Most ERMs are peripheral to the macula and produce no visual symptoms (17). However, visual changes may develop if the ERM occurs in the macula. Symptoms include decreased VA, micropsia, metamorphopsia, and monocular diplopia. These may develop either slowly or rapidly (8, 15, 16, 17, 18 and 19). Absolute scotomas are rare (8,20). Mechanisms for visual changes involve ERM opacities overlying the fovea, macular traction and distortion, macular edema, or traction-induced ischemic changes (15, 16, 17 and 18). Severity of symptoms relates to ERM type, with a thin ERM producing the mildest symptoms. Eyes with thin idiopathic ERMs retain 20/200 vision or better in 95% of cases, and commonly maintain 20/50 VA (8, 19, 20 and 21). Thin idiopathic ERMs are generally stable, produce no further decrease in VA after diagnosis in 87% of cases, and undergo no change in clinical appearance after 38 months in 83% of cases (11,19). ERMs associated with proliferative vitreoretinopathy (PVR) are typically thicker and possess an avascular, fibrocellular appearance (Fig. 27-1) (22). Diabetic ERMs are commonly fibrovascular (23). Visual prognosis with these membranes may be limited by associated macular disease. Occasionally, visual symptoms from an ERM may spontaneously resolve after a PVD separates the ERM from the retina (24,25).

Biomicroscopically, ERMs demonstrate a spectrum of clinical signs. In the mildest cases, the ERM may be just a glinting, shifting light reflex on the retinal surface seen only with redfree light (Fig. 27-2) (14,16). In more severe cases, the ERM may be opaque and produce additional fundus changes. Superficial retinal striae may form adjacent to the ERM (Fig. 27-3)
(12,14). Retinal capillaries may become dark, dilated, and tortuous from ERM retinal traction. Major retinal vessels may appear straightened and drawn together (6,14). Typically, retinal dragging, macular heterotopia, and tractional retinal detachment only occur when ERM contraction is severe (Fig. 27-4) (7,12 and 16). Pseudoholes may form (Fig. 27-5) (16,26), and these represent contractions of perimacular ERM that do not extend over the fovea. Pseudoholes must be distinguished from lamellar and full-thickness holes since treatment for each is different. Pseudoholes contain retinal tissue and vessels in their base, have no retinal edge, display no cuff of subretinal fluid, and show no central hyperfluorescence on fluorescein angiography (FA) (12,14). It should be remembered that ERMs can occur in eyes with full thickness macular holes (14). Microaneurysms, blot hemorrhages, and yellow hard exudates may develop, with or without retinal edema (8,12,16 and 20). In cases of severe retinal thickening, one sees shadows of the superficial retinal vessels on the retinal pigment epithelium (RPE) (20). Frequently, FA demonstrates irregular leakage of dye in this region (14). Typical cystoid leakage may not be apparent because of retinal distortion. Retinal cystoid spaces may form as the retinal edema coalesces. One should always consider choroidal neovascularization (CNV) as an etiology for retinal edema and hard exudates in older patients. Cotton wool spots and fluffy white retinal opacities may form. These are felt to be from blockage of axoplasmic flow from retinal traction (27). They usually resolve within several days after ERM removal. Retinal pigmentary changes may occur, namely RPE hypertrophy and atrophy. These are poor prognostic signs and can be from ERM-induced retinal traction or the original event that induced ERM formation (trauma or inflammation). Occasionally, pigment may be seen within the ERM itself (14). This represents ingestion of melanin or hemosiderin by macrophages within the ERM, or the proliferation of RPE cells in the ERM. Intraocular inflammatory cells are usually not seen with the ERM. Their presence suggests an underlying inflammatory etiology (14). A thorough funduscopic examination with peripheral retinal assessment is recommended in all patients with ERM to rule
out retinal vascular disease or the presence of a retinal break. FA may be obtained prior to surgery to document retinal changes, to rule out the presence of CNV, and to exclude the possibility of macular ischemia from retinal vascular occlusive disease. Optical coherence tomography (OCT) is also routinely obtained to document the appearance of the ERM, and it is also employed in the decision-making process of deciding whether or not to perform surgical removal of the ERM. The use of OCT will be discussed in greater detail later in this chapter.

No standard nomenclature is currently used to describe ERMs, although several systems have been proposed. Gass (14) offered the following classification of ERMs based on clinical appearance:

Grade 0: Translucent membranes unassociated with retinal distortion (cellophane maculopathy)

Grade 1: Membranes causing irregular wrinkling of the inner retina (crinkled cellophane maculopathy)

Grade 2: Opaque membranes obscuring the underlying vessels with prominent retinal distortion (macular pucker)

Joondeph (28) stratified ERMs into four grades depending on their appearance and anatomic severity:

Grade 1: Transparent ERMs characterized by changes in the light reflex without any appreciable distortion of the retinal tissue; the membrane is completely transparent and is in its earliest stage

Grade 2: Translucent ERMs obscuring some of the underlying retinal landmarks with mild distortion of the retinal architecture but no distinct striae

Grade 3: Translucent to opaque ERMs showing marked distortion of the underlying retina, frequently with retinal striae

Grade 4: ERMs exhibiting severe retinal distortion with complications such as tractional elevation or macular holes

Depending on the age range and race examined, ERMs occur in about 4% to 18% of the adult population and are bilateral in up to 20% of patients (17, 29, 30, 31, 32, 33, 34 and 35). The stimulus for ERM formation remains poorly understood. In a recent study, no etiology for ERM formation was found in 68% of cases. In the remaining 32%, factors associated with ERM formation included retinal surgery (scleral buckling, laser photocoagulation, cryotherapy, or vitrectomy) (28%), ocular inflammation (2%), ocular trauma (<1%), or retinal vascular disease (<1%) (36). Additional risk factors for ERM are proliferative diabetic retinopathy (PDR), vitreous hemorrhage, and nonretinal ocular surgery such as cataract extraction (2,4-6,8,12,15-17,30,37,38).

Numerous cytokines, receptors, and extracellular matrix proteins have been implicated in ERM formation. In ERMs in diabetic eyes, for example, immunohistochemistry has identified insulinlike growth factor receptor/binding proteins, erythropoietin receptors, hypoxia inducible factor, angiopoietin, and vascular endothelial growth factor (39, 40, 41 and 42). These factors are likely to play a role in the proliferation of endothelial cells and the development of vascular ERMs. PVR membranes have been shown to express inflammatory mediators and growth factors such as interleukins, tumor necrosis factor alpha, urokinase, tissue plasminogen activator, endothelin 1, and platelet-derived growth factor (PDGF) (43, 44, 45 and 46). Interestingly, PDGF induces migration of RPE cells across the retina in vitro and in vivo (47, 48, 49, 50 and 51). Finally, in addition to endothelial cells and RPE cells, glial cells are also likely to play a role in ERM formation through the expression of trophic factors, transcription factors, and cell cycle molecules such as NF-kappaB and cyclin D1 (52,53).

Mechanical stimuli may also play a role in the formation of ERMs. In particular, the process of posterior vitreous detachment (PVD) has been proposed to cause ERM formation by introducing a small amount of trauma or causing discontinuities in the ILM. Several lines of evidence point to an association between PVD and ERM formation. First, the incidence of idiopathic membranes and PVD both increase with age. One study noted a 10-fold increase in ERMs, from 2% to 20%, when two groups of patients, aged 50 and 75 years, respectively, were compared (2). Second, PVDs have been estimated to be present in 80% to 95% of eyes with ERMs (2,6,11,20-22,29,54-56).
Third, Wiznia (19) described 9% of eyes developing an ERM within 7 days of a PVD, and 41% within 18 months, which suggests that a PVD may directly cause ERM formation. Finally, in PVDs associated with retinal breaks, dispersion of RPE cells through the break can contribute to ERM formation.

On the other hand, a PVD is certainly not required for ERM formation. If PVDs are present in 80% to 95% of eyes with ERMs, this leaves 5% to 20% of eyes with ERMs but no PVDs. Moreover, an ERM can develop on the surface of an attached hyaloid membrane (57). These findings, in combination with the low incidence of ERMs superior to the macula (the site where PVDs often first occur), argue against the requirement of PVD for ERM formation (2). Foos (58) suggested that an ERM may actually induce a PVD by disturbing the vitreolaminar interface, and thus PVDs may be both a cause and an effect of ERMs.

Hirokawa et al. (56) studied 250 eyes with idiopathic ERMs and classified them into four categories based on relationship with the vitreous:

Group 1: No PVD

Group 2: Partial PVD but no vitreoretinal adhesion or traction to the area of preretinal macular fibrosis

Group 3: Partial PVD with vitreous traction to the area of preretinal fibrosis

Group 4: Complete PVD

Interestingly, the worst VA was found in eyes in Group 3 as opposed to patients with a complete PVD or no PVD whatsoever. This configuration of vitreous traction to the area of an ERM is now called vitreomacular traction (VMT) syndrome (18). It is readily diagnosed using OCT (as is discussed later in the chapter).

In short, the exact pathogenesis underlying ERM formation is not precisely understood and depends on a combination of chemical and mechanical factors. The stimulus for ERM formation differs in different clinical settings such as PDR or PVR. Whatever the initiating stimulus, ERM formation is likely an immune process of ocular wound healing and extracellular matrix protein remodeling (59,60).

ERMs are fibrocellular sheets of collagen with interspersed cells. Their composition most commonly involves collagen, glial cells, RPE cells, and macrophages (6, 37, 47, 61, 62 and 63). They may vary in thickness and display a spectrum of histologic composition. In one study of 168 ERMs, one of six predominant matrices was present: glial cells (36%), fibrovascular tissue (17%), cortical vitreous (13%), RPE cells (10%), fibroinflammatory tissue (10%), or a combination (14%) (54). All ERMs contain collagen (63

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