flow, including hyperbaric oxygen treatment, is thought to alter blood flow via vasoconstriction, and facilitates the reformation of damaged junctional complexes in the vessel wall. However, despite an improvement in visual acuity in patients with chronic CME after cataract extraction, there was no correlation to macular edema.⁸⁵ In uveitis-associated CME hyperbaric oxygen had no signifcant effect. Other rheological treatments such as plasma membrane filtration demonstrated good effects in initial studies; however these treatments did not enter large-scale prospective studies.⁸⁶ Still, there is no evidence that rheological measures have any effect on inflammatory or DME.

Medical treatment of macular edema so far is best established in postsurgical and predominantly inflammatory edema, e.g., in uveitis, but gaining importance in the treatment of DME. The majority of the therapeutic strategies inhibit the release of inflammatory mediators and therefore target the pathogenetic factors responsible for the altered vascular permeability.

Medical treatment for macular edema consists of therapeutic agents that are collectively categorized into three groups: corticosteroids, cyclooxygenase (COX) inhibitors, and carbonic anhydrase (CA) inhibitors.

Carbonic anhydrase inhibitors and nonsteroidal anti-inflammatory drugs

CA inhibitors have been used clinically for over 20 years in the treatment of macular edema. The initial observation on its therapeutic efficacy was reported in 1988 in a study of 41 patients with CME of various etiologies.⁸⁷ The rationale of CA inhibitors as a therapeutic agent in the treatment of macular edema is to improve the ability of the RPE to pump fluid out of the retina by modulating the polarized distribution of CA at the level of the RPE.⁸⁸

In the retina, CA is found in the cytoplasm of red/green cones (albeit not in rods) and especially inside Müller cells. The RPE, however, appears to contain almost exclusively the membrane-bound form of CA.⁸⁹ The latter appears to regulate and modulate the extracellular pH gradients created by the metabolic activity of cells and may act as a bicarbonate channel.^89,⁹⁰ The CA activity in the RPE shows a clearcut polarized distribution with a large amount of enzyme on the apical surface of the cell, whereas there is less CA activity on the basolateral portion of the cell membrane.⁹¹ Further immunohistochemical differentiation has shown the isozyme IV is responsible for apical CA activity in the RPE.⁸⁹ Intravenous injection of acetazolamide has been shown to decrease the pH in the subretinal space in both chicks and cats.^89,⁹² This acidification was followed immediately by a reduction of the subretinal volume, and it has been postulated that it is the acidification that induces changes in ion and consequent fluid transport through the RPE⁹¹ (Fig. 28.11, panel B online).

Fig. 28.11 (A) Schematic diagram showing selected ion channels in the retinal pigment epithelium. Note that carbonic anhydrase inhibitors act on the bicarbonate/chloride exchange channel in the basal membrane, and nonsteroidal inflammatory drugs have been shown to act on the chloride channel in the basal membrane of the retinal pigment epithelium. Both channels are associated with transcellular fluid transport. (Panel B online.)

Fig. 28.11, online (B) Membrane-bound carbonic anhydrase (CA IV) 55 kDa. NSAIDs, nonsteroidal anti-inflammatory drugs.

(Adapted with permission from Wolfensberger TJ, Mahieu I, Jarvis-Evans J, et al. Membrane-bound carbonic anhydrase in human retinal pigment epithelium. Invest Ophtholmol Vis Sci 1994;35:3401–7.)

Under normal conditions, roughly 70% of the subretinal fluid is removed by metabolic transport to the choroid. In an in vivo rabbit model, this fluid transport, which is driven to a large extent by active ion transport through the RPE, can be enhanced by acetazolamide ^93,⁹⁴ Furthermore, experiments in an animal model of iatrogenically induced retinal detachments showed that the disappearance of fluorescein through the RPE increased by 25% after intravenous injection of acetazolamide.⁹⁵ The same authors also observed a marked increase in resorption of subretinal fluid at a higher dosage of 50–65 mg/kg body weight. Further studies on the frog RPE demonstrated that active chloride and bicarbonate transport probably occurs at the basal surface, which faces the choroidal blood supply and it was postulated that subretinal fluid absorption occurs at this level.⁹⁰

Currently, there are no randomized studies available that confirm a beneficial effect of CA inhibitors in the treatment of macular edema. Nonrandomized observations demonstrated improved visual function in patients with postsurgical macular edema, e.g., after cataract surgery or buckling procedures.^87,⁹⁶ The effect lasts only as long as the patient takes the drug (on–off effect, tachyphylaxis).⁹⁶ The favorable reports that were described at first regarding the application of CA inhibition in patients with macular edema secondary to retinitis pigmentosa are not supported by the long-term observation. With the continuous use of methazolamide a rebound phenomenon is observed.⁹⁷

Contrary to tenacious clinical habit, the use of CA inhibition for intraretinal macular edema is not based upon scientific evidence to date. The use of CA inhibitors for DME is not recommended.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

As COX inhibitors block the synthesis and release of prostaglandins, nonsteroidal drugs have been investigated in the prophylaxis and therapy of postsurgical CME. The action is based on the inhibition of the enzyme COX, which in turn inhibits the production of prostaglandins, a degradation product of arachidonic acid in the eye.⁹⁸ Diclofenac sodium in high doses inhibits the formation of leukotrienes, which amplify cellular infiltration during an inflammatory reaction. Other NSAIDs have been shown to modulate chloride movement, and, as a consequence, fluid movement through the RPE.⁹⁹ The effect of COX inhibitors on inflammatory aspects of DME was only demonstrated in preclinical studies¹³ (Fig. 28.12, online).

Fig. 28.12, online Nonsteroidal anti-inflammatory drugs (NSAIDs). Interaction of NSAID with vascular endothelial growth factor (VEGF) and inflammatory cytokines and their signaling pathways. COX-1, cyclooxygenase 1; PGs, prostaglandins; TXs, thromboxanes; TNF-a, tumor necrosis factor-alpha; NF-kB, nuclear factor-kappa B; eNOS, endothelial nitric oxide synthase; NO, nitric oxide; ICAM-1, intercellular adhesion molecule 1; MEK, miogen-activated protein kinase.

Thus, NSAIDS target the inflammatory mediators that are responsible for the edema formation and, although they may not be an optimal standalone treatment, they can be used as steroid-sparing agents. Topical NSAIDs have become the mainstay in the treatment of inflammatory CME.¹⁰⁰ The clinical efficacy of topical NSAIDs has been shown to be of value both in the prevention¹⁰¹^–¹⁰³ and in the treatment^104,¹⁰⁵ of inflammatory CME, particularly when related to cataract surgery. Two double-masked, placebo-controlled studies in which corticosteroids were not used demonstrated that ketorolac 0.5% ophthalmic solution, administered for up to 3 months, improves vision in some patients with chronic CME after cataract surgery.^106,¹⁰⁷ A meta-analysis of the results from several different randomized controlled trials suggests that NSAIDs are beneficial as a medical prophylaxis for aphakic and pseudophakic CME and as medical treatment for chronic CME.¹⁰⁸

On the basis of these findings, it has been suggested to employ topical NSAIDs in the treatment of inflammatory CME, especially when related to ocular surgery.

There may be several explanations for why NSAIDs cannot improve vision in DME, such as chronic edema, inflammation, and ischemia that induce permanent structural alterations. Although effects on diabetic vascular leakage were achieved in preclinical studies,¹³ there is so far no clinical evidence for an effect of NSAIDs in DME.

Corticosteroids

Steroids are currently regaining attention by the growing use of intravitreal triamcinolone. Corticosteroids block the release of arachidonic acid from cell membranes by inhibiting the enzyme COX and thus reduce the synthesis of prostaglandins, but they also have a multitude of other anti-inflammatory effects by acting, among others, on IL-1 and by reducing vascular permeability ¹⁰⁹ (Fig. 28.13A, online). Their additive anti-inflammatory effect to NSAIDs has been shown to be useful in the treatment of various postoperative inflammatory conditions. One potential mode of action is the increased resorption of fluid through the RPE, although the exact mechanism of this is not as yet clear. Steroids specifically stabilize endothelial tight junctions and increase their numbers.^110,¹¹¹ Another action of steroids is the downregulation of the production of the VEGF, which, in turn, renders the BRB tighter (Fig. 28.13B, online). Steroids also downregulate VEGF production,¹¹² specifically in the retina,^113,¹¹⁴ and this explains the clinical observation that the application of steroids both intravitreally and into the subtenon space can reduce macular edema considerably. Furthermore, steroids have been shown to prevent the induction of VEGF production by platelet-activating factor and platelet-derived growth factor.¹¹⁵ Triamcinolone also inhibits IL-6- and VEGF-induced angiogenesis downstream of the IL-6 and VEGF receptors.¹¹⁶ Leukocyte adhesion plays an important role in macular edema – particularly so in diabetic maculopathy.^11,¹² The endothelial damage resulting from this leukocyte adherence to vessel walls is mediated by nitric oxide, adhesion molecules, and other inflammatory mediators.^17,¹¹⁷ Subtenon triamcinolone inhibits leukocyte–endothelium interactions in the retina and downregulates adhesion molecules of retinal vascular endothelium¹¹⁸ and thus decreases the retinal thickness.

Fig. 28.13, online (A) Action of steroids on arachidonic acid. (B) Action of steroids on growth factor release. COX, cyclooxygenase; NSAIDs, nonsteroidal anti-inflammatory drugs; PG, prostaglandin; TX, thromboxane; LT, leukotriene; VEGF, vascular endothelial growth factor; PDGF, platelet-derived growth factor; PAF, platelet-activating factor; BRB, blood–retinal barrier.

The Müller cells represent a further site of action of steroids.¹¹⁹ Macular edema is thought to be partly linked to the downregulation of the Müller cell protein Kir4.1. The resultant increase in intracellular K⁺ leads to the uptake of proteins and osmotic swelling of the Müller cells via aquaporin 4 channels. The administration of triamcinolone reduces the production of VEGF, arachidonic acid, and prostaglandins, allowing the reactivation of fluid clearance by Müller cells via endogenous adenosine and an increase in TWIK-related acid-sensitive potassium (TASK) channels. These processes lead to an efflux of potassium, thus correcting the downregulation of the Kir4.1 protein.¹¹⁹

Corticosteroids have different potency levels depending on their chemical composition ¹²⁰ and the newer synthetically produced compounds show an up to 25-fold increase in activity, as compared to cortisone. These new agents, such as triamcinolone, dexamethasone, and fluocinolone acetonide, have fluor at the 9α position, which increases corticosteroid receptor binding. Routes of clinical administrations are manifold, including topical, periocular, intraocular, oral, and intravenous routes. Subtenon injections of corticosteroids are widely used in patients with asymmetric or unilateral uveitis. The advantages of the periocular injections are high concentrations of corticosteroids in the posterior eye, and reduction of the adverse effects compared to systemic administration. Intraocular levels of corticosteroids are identical between subtenon and retrobulbar administration.¹²¹ For oral administration, the initial high dose (1–1.5 mg/kg) is subsequently decreased according to clinical effect.¹²²

Recent publications suggest that the intravitreal application of triamcinolone seems to be a promising therapeutic method for macular edema that fails to respond to conventional treatment.^123,¹²⁴ Martidis et al. published a prospective, noncomparative, interventional case series to determine if intravitreal injection of triamcinolone acetonide is safe and effective in treating DME unresponsive to prior laser photocoagulation.¹²⁴ Most recent data of a randomized clinical trial demonstrated that, over a 2-year period, focal/grid photocoagulation is more effective and has fewer side-effects than intravitreal triamcinolone, supporting that focal/grid photocoagulation currently should be the benchmark against which other treatments are compared in clinical trials of DME.¹²⁵ In comparison to VEGF inhibitors triamcinolone has a lesser long-term effect. Cataract and secondary glaucoma formation have to be taken into consideration.

Similar studies were performed for patients with uveitic macular edema, central vein occlusion, and CME after cataract surgery.^123,¹²⁴ In most published reports, complications do not appear to be prohibitive.

Reviewing the published data on intravitreal injections of triamcinolone acetonide, the therapeutic window seems very wide. The dose range of intravitreally injected triamcinolone acetonide varies from 2 mg ¹²⁵ to 4 mg¹²⁴ and even 25 mg in a single report.¹²⁶ Interestingly, reaccumulation of fluid in cystoid spaces occurs between 6 weeks and 3 months after injection, and this does not seem to be dose-dependent. Repeated injections at intervals ranging from 10 weeks¹²⁷ to more than 6 months show a variable treatment response.

There are currently no data on the pharmacokinetic profile of intravitreal triamcinolone, which might be altered from a previous vitrectomy. Physiological intravitreal cortisol levels are reported to be 5.1 ng/mL, vitreous levels after peribulbar injections are in the range of 13 mg/mL. The effective dose of the triamcinolone acetonide is further influenced by the mandatory washes of the widely used stabilizing agent benzylethanol during the preparation of the injection that, even if standardized, they alter the remaining amounts of the drug in the solution. Additionally, an inhibitory effect of the stabilizing agent on the drug cannot be excluded.

Jaffe and coworkers ^128,¹²⁹ constructed a fluocinolone acetonide drug delivery device that releases fluocinolone acetonide in a linear manner over an extended period. A clinical phase III study by Bausch & Lomb investigated the efficacy of 0.5 mg (slow-release) fluocinolone acetonide in 80 patients with diffuse DME. Patients receiving the implant showed a statistically significant regression of retinal thickness after 6 months in comparison to the control group.

The safety and efficacy of dexamethasone intravitreal implant (DEX implant; Ozurdex, Allergan, Irvine, CA) compared with sham in eyes with vision loss due to macular edema associated with branch retinal vein occlusion or central retinal vein occlusion as well as posterior uveitis was assessed. The device was found to reduce the risk of vision loss in these conditions, while the vitreoretinal pharmacokinetic profiles were, in contrast to triamcinolone, similar between nonvitrectomized and vitrectomized eyes.¹³⁰^–¹³²

Antiangiogenic treatment

Anti-VEGF agents

As discussed above, there are several reports which support the notion that corticosteroids act as indirect anti-VEGF agents. However, more recently, directly acting anti-VEGF agents have come to the forefront as promising treatment options for macular edema of different origins.¹³³^–¹³⁵ Ranibizumab (Lucentis) and bevacizumab (Avastin) are antibodies with high affinity for VEGF, which bind to all VEGF isoforms.

The intravitreal injection of bevacizumab potentially reduces not only VEGF but also stromal cell-derived factor 1α. This suggests that intravitreal bevacizumab may influence intraocular mediators other than VEGF.¹³⁶

Clinical studies have proven the effect of ranibizumab in several forms of macular edema; it is approved for the treatment of DME and macular edema after vein occlusion in the USA and Europe (Fig. 28.14). Other VEGF inhibitors such as VEGF trap or small-molecule inhibitors are currently being investigated in clinical trials. The VEGF aptamer pegaptanib (modified RNA oligonucleotide, which binds and inactivates VEGF165 only) has been shown in animal models to restore the BRB in diabetic retinopathy.¹³⁷ Similar to the developments in AMD, lesser injections and slow-release systems are in demand as well as better knowledge about the combination of VEGF inhibitors with systemic treatment of the underlying disease.

Fig. 28.14 Optical coherence tomography imaging of diabetic macular edema before and after injection of ranibizumab. (A) Prior to injection: cystoid spaces and macula thickening. (B) Resolution of the cystic spaces 3 weeks after injection. (C) Four weeks after second injection, the macula remains “normal.”

Other medical treatments

Steroid-sparing immunosuppressive drugs are frequently used as additional second-line agents, particularly in patients with severe intraocular inflammation and CME.¹ The rationale for these treatments relies on the inhibition of several different proinflammatory cytokines, which are specifically involved in causing macular edema by breaking down the BRB in intraocular inflammatory disorders.

Apart from the well-known agents such as VEGF, prostaglandins, and leukotrienes, these cytokines also include insulin-like growth factor 1, IL-6, stromal cell-derived factor 1, and hepatocyte growth factor. Particularly elevated levels of intraocular VEGF and IL-6 have been correlated with the severity of uveitic macular edema ¹³⁸ and treatments directed specifically against these factors have been proposed.

Promising results have also been reported using interferon α₂ ¹³⁹ as a treatment for long-standing refractory CME in uveitis. In addition, a beneficial effect of interferon on inflammatory CME was noted in a retrospective study of patients with multiple sclerosis-associated intermediate uveitis.¹⁴⁰ Others reported comparable efficacy of cyclosporine A to prednisolone in the treatment of macular edema in patients with endogenous uveitis.¹⁴¹ Anti-TNF therapy has also been demonstrated as a promising therapy for uveitic macular edema.¹⁴² Somatostatin analogs such as octreotide may also be effective in the treatment of CME by blocking the local and systemic production of growth hormone, insulin-like growth factor, and VEGF.¹⁴³ Treatment with octreotide resulted in marked improvement, or even complete resolution, of CME in uveitic patients.¹⁴⁴ Similarly, calcium dobesilate prevents the BRB breakdown induced by diabetes, by restoring tight junction protein levels and organization and decreasing leukocyte adhesion to retinal vessels. The protective effects of calcium dobesilate likely involve the inhibition of p38 mitogen-activated protein kinase and NF-κB activation, possibly through the inhibition of oxidative/nitrosative stress.

Surgical approaches

Vitrectomy with or without peeling of posterior hyaloid membrane may be beneficial for the treatment of DME in eyes that are resistant to laser photocoagulation and/or steroid injection.

There is clinical evidence that traction forces at the vitreoretinal interface may play an important role in the pathogenesis of macular edema. Several authors have studied vitrectomy for persistent macular edema and have suggested that release of the tractional forces at the vitreomacular interface may improve resolution of the macular edema and restore visual acuity (Fig. 28.15).

Fig. 28.15 Release of traction after spontaneous posterior vitreous detachment in a 34-year-old diabetic patient. (A) Visual acuity 20/200 with cystoid edema and vitreomacular traction. (B) Spontaneous resolution of the traction with vitreous detachment. Visual acuity 20/30.

Although pars plana vitrectomy may be considered as a very simple surgical procedure, its manifold effects on a cellular level are becoming more and more understood.²

Tractional origin of macular edema and surgical aspects

The initial rationale for using vitrectomy in cases of macular edema was entirely structural, i.e., aimed at the removal of vitreous traction on the macula.^55,¹⁴⁵ The effect of traction on retinal structures becomes more understandable using Newton’s third law: to any action there is always an equal reaction in the opposite direction. The force of vitreoretinal traction will thus be met by an equal and opposite force in the retina, resulting in the retinal tissues being pulled apart. Eventually this results in the lowering of the tissue pressure within the retina, which in turn increases the difference between the hydrostatic pressure in the blood vessels and the tissue and contributes thus to edema formation (Starling’s law). Releasing the traction will increase tissue pressure and lower the hydrostatic pressure gradient, reducing the water flux from blood vessels into retinal tissue.²

Vitreoretinal traction associated with macular edema has been identified in diabetic retinopathy, following complicated cataract surgery (Irvine–Gass syndrome) and in several other disease entities. The removal of such traction by vitreoretinal surgery has been found to be beneficial.^55,^145,¹⁴⁶ Peeling of the ILM of the retina ensures complete release of tractional forces, removes a potential diffusional barrier, and inhibits reproliferation of fibrous astrocytes.¹⁴⁷

The rational for vitrectomy (removal of the hyaloid) plus peeling of the ILM is the postulated improvement of fluid diffusion from the retina to the vitreous cavity and is explained in more detail in Chapter 118, CME and vitreomacular traction.

However, vitrectomy may not only be beneficial in the presence of macular traction, but also in cases where no particular deformation of the macula can be identified.

This is particularly true for macular edema of vascular origin, such as diabetes or retinal vein occlusion. The beneficial effect of vitrectomy is thought to be based, at least in part, on two mechanisms. First, it has been found, for example, that oxygen transport between the anterior and posterior segments of the eye is increased in the vitrectomized lentectomized eyes.^148,¹⁴⁹ Others have shown that pharmacologic vitreolysis also improves oxygen diffusion within the vitreous cavity.¹⁵⁰ This means that following vitrectomy and/or posterior vitreous detachment, the transport of molecules to and from the retina is increased.

Second, it has been shown that several growth factors such as VEGF, IL-6, platelet-derived growth factor, and others are secreted in large amounts into the vitreous during proliferative vasculopathies such as diabetic retinopathy or retinal vein occlusion ^151,¹⁵² and it is conceivable that a complete vitrectomy will remove this excess of growth factors mechanically with the desired effect of a restitution of the BRB. The rapid clearance of VEGF and other cytokines may thus help to prevent macular edema and retinal neovascularization in ischemic retinopathies, such as diabetic retinopathy and retinal vein occlusions. Vitreous clearance of growth factors may indeed have the same effect as the presence of, for example, VEGF antibodies in the vitreous cavity.^2,^153,¹⁵⁴

If judging the final benefit, the complications encountered with pars plana vitrectomy for DME should be considered, and include cataract formation (up to 63%), retinal detachment (10%), retinal tear (14–21%), tractional rhegmatogenous retinal detachment (5–8%), vitreous hemorrhage (12–16%), epiretinal membrane formation (8–12%), fibrinoid syndrome (8%), glaucoma (2–8%), development of hard exudates (4%), macular ischemia (11%), and neovascular glaucoma (4–8%).

Discussion and conclusion

Unfortunately, even the currently available surgical and pharmacological treatments have suboptimal results in many cases. Therefore, there is an obvious need for the development of a more effective and targeted treatment that can be satisfied only by a better understanding of the pathophysiology. There is still a need for discussion of functional endpoints for clinical studies (e.g., microperimetry or near visual acuity) and of clinical monitoring (decrease in retinal thickness on optical coherence tomography, or a “dry macula” on angiography). Further, clinically feasible retreatment criteria need to be determined for the absolute and relative thickness variations as well as visual acuity measures.

Ischemic maculopathy remains untreatable in the area of laser coagulation. A foveal avascular zone of more than 500 µm should be considered ischemic and thus, to the current recommendations, cannot be treated. The value of treatment for ischemic maculopathy requires further investigation when determined upon angiography.

Early intervention in macular edema is undoubtedly advantageous, as the risk of ultrastructural alterations induced by a persistent macular edema increases with time. Late treatment risks transition to untreatable ischemic forms of macular edema. To date, however, most surgical approaches will only be considered for persistent macular edema that is not responsive to laser treatment or pharmacological approaches. Earlier intervention could be possibly more advantageous.

The different treatment approaches are likely to affect the clinical course of macular edema at variable time points and for different time periods. While the effect of intravitreal steroids is known to deteriorate with time, similar fluctuations are likely for other treatments. Especially for the surgical options long-term data are currently unavailable. Thus, any treatment option should be evaluated for the duration of the anticipated beneficial effect and beyond. As macular edema requiring treatment appears to be mostly chronic, a follow-up of even 1 year is not sufficient.

In the future, when more specific treatments become available, study design and also routine clinical follow-up will require adjustment.

Bonus images for this chapter can be found online at http://www.expertconsult.com

Fig. 28.1(B) Schematic drawing of the central retina with large cysts (top), finally resulting in a pseudohole formation (bottom).

Fig. 28.3(A) In general, water outflow through vessels is possible via three major routes: paracellular via dysfunction of tight junctions, transcellular via increased transport, e.g., mediated via growth factors, and finally directly via endothelial gaps after cell death.

Fig. 28.4 Intercellular junctions in endothelial cells. Endothelial cells are connected and communicate with each other by tight junctions and adherens junctions. Tight junctions resemble a major part of the inner blood–retinal barrier. They are built by different proteins, including occludin, ZO-1, and the claudin family.

Fig. 28.6 Inflammatory mediators are involved in leukocyte–endothelial interaction that, via reduction of tight junction protein expression and induction of apoptosis, results in vascular leakage. MCP-1, monocyte chemoattractant protein; IL-8, interleukin-8; MIB-1, macrophage-inhibitory factor; TNF-α, tumor necrosis factor-alpha; ZO-1, zona occludens-1.

Fig. 28.7 Vascular endothelial growth factor (VEGF) is the key mediator of vascular damage and finally proliferation in the diabetic retina. AGE, advanced glycation end-products; IGF, insulin-like growth factor.

Fig. 28.11(B) Membrane-bound carbonic anhydrase (CA IV) 55 kDa. NSAIDs, nonsteroidal anti-inflammatory drugs. (Adapted with permission from Wolfensberger TJ, Mahieu I, Jarvis-Evans J, et al. Membrane-bound carbonic anhydrase in human retinal pigment epithelium. Invest Ophtholmol Vis Sci 1994;35:3401–7.)

Fig. 28.12 Nonsteroidal anti-inflammatory drugs (NSAIDs). Interaction of NSAID with vascular endothelial growth factor (VEGF) and inflammatory cytokines and their signaling pathways. COX-1, cyclooxygenase 1; PGs, prostaglandins; TXs, thromboxanes; TNF-α, tumor necrosis factor-α; NF-κB, nuclear factor-kappa B; eNOS, endothelial nitric oxide synthase; NO, nitric oxide; ICAM-1, intercellular adhesion molecule 1; MEK, miogen-activated protein kinase.

Fig. 28.13(A) Action of steroids on arachidonic acid. (B) Action of steroids on growth factor release. COX, cyclooxygenase; NSAIDs, nonsteroidal anti-inflammatory drugs; PG, prostaglandin; TX, thromboxane; LT, leukotriene; VEGF, vascular endothelial growth factor; PDGF, platelet-derived growth factor; PAF, platelet-activating factor; BRB, blood–retinal barrier.

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