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September 2011 Supplement September 2011 Supplement

The Pathophysiology of Macular Edema

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Macular edema occurs when fluid and protein deposits accumulate in the macular region, causing a thickening and swelling of the macula that can be either focal or diffuse. It is believed that a breakdown of the blood-retinal barrier leading to increased retinal vascular permeability is the cause of macular edema, which is major cause of vision loss in a variety of retinal diseases, including diabetic retinopathy, retinal vein occlusion (RVO), uveitis, and Irvine-Gass syndrome.

The pathophysiology of macular edema is complex, with a variety of processes involved in its development. Abnormal retinal capillary permeability or breakdown of the blood-retinal barrier is the underlying etiology.1 This increased vascular permeability, in which the extracellular spaces expand, causes an accumulation of fluid, which overwhelms the mechanism that maintains the fluid balance, leading to macular thickening and eventual visual loss.1,2

Early vascular and inflammatory changes are most likely secondary to retinal tissue stresses, which can result from hypoxia, altered blood flow, ischemia, toxicity, surgical trauma, and inflammation. These stresses initiate an inflammatory process in the retinal vasculature leading to further alterations in the blood flow and migration of inflammatory cells (leukocytes) to the retinal vasculature. The leukocytes then begin to release inflammatory cytokines. The leukocytes are aided in their targeting of affected tissues by inflammatory adhesion molecules, including intracellular adhesion molecule 1 (ICAM-1), expressed on the inside of blood vessels in the region of retinal stress. These adhesion molecules help the leukocytes roll along and adhere to the interior surface of the blood vessel.

Once a leukocyte adheres to the inside of the vessel, monocyte chemoattractive protein 1 (MCP-1) is secreted to help activate the leukocyte and aid its migration across the vessel wall and into the tissues (Figure 1). Once in the retinal tissue, leukocytes secrete a variety of inflammatory mediators, including interleukin (IL-1), tumor necrosis factor (TNF)-alpha, and vascular endothelial growth factor (VEGF), all of which increase permeability (Figure 2). The presence of inflammatory mediators stimulates the production of more of these molecules and leads to amplification of the inflammatory response (Figure 3).

As the condition progresses, the blood-retinal barrier begins to break down, increase vascular permeability that allows fluid to leak from the vessels, and the movement of large molecules out of the vascular compartment (Figure 4). There can also be a loss of pericytes around the capillaries, which can lead to capillary wall weakness, and even the formation of microaneurysms. Endothelial basement membrane thickening can lead to focal closure of some capillaries, which in turn, may increase blood flow through nearby vessels. Müller cell processes are the principal extracellular matrix tissue of the retina and where most of the fluid begins to form. Cystic spaces have been noted on optical coherence tomography of pathologic specimens, and it appears that the junctions between the Müller cells and neuronal cell membranes become stretched (Figure 5). Müller cells are the only cells that express glucocorticoid receptors in the retina; therefore, it may be advantageous to treat with steroids to eliminate some of this fluid. Inflammation is a function of both innate and adaptive immunity that spur the body to mount an attack against foreign antigens. Physiological inflammatory cascades eliminate provoking substances and begin to repair affected tissues.

Diabetic Macular Edema

The pathophysiology of diabetic macular edema (DME) involves intracellular hyperglycemia, which induces free radicals (oxidative stress), protein kinase C (PKC) activation, and formation of advanced glycation end-products (AGE).3 This process results in hypoxia, ischemia, inflammation, and alteration of vitreomacular interface. Inflammation produces an increase in VEGF production, endothelial dysfunction, leukocyte adhesion, and PKC production. In fact, diabetic retinopathy is now considered to be a state of low-grade inflammation.4

In experimental diabetic models, signs of diabetic retinopathy occur as a result of inflammatory reactions secondary to oxidative stresses, proinflammatory cytokines, binding of leukocyte adhesion molecules CD- 18 and intracellular adhesion molecules ICAM-1. This leads to the breakdown of the blood-retinal barrier, vascular occlusion, and tissue ischemia.

Inflammatory causes of edema include: an increase of neutrophils in the choroid; increased polymorphonuclear leukocytes in the choriocapillaries associated with loss of endothelial cells; leukocyte aggregation, and capillary drop-out; elevated CD-4 and CD-6T; cells in the vitreous; elevated macrophages in the vitreous leading to proinflammatory cytokines; and up-regulation of TNF-alpha.

Retinal Vein Occlusion

In RVO, there is a combination of both increased hydrostatic pressure behind the occlusion, causing the deterioration of the endothelial cell integrity, instigating a secondary inflammation with an upregulation of VEGF and interleukin 6.5

In several studies a C-reactive protein elevation has been noted.6

The cascade in branch retinal vein occlusion (BRVO) leads to impaired recruitment of lymphocytes and macrophages to the injured area, direct cell death, and again, a weakened blood-retinal barrier, increased lymphocytes in the retina, and further edema.

The rationale for corticosteroid therapy is that inflammation may lead to compression of an arteriosclerotic central retinal artery or primary occlusion of the central retinal vein.7 In one study, chronic inflammation in the area of the thrombus in a branch vein in the vein wall or the perivenular area has been observed in 48.3% (14) of eyes with central retinal vein occlusion (CRVO).8

Further, suppression of VEGF production has been shown to inhibit inflammatory cell activity.9

Uveitis and Irvine-Gass Syndrome

Macular edema is commonly associated with uveitis. Although the cause of uveitis is often unknown, some cases have been associated with autoimmune disorders, infection, and exposure to toxins. Irvine-Gass Syndrome, also known as postoperative macular edema, is a common complication of cataract surgery.

Uveitis leads to macular edema through an inflammatory process. Uveitis activates the proinflammatory marker, such as VEGF, interleukin, tumor necrosis factor, and interfering gamma, that eventually lead to increased macular edema.

Case #1

A woman aged 78 years presented with a history of hypertension and a treatment-naïve inferotemporal BRVO with 20/30-1 visual acuity. Figure 6 shows her fluorescein angiograms at presentation and Figure 7 shows her optical coherence tomography (OCT) scans. Initially, we did not treat the patient, but when she returned approximately 2 to 3 weeks later, her vision had decreased to 20/40-2 and OCT showed thickening and edema (Figure 8) so we injected the dexamethasone intravitreal implant (Ozurdex, Allergan, Inc.). Approximately 1 month later, her vision improved to 20/25-2 and we observed a reduction of the edema (Figure 9) so at that visit, we did not treat in addition to the sustained release of dexamethasone from the implant. At 2 months post-implant, her vision decreased slightly to 20/30 but OCT did not show swelling of the edema (Figure 10) so we did not treat. We injected a second dexamethasone implant at 4 months because OCT showed some re-accumulation of edema (Figure 11; page 7). After the second injection, the patient’s vision was stable at 20/40-1 and there were no signs of re-accumulation of edema on OCT more than 2 months later (Figure 12; page 7).

Case #2

In another case, a relatively young woman, aged 59 years, presented with a history of hypertension and diabetes and a BRVO. The patient had undergone previous injections of bevacizumab (Avastin, Genentech), followed by laser at 1 month, and triamcinolone acetonide injection 1 month after laser. After these treatments, the patient had been lost to follow-up before presenting to our office 1 year later with 20/400 vision and significant edema (Figure 13; page 7). We injected bevacizumab and 2 weeks later we saw no decrease in edema on OCT (Figure 14; page 7) and the patient’s visual acuity had only improved to 20/200, so we injected the dexamethasone intravitreal implant. One month later, the patient's vision was still 20/200 but there was complete resolution of edema on OCT (Figure 15; page 7) that was maintained through 2 months (Figure 16; page 7). At this point, edema began to reaccumulate (Figure 17; page 7) and vision decreased to 20/400 so we placed focal laser. This patient should have been treated earlier, as the visual acuity did not seem to improve despite good anatomical results with dexamethasone.

Summary

The complexity of the inflammatory response suggests that therapies that target more than one part of the process could be of the greatest clinical benefit; therapies that target only one inflammatory mediator may not break the cycle of disease progression. Therefore, it is important to consider a variety of options for patients who present with macular edema caused by DME, RVO, or uveitis.

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