Abstract
Macular edema as a result of a blood–retinal barrier breakdown is common to various diseases. This chapter describes different clinical entities leading to macular edema and details the molecular and cellular interactions involved. This comprises the topics of tight junctions, the role of inflammation as well as growth factors, vasoactive factors, and vascular permeability. Furthermore, mechanisms of transcellular transport, the topic of neurovascular coupling, and the result of mechanical forces are discussed in the first part of this chapter. The second part describes current and future clinical endpoints in macular edema.
In the third part of this chapter the current treatment approaches, including laser treatment, anti-VEGF treatment, and anti-inflammatory preparations, are detailed based on the available data from randomized clinical trials and treatment recommendations. To round up the treatment part, the role of surgical treatments is evaluated.
Key words
macular edema, blood–retinal barrier, tight junctions, inflammation, VEGF, corticosteroids, neurovascular coupling, diabetic macular edema, vein occlusion
Introduction
Macular edema is a common phenomenon in various diseases where fluid accumulates in the extracellular space within the retinal neuropile. This phenomenon relates to Starling’s law which predicts that macular edema will develop if the hydrostatic pressure gradient between capillary and retinal tissue is increased. In the retina this can occur in the presence of elevated blood pressure, or if the osmotic pressure gradient is decreased by excessive protein accumulation in the extracellular space. The edema is also related to concomitant breakdown of the inner and outer blood–retinal barriers (BRBs) which are modulated by imbalances in cytokines and growth factors that disturb the integrity of the tight junctions of the capillary endothelium and retinal pigment epithelium (RPE).
Both focal, diffuse, and the cystic forms of edema are characterized by extracellular accumulation of fluid, specifically in Henle’s layer and the inner nuclear layer of the retina, but also in the subretinal space. The compartmentalization of the accumulated fluid is likely to be due in part to the slow dispersal of accumulated extracellular fluid that occurs within the plexiform layers as a consequence of the tightly packed neuronal and glial parenchyma combined with impaired fluid clearance mechanisms. Recent evidence indicates that edematous changes to the inner retina can also occur as a consequence of disruption of the normal homeostatic function of the Müller glia. This can lead to intracellular, cytoplasmic swelling of these cells that span the entire inner retina, which exacerbates disruption of the retinal interstitium and contributes to the development of edema and neurodegeneration.
Macular Edema as a Result of Various Disease Mechanisms
Causes of Macular Edema
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 the different conditions ( Table 30.1 online 
).
| Disease Group | Disorder | Pathogenesis |
|---|---|---|
| Metabolic alterations | Diabetes | Abnormal glucose metabolism Aldose reductase Both inner and outer BRB are affected |
| 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 | Predominantly inner BRB (retinal capillary hypoperfusion) |
| 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 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 | Lymphocytes: T-cells, microglia activation | |
| Pharmacotoxic effects | For example: Epinephrine (in aphakia) Betaxolol Latanoprost | Mostly via prostaglandins |
The classic pattern of cystoid macular edema (CME) with a petaloid appearance originating from the fluorescein leakage from perifoveal capillaries may be seen in cases of advanced edema of various origins ( Fig. 30.1A ). 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), arterial macroaneurysm, inherited retinal disorders such as retinitis pigmentosa, choroidal neovascularization, and radiation retinopathy.
). Given the heterogeneous etiology of macular edema, its effective treatment depends upon a better understanding of the underlying pathogenesis.
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 peripheral retina leads to formation of macular edema. Decreased perfusion of the retinal capillaries on the arterial side is seen, for example, 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 vein 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 may also promote macular edema by physical forces.
Inflammation is important in the pathogenesis of macular edema in conditions such as posterior uveitis, postoperative CME (Irvine–Gass syndrome), diabetic macular edema (DME), and various diseases linked to choroidal inflammation such as Vogt–Koyanagi–Harada disease and birdshot retinochoroidopathy. All prostaglandin-like pharmacologic agents, even if applied topically for treatment of glaucoma, 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 among patients, retinal disease, and even during disease progression. It should also take into account the site of disturbance (i.e., breakdown of inner or outer BRB or both).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 studies based on animal models, especially relating to early-stage diabetic retinopathy, experimental autoimmune uveitis, and ischemia-induced leakage. A variety of techniques measuring accumulation of material from plasma in the neural retina have been investigated as indicators of 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. 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 to the intraretinal or subretinal space. Intracellular edema (formerly also referred to as “cytotoxic edema”) is defined as cellular swelling that occurs independent of the BRB. Extracellular edema (sometimes referred to as “vasogenic edema”) is characterized by retinal thickening in association with loss of BRB integrity ( Fig. 30.2 ). Combinations thereof are possible.
The breakdown of the inner BRB, as a result of a variable contribution of dysfunction of intercellular junctions, increased transcellular transport, or endothelial cell and pericyte dysfunction/loss, leads to an increased vascular permeability ( Fig. 30.3 online 
). 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, most knowledge from preclinical models is related to diabetic models.
). While for diabetes and ischemic retinopathies the inner-BRB is believed to play a dominant role in vascular leakage, the importance of the outer BRB has recently been supported. The outer BRB separates the neural retina from the choroidal vasculature, which is responsible for approximately 80% of the blood supply in the eye ( Fig. 30.4 ).
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. The role of the outer BRB is largely underestimated but has significant clinical implications.
Cell-to-Cell Junctions and Vascular Permeability
Fluid homeostasis and capillary permeability are regulated by the complex intercellular communications within the cells of the neurovascular unit which comprises endothelial cells, pericytes and closely associated macro- and microglia and neurons. This cellular unit responds dynamically to complex circulatory and neural cues to control blood flow and regulate the intercellular junctions of the inner BRB. Intercellular junctions are complex structures formed by the assembly of 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 and are most relevant for the BRB ( Fig. 30.5 online 
). 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. Expression of selected endothelial cell tight-junction genes and particularly that of occludin and claudin-5 are reduced in the diabetic retina. 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 (TNF)-α signals through protein kinase C (PKC)ζ/nuclear factor (NF)-κB alter the tight-junction complex and increase retinal endothelial cell permeability. Endothelial junctions also regulate leukocyte extravasation. Once leukocytes have adhered to the endothelium, a coordinated opening of interendothelial cell junctions occurs.
Fluid moves from the retina to the choroid largely due to the osmotic pressure exerted by the proteins in the choroidal stroma and disruption of this normal flow can lead to significant edema. Especially in the context of ischemia and diabetic retinopathy, there is evidence that the RPE becomes dysfunctional and that leakage from the choriocapillaris occurs in unison with impaired fluid clearance contributing to retinal edema. When the RPE shows stress responses resulting from oxidative or nitrosative damage, this can result in significant loss of fluid control and damage to junctional integrity. Similar to the breakdown of the inner BRB, the breakdown of the outer BRB is associated with a significant depletion of the occludin in the RPE of ischemic and diabetic rodents.
Inflammation and Vascular Permeability
“Inflammation” comprises a broad range of reactions from intravascular leukostasis and reactive glial activation as seen in diabetic retinopathy to overt inflammatory responses as in pars planitis, or choroidal inflammatory diseases.
Diseases not primarily called inflammatory such as diabetes present with activated leukocytes with abnormal adherence to the retinal vascular endothelium. So-called leukostasis is initiated by activation of vascular endothelium and circulating myeloid cells such as neutrophils and monocytes. In diabetes, for example, the leukostasis phenomenon is typified by immune cells becoming trapped in narrow-channel retinal capillaries leading to occlusion and nonperfusion which 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 causing vascular obstruction and vascular leakage. Endothelial cell death precedes the formation of acellular capillaries. 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 ( Fig. 30.6 online 
). This process is triggered by various growth factors and inflammatory cytokines. Inflammatory cytokines such as TNF-α decrease the protein and mRNA content of the tight-junction proteins zonula occludens (ZO)-1 and claudin-5. 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 ( Fig. 30.7 online 
). Furthermore, TNF-α is involved in ischemic vascular changes. While a variety of cells may express these cytokines including endothelial cells, perivascular cells, and Müller glia, a bulk of expression is probably linked to activation of retina-resident microglia and infiltrating monocytes.
While this is typical for overt inflammatory retinal disorders such as uveitis, such cell activation responses are now known to also be central to inflammatory responses developing during diabetic retinopathy. For example, a number of in vitro studies and in vivo investigations of animal models and human postmortem specimens indicate that activation of retinal microglia could play an important regulatory role in diabetes-mediated retinal inflammation by modulating cytokine expression and other pathologic responses. Monocytes that infiltrate the retina are distinct from microglia, and they reside in proximity to blood vessels (perivascular macrophages) or within various layers of the neuropile. While both monocytes and microglia have important roles in retinal homeostasis, they are also central to neuroinflammation responses that lead to retinal 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 ( Fig. 30.8 ).
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. 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. The importance of Müller cells on the formation of neuronal and vascular pathology has been confirmed in transgenic models recently.
Growth Factors, Vasoactive Factors, and Vascular Permeability
The disruption of endothelial integrity leads to retinal ischemia with an ensuing hypoxia response by the oxygen-deprived retina. At a molecular level this is typified by stabilization and nuclear translocation of hypoxia-inducible factor-1 alpha (HIF-1α) in the neurons and glia. HIF-1α is one of a family of hypoxia-inducible transcription factors that bind to hypoxia response elements in inducible target genes and control gene expression of proteins such as erythropoietin (EPO), vascular endothelial growth factor (VEGF), and glucose transporters. VEGF is most well appreciated in the ophthalmology field since it drives iris and retinal neovascularization. Also known as vascular permeability factor (VPF), VEGF is 50,000 times more potent than histamine in causing increased vascular permeability. Previous work has shown that retinal VEGF levels correlate with diabetic BRB breakdown in rodents and humans. Flt-1(1-3Ig)F c , a soluble VEGF receptor, reverses early diabetic BRB breakdown and diabetic leukostasis in a dose-dependent manner. Early BRB breakdown localizes, in part, to retinal venules and capillaries of the superficial inner retinal circulation and can be sufficiently reduced by VEGF inhibition ( Fig. 30.9 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.
On a cellular level, VEGF has been implicated in many different mechanisms that 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 the breakdown of the BRB. VEGF-induced BRB breakdown appears to be effected via nitric oxide. VEGF also increases paracellular transport without altering the solvent drag reflection coefficient. Furthermore, VEGF activation of PKC stimulates occludin phosphorylation and contributes to endothelial permeability.
There are established tight connections between inflammation and VEGF expression. Müller-cell derived VEGF has been shown to be essential for diabetes-induced retinal inflammation and vascular leakage.
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 expression of inflammatory biomarkers, a reduced depletion of tight-junction proteins, reduced numbers of acellular capillaries, and reduced vascular leakage compared to diabetic control mice.
In vitro investigations on cell–cell interactions by D’Amore and coworkers demonstrated an inhibitory effect of transforming growth factor (TGF)-ß secreted by pericytes on endothelial cell growth. In diabetic retinopathy formation of sorbitol via aldose reductase leads to PKC activation resulting in pericyte damage and subsequently a loss of the inhibitory balance via TGF-ß secretion ( Fig. 30.10 ).
High glucose concentration leads to increased diacylglycerol (DAG) by two pathways: de novo synthesis and through dehydrogenation of phosphatidylcholine (PC). 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.
PKC activation causes vasoconstriction by increasing the expression of endothelins (ET), especially ET-1. The expression of endothelins 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. 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. Interestingly, Aiello and coworkers showed that administration of LY333531, a PKC-β isoform-selective inhibitor, does not significantly decrease histamine-induced permeability but rather VEGF-induced permeability. In contrast, administration of non-isoform-selective PKC inhibitors did significantly suppress histamine-induced permeability.
Furthermore, in vascular endothelial cells, advanced glycation endproducts (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.
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 may become “fibrin locked.” Endothelial cells deprived of their circulation and nutrition die and only acellular basement membranes persist. 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.
Similarly, in diabetes, BRB 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). 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 molecules 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. 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
In diabetic retinopathy matrix changes are mostly related to basement membrane thickening of the capillaries which arises because of increased synthesis of protein components such as collagen IV, fibronectin, and laminin in combination with reduced degradation by catabolic enzymes. 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 is exerted by matrix metalloproteinases (MMPs), a family of zinc-binding, calcium-dependent enzymes. Elevation of MMP-9 and MMP-2 expression has been shown in diabetic neovascular membranes, , although a direct effect of glucose on MMP-9 expression in vascular endothelial cells could not be shown. 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 function to active participation in endothelial and pericyte cell death that occurs late in the course of the disease. Taken together, the degradation of extracellular matrix affect the blood vessels not just because then the blood vessels do not have support (i.e., mechanical effect) but also via altered interactions between endothelial cells and perivascular cells and an altered distribution of soluble growth factors and cytokines.
Although basement membrane thickening is a hallmark lesion in diabetic retinopathy it is still uncertain if it is of primary or secondary importance in the development of microvasculopathy. In the context of vasopermeability abnormalities, changes to this extracellular matrix impact the integrity of the neurovascular unit and normal cell–cell communication. Even from a structural perspective, changes in protein and proteoglycan composition of the basement membrane, as occurs in diabetes, influence charge selectivity which contributes to capillary barrier function.
Transcellular Transport and Vascular Permeability
Disruption of the BRB is an early phenomenon in preclinical diabetic retinopathy (PCDR). 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 and pinocytic transport). 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. 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.
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 vesiculo-vacuolar 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. Whereas in highly permeable blood vessels the number of pinocytotic vesicles at the endothelial luminal membrane transporting plasma IgG is significantly increased, no fenestrations or vesicles were found in the endothelial cells of the VEGF affected eyes when examined by electron microscopy.
Neurovascular Coupling
Neuronal degeneration is a common feature of long-standing macular edema but has been recently shown to occur early in the pathogenesis of various origins of macular edema.
The retina consists of a network of neurons and specialized sensory cells (photoreceptors, bipolar cells, horizontal cells, amacrine cells, and ganglion cells) 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. As the network of retinal neurons and glia are intimately linked, there is no doubt that the neural and vascular components of the retina are closely associated by metabolic synergy and paracrine communication.
There are complex neural, glial and vascular cell interactions occurring with both large and small retinal vessels and these play important roles in controlling retina homeostasis, including blood flow, water balance, and vasopermeability. The phenomenon called neurovascular coupling refers to the process by which retinal blood flow and vasoreactivity is matched to the metabolic (particularly oxygen) demands of the neuropile. This interplay between the cell-types can become dysfunctional in disease states. For example, in the diabetic retina, regulation of vascular smooth muscle reactivity is depressed and this correlates with the severity of retinopathy. In an animal model of diabetes, the impairment of neurovascular coupling in the retina has been attributed to alterations in the NO signaling pathway since the response could be restored by inhibition of the enzyme inducible nitric oxide synthase (iNOS). Such interactions can increase or decrease blood flow depending on local oxygen concentration, but how this switch occurs remains unclear.
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. 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. 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.
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 internal 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. Striated collagen fibrils of the vitreous cortex insert into the inner portion of the ILM, 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.
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. Traditionally, the ILM has been considered to be synthesized by Müller cells. This concept has been challenged by data presented from Sarthy and coworkers, who investigated the expression of collagen type IV during development of the mouse eye. 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 that 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.
Diffuse DME has been found in association with an attached, thickened, and taut posterior hyaloids. As immunocytochemical staining for cytokeratin (found in RPE) and GFAP (found in astrocytes and Müller cells) demonstrated the existence of RPE and Müller cells or astrocytes in the premacular posterior hyaloid, it suggested 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.
Fig. 30.11 is a schematic illustration of macular edema of different origins.
Clinical Endpoints in Macular Edema
Best corrected visual acuity (BCVA) is the only endpoint that has gained acceptance by regulatory and health technology agencies as being patient-relevant. BCVA, for example, has been used as primary outcome measure in all landmark clinical trials on new treatments for macular edema.
However, BCVA alone does not provide a good indication of the visual function and potential restrictions patients may experience as a result of disease. Indeed, several eye disorders may adversely affect the visual function and the quality of life of individuals without impacting on BCVA. Furthermore, in certain diseases, BCVA is only affected once irreversible damage has taken place. Thus, new validated endpoints able to better capture functional deficits that affect and restrict patients as well as incipient changes related to early disease are needed. This may comprise distinct psychophysical tests, e.g., low luminance acuity, retinal sensitivity by microperimetry (photopic and scotopic) as a surrogate for topographic localization of retinal deficits.
Structural outcomes related to patient-reported outcomes or predictive of future functional loss and disease progression should be also sought. Besides an improvement of current imaging protocols (spectral domain optical coherence tomography SD-OCT) new approaches may include active eye-tracking technology. Phase variance OCT (PV-OCT) allows for volumetric imaging of the retinal vasculature of the eye. This novel approach, also referred to as OCT-angiography, has the added advantage of a noninvasive imaging technique not requiring potentially toxic contrast agents such as fluorescein, however not presenting vascular perfusion, but rather the outer vascular outlines. To overcome this problem and to better assess perfusion Doppler-OCT technology is currently being developed. Oximetry in diabetic retinopathy has extensively been reported. Longitudinal data on oxygenation, perfusion, and oxygen extraction of the retina is currently lacking in diabetic retinopathy and is currently been generated. In the future, combination of Doppler-OCT with oximetry measures will allow determination of oxygen concentration and tissue metabolism as well as delineation of normoxic and hypoxic retina. All the above imaging technologies require validation and, in the context of macular edema, would need to demonstrate their value on this particular disorder.
Ideally, in order to identify the most adequate outcome measures, an integrated approach should be conducted, which should include a visual function and structural assessment, an evaluation of patients’ perception of the impact of the disease in their daily living through patient reported outcomes (PROs), and, importantly, a study of molecular markers at the different stages of the disease process. Given the high output that such an approach would generate, a robust data management would be needed to allow integrating data of the individual patient and compare them with data from peer groups. To achieve this, a system medicine approach could be used which, by integrating all data generated, would allow improved characterization of disease phenotypes, better understanding of disease mechanisms, establishment of predictive models of disease progression and response to treatment. Advanced machine learning/statistics procedures need to be used to identify correlations between different parameters to gain insights into disease mechanisms and to identify and validate biomarkers: computational models of disease status within individual patients are required. For this reason object-oriented modeling systems, based on standard human pathway information, need to be adapted to the situation in the eye. As models become more complex and parameters become better defined, unknown mechanisms can be identified as systematic mismatches between prediction and measurement, accelerating progress in the identification of disease mechanisms, clinical endpoints, and biomarkers, revealing matches between different biomarkers that show relevance for prognosis of disease progression or susceptibility to treatment approaches.
Treatment of Macular Edema
The current therapy for macular edema targets conditions where mechanical traction, hydrostatic force, or inflammation play a pathogenetic role. Laser photocoagulation, pharmacologic approaches, and surgical measures are the most frequently used therapies.
Laser Treatment
Many studies have demonstrated a beneficial effect of photocoagulation therapy for DME.
Traditionally argon laser photocoagulation was used to treat DME in an attempt to stabilize vision and prevent further visual loss. The Early Treatment of Diabetic Retinopathy Study (ETDRS) showed that laser treatment reduced the risk of moderate visual loss by 50% during 3 years of follow-up; however, only a small proportion of patients (<3%) experienced visual improvement of ≥15 letters.
Recent randomized trials have shown that a much higher proportion (about 30%) of patients with DME can experience a clinically relevant (≥10 ETDRS letters) improvement in visual acuity following laser treatment. Thus, in a study conducted by the (US–Canadian) Diabetic Retinopathy Clinical Research network ( DRCR.net ), laser treatment for “center-involving DME” achieved gains of ≥10 letters in 32% of patients at 2 years.
The probability of improvement was similar in naive eyes and those that had previously received ≥3 laser treatments. Similarly, in a more recently conducted study by DRCR.net , an improvement in visual acuity of ≥10 letters was observed in 28% of patients who had received laser treatment after one year. Thus, it is clear that laser treatment can actually improve, not just stabilize, vision in some patients. Appropriate selection of patients, however, is required. It is likely that people with “thinner” retinas would respond better to laser treatment that those with “thicker” retinas, and thus, be clinically effective and cost-effective in the former, as suggested by the UK National Institute for Health and Care Excellence (NICE) Single Technology Assessments for anti-VEGF therapies. There may be other factors that modulate clinical response; and ability to identify the “responders” in advance would be of great benefit to patients and to health services.
Laser treatment to areas of peripheral retinal ischemia, as determined by wide-angle fluorescein angiography, has been evaluated in small studies with good preliminary success (Tornambe PE, personal communication).
The exact mechanism of action of laser photocoagulation-induced resolution of DME still remains unknown. 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 raise 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. There are contrasting data whether an increased preretinal oxygen partial pressure is involved and allows for microvascular repair in the treated areas.
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.
According to another theory, the beneficial effect of laser photocoagulation is due to an enhanced proliferation of RPE and endothelial cells leading to a repair and restoration of the BRB. 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.
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. This theory, however, cannot be reconciled with the fact that current techniques used for focal/grid laser treatment for DME, including subthreshold laser (as opposed to what was used initially, which implied applying a much stronger laser) do not cause cell death. The effect of the laser can be observed even when damage is not detected by current imaging modalities including fundus autofluorescence imaging. Similarly, by using this milder form of treatment, reported side-effects of laser, such as choroidal neovascularization (CNV) are no longer seen ( Fig. 30.12 ). A lack of an effect of laser treatment in cases of diffuse edema, especially when causing large increases in retinal thickness, may occur ( Fig. 30.13 ).
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