Chapter 129 – Epiretinal Membrane
MARK W. JOHNSON
• An avascular, fibrocellular membrane that proliferates on the inner surface of the retina to produce various degrees of macular dysfunction
• Transparent, translucent, opaque, or pigmented membrane on the inner retinal surface
• Tangential traction on the macula
• Partial or complete posterior vitreous separation
• Central vision loss with or without metamorphopsia
• Glistening light reflex
• Retinal distortion
• Macular edema
• Retinal whitening (axoplasmic stasis)
• Intraretinal or preretinal hemorrhage
• Macular hole or pseudohole
The proliferation of fibrocellular membranes on the inner retinal surface in the macular area may occur in otherwise healthy eyes or secondary to retinal breaks and rhegmatogenous retinal detachment, retinal vascular diseases, intraocular inflammation, blunt or penetrating trauma, and other ocular disorders. Common synonyms applied to epiretinal membranes include macular pucker, premacular fibrosis or gliosis, cellophane maculopathy, surface wrinkling retinopathy, and epimacular membrane. Visual symptoms associated with epiretinal membranes range in severity, depending on the opacity of the membrane and the amount of macular distortion induced by the contracting fibrocellular tissue. Surgical peeling of epiretinal membranes in patients who have significant visual symptoms typically results in improved visual acuity and reduced metamorphopsia.
EPIDEMIOLOGY AND PATHOGENESIS
The majority of patients who have idiopathic epiretinal membranes are over 50 years old; however, children and young adults occasionally are affected.   The prevalence of idiopathic epiretinal membrane in consecutive patients seen for eye examination and aged 50 years or older is approximately 6%. Similarly, epiretinal membranes are found in approximately 6% of eyes examined at autopsy, with increasing prevalence in advancing age groups.  Many large series suggest a higher incidence of epiretinal formation in women than in men.    Although idiopathic epiretinal membranes are bilateral in 20–30% of cases,   significant bilateral loss of central vision is uncommon.
The incidence of symptomatic epimacular membrane formation is 4–8% after repair of rhegmatogenous retinal detachment    and 1–2% after prophylactic treatment of peripheral retinal breaks.  Risk factors for the development of macular epiretinal membranes after conventional retinal detachment surgery include older age, preoperative vitreous hemorrhage, macular detachment, preoperative signs of proliferative vitreoretinopathy, large retinal breaks, intraoperative use of cryotherapy, and multiple operations.   
Mild epiretinal membrane formation occurs commonly in association with blunt or penetrating ocular trauma, vitreous inflammatory conditions, retinal vascular diseases that cause chronic intraretinal edema, and long-standing vitreous hemorrhage.  Apart from penetrating trauma, these are uncommon clinical contexts in which to find significant macular dysfunction as a result of epiretinal membrane contracture.
A clue to the pathogenesis of epiretinal membrane formation is the observation that posterior vitreous detachment is present in approximately 90% of eyes that have idiopathic membranes,     and in virtually all eyes that have epiretinal membranes that develop after retinal breaks or rhegmatogenous retinal detachment. It is believed widely that idiopathic epiretinal membranes are produced by retinal glial cells that migrate through defects in the internal limiting membrane to proliferate and contract on the inner retinal surface.   In most patients, such dehiscences in the internal limiting membrane probably are created at the time of vitreous separation. However, idiopathic epiretinal membrane formation is well documented in eyes that have no evidence of posterior vitreous detachment, suggesting that cellular migration may sometimes occur through preexisting defects or thinning in the internal limiting membrane. An alternative proposed mechanism for idiopathic epiretinal membrane formation involves proliferation, fibrous metaplasia, and contraction of hyalocytes left behind on the inner retinal surface after posterior vitreous detachment.
Epiretinal membranes that develop in eyes that have retinal breaks most likely represent a mild form of proliferative vitreoretinopathy caused by retinal pigment epithelial cells that are liberated into the vitreous cavity and proliferate, along with other cellular constituents, to form contractile membranes on the retinal surface. Cellular proliferation stimulated by vitreous inflammation or breakdown of the blood–retinal barrier is a plausible pathogenic mechanism for the remaining types of secondary epiretinal membranes.
The clinical appearance of an epiretinal membrane depends on its thickness and the extent to which it has undergone shrinkage or contraction. In its mildest form, sometimes called cellophane maculopathy, the membrane is thin and transparent, produces no distortion of the inner retinal surface, and leaves the patient asymptomatic. It is detectable on biomicroscopic examination only by an abnormal glistening light reflex from the inner retinal surface ( Fig. 129-1 ).
Thin membranes that have undergone limited contraction or shrinkage produce a series of fine, irregular striations or wrinkles that are confined to the internal limiting membrane and
Figure 129-1 Mild asymptomatic epiretinal membrane. This thin, transparent membrane is detectable only from an irregular, glistening (cellophane) light reflex from the inner retinal surface.
Figure 129-2 Transparent epiretinal membrane here seen to produce significant retinal vascular distortion.
Figure 129-3 Typical appearance of gray–white translucent epiretinal membrane. Notice the partially obscured, distorted retinal vessels and multiple inner retinal striae.
inner retinal tissue. The inner retinal striae typically are most apparent where they radiate out from the margins of the membrane, but they also may develop in a radiating pattern around one or more epicenters of membrane contraction. The fine macular capillaries may be tortuous, even in the absence of large-vessel displacement. Patients who have such membranes may be asymptomatic and have normal visual acuity. Others may complain of vague visual disturbance or mild metamorphopsia, or both. Thicker, more contracted epiretinal membranes produce tangential traction on the full-thickness neural retina, which results in more severe degrees of macular dysfunction. The membrane itself may remain largely invisible, despite significant underlying retinal vascular tortuosity or straightening ( Fig. 129-2 ). In other cases, the membrane is visible as a gray–white translucent membrane that partially obscures visualization of retinal vessels ( Fig. 129-3 ). Some membranes, particularly those that develop subsequent to retinal breaks or rhegmatogenous retinal detachment, are thick and opaque, usually white in color, but occasionally darkly pigmented. Often, a significant component of the membrane’s apparent opacity is whitening of the inner retina that underlies the membrane; presumably this results from traction-induced axoplasmic stasis in the nerve fiber layer ( Fig. 129-4 ).
Patients who have epiretinal membranes that produce full-thickness macular distortion, folding, or puckering typically complain of marked metamorphopsia, loss of visual acuity, and occasionally central photopsia. The tractional effects of the membrane on the retina may cause macular edema, preretinal
Figure 129-4 Severe macular puckering by an opaque epiretinal membrane after retinal detachment surgery. Much of the apparent opacity is due to inner retinal whitening from axoplasmic stasis.
Figure 129-5 Preretinal hemorrhage induced by traction from an epiretinal membrane.
Figure 129-6 Epiretinal membrane with macular pseudohole. The visual acuity is 20/25 (6/8) and slit-lamp biomicroscopy shows retinal tissue in the base of the apparent macular hole.
or intraretinal hemorrhage ( Fig. 129-5 ), or traction macular detachment. Traction-induced detachments of the macula may be subtle, shallow, “tabletop” elevations visible only by contact lens biomicroscopy, or obvious ridges of detachment that pass through the macula. In some patients, an eccentrically located epiretinal membrane may cause lateral displacement of the fovea without detachment from the pigment epithelium (foveal ectopia); this results in relative preservation of visual acuity and symptoms of central binocular diplopia. Other patients who have epiretinal membranes that do not result in severe acuity loss complain of macropsia, presumably because of the crowding of photoreceptors caused by tangential retinal traction.
A defect in the prefoveolar portion of an epiretinal membrane may simulate the appearance of a full-thickness macular hole ( Fig. 129-6 ). A macular pseudohole is a result of the defect in the epiretinal tissue itself, as well as of the anterior and central displacement of the perifoveolar retina (clivus) during contraction of the epiretinal membrane. In some cases, a pseudohole also involves an inner lamellar macular defect that developed at the time of vitreofoveolar separation. Unlike eyes that have true macular holes, those with pseudoholes usually are minimally symptomatic and have normal or near-normal visual acuities. Biomicroscopic clues that help differentiate a macular pseudohole from a true macular hole include the following:
• Wrinkling of the inner retinal surface that surrounds the hole
• Retinal tissue in the base of the pseudohole
• Absence of characteristic features of full-thickness macular holes, such as yellow retinal pigment epithelium (RPE) deposits
in the base of the hole, a halo of neural detachment, and an overlying operculum or pseudo-operculum.
In equivocal cases, optical coherence tomography usually can distinguish between a full-thickness macular hole and a macular pseudohole. Additionally, fluorescein angiography of pseudoholes typically shows either no or only mild hyperfluorescence, in contrast to the prominent transmission defect seen in full-thickness macular holes. Although it is an uncommon mechanism, tangential foveal traction from contraction of an eccentric epiretinal membrane occasionally causes full-thickness macular hole formation. On the other hand, mild degrees of cellophane epiretinal membrane commonly form around idiopathic macular holes, presumably as a wound-healing response.
Rarely, contracture of an epiretinal membrane with a central dehiscence causes anterior prolapse of foveal tissue through the hole in the membrane. Long-standing macular traction or retinal vascular leakage induced by epiretinal membranes may cause atrophic or hypertrophic RPE alterations. Such changes generally are considered poor prognostic signs for visual recovery after surgical removal of the epiretinal membrane. Occasionally, intraretinal lipid (hard) exudates and microvascular changes, such as microaneurysms, are produced by the retinal vascular traction and leakage caused by idiopathic epiretinal membranes. Such findings, however, also may signal the presence of associated pathology, such as a choroidal neovascular membrane or long-standing branch retinal vein occlusion, which may require different management approaches and alter the visual prognosis.
DIAGNOSIS AND ANCILLARY TESTING
The diagnosis of epiretinal membranes is clinical, based on biomicroscopic observation of the physical features detailed in the previous section. In patients who have obvious membranes and clear media, ancillary testing generally is unnecessary. Contact lens biomicroscopy frequently is helpful in the detection of subtle transparent or translucent epiretinal membranes, particularly in eyes that have corneal surface irregularities or media opacities. Furthermore, the excellent resolution and stereopsis afforded by the fundus contact lens permit detailed assessment of the extent to which the macula is distorted, thickened, displaced, or detached by the membrane. Detection of subtle membrane edges by contact lens examination may help to plan the surgical approach. Examination or photography, or both, of the macula with red-free light may highlight glistening reflexes and thereby assist in assessment of the extent of the membrane. The Watzke–Allen (slit-beam) test or aiming beam laser perimetry occasionally may help to differentiate a macular pseudohole from a full-thickness macular hole that complicates an epiretinal membrane. Optical coherence tomography is probably the most reliable ancillary test for distinguishing between full-thickness macular holes and pseudoholes, and for confirming a component of vitreomacular traction.
In eyes that have media opacities that preclude adequate macular examination, fluorescein angiography often is helpful diagnostically, because it demonstrates the retinal vascular distortion that underlies an epiretinal membrane. Although not necessary in every case, angiography also may be valuable to assess the degree of retinal vascular distortion, confirm the presence of foveal ectopia, detect associated macular edema, differentiate pseudoholes from full-thickness macular holes, and highlight underlying RPE changes. Macular edema caused by an epiretinal membrane often can be differentiated angiographically from pseudophakic cystoid macular edema by the irregular and asymmetrical pattern of leakage typically induced by epiretinal membranes. Finally, fluorescein angiography may be critical in the exclusion of associated macular pathology, such as choroidal neovascularization or venous obstructive disease ( Fig. 129-7 ).
The differential diagnosis of epiretinal membranes is given in Box 129-1 . The most common diagnoses that must be differentiated
Figure 129-7 Fluorescein angiography of an epiretinal membrane that complicates an old branch retinal vein occlusion. Notice the collateral vessel formation, in addition to the marked vascular distortion.
from epiretinal membrane and its associated features include the vitreomacular traction syndrome, postoperative cystoid macular edema, and full-thickness macular hole (as opposed to epiretinal membrane with macular pseudohole). Such differentiations are important to make because each of these clinical entities (discussed in detail in the chapters listed) differs from epiretinal membrane in its management and prognosis.
Histopathological and ultrastructural studies have shown that epiretinal membranes consist of a fibrocellular sheet of varying thickness, in which both native vitreous and newly synthesized collagen have been found.         Fragments of internal limiting membrane are seen commonly in surgical specimens,  which suggests that the inadvertent or intentional removal of this membrane does not preclude good visual outcomes.
The cellular elements of most epiretinal membranes include one or more of the following: RPE cells, fibrous astrocytes, fibrocytes, and macrophages. The cell types found in a particular membrane may depend in part on the associated ocular disorders.    Furthermore, the precise identification of the cells of origin within epiretinal membranes is hampered by the ability of each of the common constituent cells to transform into cells with similar morphology and function. The observation that RPE cells are the main cell type in many cases of idiopathic epiretinal membrane is poorly understood but possibly may involve transretinal migration of RPE cells in response to biochemical stimuli. Most of the cell types found in epiretinal membranes have the capacity to assume myofibroblastic properties, which allows them to change shape and cause the membrane to contract. 
No treatment is indicated for mild epiretinal membranes that produce minimal symptoms. Patients whose membranes have more severe characteristics and produce significant visual loss and metamorphopsia usually benefit from vitreous surgery, with peeling of the epiretinal membrane from the surface of the macula. The goal of membrane peeling is to reduce or eliminate the most common mechanisms of visual loss, including macular distortion, traction macular detachment, foveal ectopia, tissue that covers the fovea, retinal vascular leakage with macular edema, and traction-induced obstruction of axoplasmic flow.
Surgical membrane peeling generally is recommended for patients who have substantial visual acuity loss, marked metamorphopsia, or disabling central binocular diplopia. Because epiretinal membranes often show little or no progression after the initial diagnosis, surgery is not performed prophylactically on membranes that cause only mild symptoms. The best candidates for surgery are those who have had membranes for a relatively short time, because the potential for visual recovery decreases with increasing duration of preoperative symptoms. However, excellent visual recovery is not necessarily precluded
Differential Diagnosis of Epiretinal Membranes
Vitreomacular traction syndrome ( Chapter 130 )
Combined retinal pigment epithelium and retinal hamartoma ( Chapter 157 )
Prominent macular light reflex in young patients
Cystoid macular edema (pseudophakic or aphakic) ( Chapter 131 )
Optic disk swelling (juxtapapillary epiretinal membrane)
Idiopathic macular hole ( Chapter 128 )
in patients who have symptoms that have lasted longer than 1 year. Careful preoperative evaluation of all eyes should exclude additional causes of vision loss, such as choroidal neovascularization, macular ischemia from previous retinal vascular occlusion, or other preexisting macular disease.
Conventional pars plana vitreous surgical techniques are used to remove the vitreous gel, which in most cases has separated previously from the posterior retina. An edge of the epiretinal membrane is engaged with a vitreoretinal pick or forceps, or created with a sharp bent-tip needle. After the edge has been developed, the membrane typically is peeled from the retina with forceps, usually as a single piece. Rarely, sites of firm adhesion to the retina are encountered; at these the membrane may be amputated in preference to the creation of retinal breaks in the macular area. Some vitreoretinal surgeons use indocyanine green dye intraoperatively to stain the internal limiting membrane, thereby clarifying the extent of the epiretinal membrane or facilitating the intentional removal of the internal limiting membrane.
The most common surgical complication is progressive nuclear sclerotic cataract, which occurs in 60–70% of eyes within 2 years of surgery, with a much lower incidence in patients under 50 years of age.  Other less common complications include peripheral retinal breaks, rhegmatogenous retinal detachment, posterior retinal breaks, photic maculopathy, and endophthalmitis. Late postoperative recurrence of symptomatic epiretinal tissue occurs in approximately 5% of patients. 
COURSE AND OUTCOMES
Most patients who have epiretinal membranes experience little or no symptom progression after the initial diagnosis, which implies that membrane contraction usually occurs soon after its formation and then stabilizes. Only 10–25% of eyes show a decline in visual acuity over time—rates of progression vary from over several months to many years.   Rarely, epiretinal membranes separate spontaneously from the retina, which results in visual improvement. Approximately 20% of patients who develop macular pucker after scleral buckling experience spontaneous improvement in visual acuity as a result of resolution of the macular edema and relaxation or partial peeling of the epiretinal membrane.
Following surgical removal of epiretinal membranes, most of the macular distortion and all of the retinal whitening resolves, typically within days or weeks of the operation ( Fig. 129-8 ). Associated cystoid macular edema may resolve or persist chronically. Visual improvement of two or more Snellen lines occurs in 60–85% of eyes and may continue for 6–12 months after surgery.   A small number of eyes (2–15%) have worse visual acuity postoperatively.   
Although visual acuity improves and metamorphopsia is reduced significantly in most eyes after epiretinal membrane peeling, the visual function rarely returns to normal. Patients commonly are advised to expect improvement in visual acuity that is approximately halfway between the preoperative acuity and that before the membrane developed. Preoperative factors prognostic of the final visual acuity include the level of preoperative visual acuity, duration of symptoms before surgery, and nature of previous macular damage (such as by retinal detachment involving the macula).  Eyes that have lower levels of preoperative visual acuity typically improve by the greatest number of lines but tend
Figure 129-8 Postoperative appearance of the eye shown in Figure 129-4 . After membrane peeling, the retinal whitening and most of the macular distortion has resolved. The visual acuity improved from 20/100 (6/30) to 20/30 (6/9).
to have lower final acuities than eyes that had better preoperative vision. Although the prognostic value of preoperative macular edema is controversial, fluorescein angiography probably does not help to predict the visual outcome in patients who undergo surgery for idiopathic epiretinal membrane. 
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