18.1.1 Introduction

First described by Iwanoff ¹ in 1865, the proliferation of fibrocellular membranes on the inner surface of the macula is a relatively common and well-studied phenomenon. The nomenclature used to describe these membranes has been extensive, including but not limited to surface wrinkling retinopathy, ² cellophane maculopathy, ³ preretinal macular gliosis, ⁴ premacular membrane, ⁵ and macular pucker. ⁶ However, at present, the most commonly used terminology is epiretinal membrane (ERM). This chapter will review the epidemiology, clinical features and diagnosis, pathogenesis, mechanisms of visual impairment, and treatment options for this macular condition.

18.1.2 Epidemiology

With more than 30 million people affected in the United States alone, ERM is one of the most common vitreoretinal disorders. In the adult population, the overall prevalence has been reported to be between 6 and 11.8%. ^{7 ,​ 8 ,​ 9} The prevalence in the population older than 70 years has been reported to be as high as 15.1%. ⁹ Autopsy studies have shown similar rates, with a prevalence of approximately 6% that increases with age. ¹⁰ In healthy adults older than 50 years, the 5-year incidence of developing ERM is 5.3%. ¹¹

Several modifiable and nonmodifiable risk factors for ERM have been identified. Although ERMs have been described in young individuals, ^{12 ,​ 13} the most significant risk factor is age and most cases are diagnosed after the age of 50 years. ^{14 ,​ 15} While ERMs show no gender preference in adults, ^{7 ,​ 9} boys are affected more frequently in the pediatric population. ¹⁶ Ethnicity plays only a minor role, with Asians (particularly Chinese) and Hispanics having a slightly higher prevalence of ERM than Caucasians or African Americans. ^{15 ,​ 17} Presence of ERM in one eye is a major risk factor for its development in the fellow eye, with approximately 20 to 30% of cases being bilateral. ^{2 ,​ 8 ,​ 10 ,​ 11 ,​ 18} The 5-year incidence of developing ERM in one eye if the contralateral eye has ERM at baseline is 13.5%. ¹¹ Other risk factors include high cholesterol, diabetes (with or without retinopathy), penetrating trauma, and smoking. ^{7 ,​ 13 ,​ 17} The incidence of symptomatic ERM following surgical repair of rhegmatogenous retinal detachment is between 4 and 8%. ^{19 ,​ 20 ,​ 21} Lower rates, around 1 to 2%, are seen following prophylactic repair of peripheral retinal breaks. ²²

18.1.3 Clinical Features and Diagnosis

The clinical manifestations of ERM are varied and depend largely on the thickness and contracture of the membrane. In its mildest form, the membrane is thin and virtually transparent with minimal contraction. This is commonly referred to as cellophane maculopathy due to the irregular cellophane-like reflection of light from the surface of the membrane. ^{3 ,​ 18} Although this stage is frequently asymptomatic, symptoms such as metamorphopsia and decreased visual acuity commonly develop as the membrane progresses. Other symptoms less frequently reported include macropsia, photopsia, central binocular diplopia, and interference with vision in the fellow eye. ^{8 ,​ 18} The majority of patients with ERMs have mild symptoms and remain stable or experience little progression over time. ²³

At presentation, visual acuity is typically 20/30 to 20/70, ^{2 ,​ 4} with only 15% of eyes having less than 20/70 vision. ²⁴ Progression of ERM is uncommon but highly variable. One large prospective cohort showed a 28% rate of progression in terms of size of macular involvement over 5 years and a similar 25% rate of spontaneous improvement when classified as mild at presentation. ¹¹ Cases that were more advanced at presentation were even less likely to progress. Other studies have shown similar rates for progression of vision loss, ranging from 13 to 29% over a 2- to 4-year follow-up period. ^{4 ,​ 24} Less than 5% of all patients will progress to visual acuities of 20/200 or worse. ¹⁸ Cases associated with retinal tears are more likely to progress rapidly, although this is still rare. ²⁵

The diagnosis of ERM is clinical, but can be aided by ancillary testing. Biomicroscopic features begin with a glistening light reflex, which can be assessed more easily using red-free light. Later findings include wrinkling of the internal limiting membrane (ILM) and retinal striae (Fig. 18-1a,b). Retinal vessels may show straightening toward the membrane and marked tortuosity under areas of membrane contracture (Fig. 18-1c,d). The normal arcuate pattern of the major arcades may exhibit a reversal of its usual curvature, with vascular segments that point in a radiating fashion toward the contracted membrane. The retina underlying the ERM is typically thickened, sometimes folded, and occasionally demonstrates intraretinal hemorrhages or patches of retinal whitening similar to cotton-wool spots. Rarely, ectopia or even shallow traction detachment of the macula can result. There may be cystoid spaces and occasionally full-thickness holes in the fovea. Pseudoholes of the macula, caused by fenestrations in the ERM overlying or adjacent to the fovea, may also be present (Fig. 18-2).

The most useful ancillary test for diagnosis and assessment of ERM is optical coherence tomography (OCT). OCT clearly highlights ERMs as a preretinal hyperreflective band of varying thickness (Fig. 18-1b). A near-universal OCT finding in ERM is retinal thickening, which varies greatly in its severity. ²⁶ Additional features that can be identified by OCT include multifocal retinal contraction centers, ²⁷ intraretinal cystoid spaces, disruptions of the ellipsoid zone, and small accumulations of hyperreflective (vitelliform) material beneath the fovea (Fig. 18-3). The ellipsoid zone has been of particular interest as disruptions in this layer appear to be predictive of poorer postoperative visual outcomes. ^{28 ,​ 29 ,​ 30 ,​ 31}

Fluorescein angiography may also be a useful adjunct in evaluating ERMs. Fluorescein angiography typically shows alterations in the retinal vascular pattern, such as straightening of vessels and areas of increased vascular tortuosity (Fig. 18-4). Late-phase angiograms may show varying amounts of fluorescein leakage resulting from traction-induced vascular permeability alterations. Additionally, fluorescein angiography may eliminate other possible retinal vascular anomalies that can be confused with ERM formation, such as pseudophakic cystoid macular edema and branch retinal vein occlusion. Finally, fluorescein angiography may rule out the presence of a choroidal neovascular membrane, which may lie occult beneath an ERM. ³

Gass classified ERMs according to the degree of distortion they create in the underlying retina. ³ In Gass’s classification, cellophane maculopathy (grade 0) is defined as a thin transparent membrane without associated retinal distortion. Crinkled cellophane maculopathy (grade 1) denotes membranes that produce minimal distortion of the retina, causing radiating striae and some tortuosity of retinal vessels. Such membranes generally cause mild symptoms of visual blurring with or without metamorphopsia. Macular pucker (grade 2) refers to membranes that are more dense and contracted, often appearing as a grayish sheet and causing marked distortion of the underlying retina with significant metamorphopsia and reduction in central visual function. This grading system has been useful in clinical research but is not widely used in clinical practice.

An important clinical consideration is determining whether an ERM is primary or secondary to other pathology. Posterior vitreous detachment (PVD) is a near-universal precursor to primary or idiopathic ERM formation. ^{4 ,​ 14 ,​ 32 ,​ 33 ,​ 34} Features consistent with idiopathic ERM include older age and better visual acuity compared to secondary membranes. ³⁵ Secondary ERMs can arise from a variety of underlying pathologies, including diabetic retinopathy, retinal vein occlusion, sickle cell disease, retinal detachment, trauma, and ocular surgery (Fig. 18-5). ^{21 ,​ 35 ,​ 36 ,​ 37 ,​ 38} Unlike primary ERMs, secondary membranes may be seen in younger patients ¹⁶ and portend a worse visual prognosis. An important structural difference between primary and secondary membranes is that primary membranes have a more fascial adherence to the retina, whereas secondary membranes are more focally adherent. ³⁹ Additionally, secondary membranes are more frequently found to have associated cystoid macular edema, ³⁵ which contributes to worse visual outcomes.

18.1.4 Pathogenesis and Pathology

The pathogenesis of ERMs is not clearly defined, and several theories exist. Additionally, idiopathic ERMs likely have a different pathogenesis than those secondary to other causes such as trauma or retinal detachment. The two prevailing modern theories for the formation of idiopathic ERMs are (1) glial cell migration through inner retinal microbreaks and (2) transdifferentiation of epiretinal vitreous remnants resulting from vitreoretinal separation with vitreoschisis. Both theories underscore the importance of PVD as the primary pathogenic event.

Idiopathic ERM has long been known to be strongly associated with age-related PVD. ³⁴ Modern studies have documented PVD in 80 to 95% of all cases of ERM. ^{14 ,​ 27 ,​ 32 ,​ 40} Even in cases where a complete separation of the vitreous from the retina is not seen, a partial PVD involving the perifoveal or entire macular area can almost always be identified on ultrasound or OCT imaging. ^{41 ,​ 42} The perifoveal macula is typically the first site of vitreous detachment because the premacular vitreous liquefies early in life (resulting in a premacular bursa or lacuna) and because the perifoveal posterior hyaloid is weakly attached to the thin perifoveal ILM. ^{5 ,​ 41 ,​ 43 ,​ 44}

An early theory concerning the formation of idiopathic ERMs involved migration of glial cells through microbreaks in the ILM. The microbreaks were presumed to be secondary to traction caused by a prior PVD. ^{10 ,​ 45 ,​ 46} Once the glial cells have access to the preretinal space, this theory proposes that they migrate along the retinal surface and proliferate to form patches or sheets of ERM. On histologic examination of ERMs, the cells resemble glial cells ⁴⁷ and have similar immunofluorescence staining. ⁴⁸ While it remains unclear whether the microbreak theory plays a role in most cases of idiopathic ERM, it is likely important in the setting of known retinal tears as retinal pigment epithelial cells are known to be present in higher numbers in membranes in these eyes. ^{48 ,​ 49 ,​ 50}

The second theory of pathogenesis of ERMs proposes that they arise from cells found within the vitreous cortex. This concept dates back to the 1960s, ^{51 ,​ 52 ,​ 53 ,​ 54} but has been further elucidated more recently by Sebag. ^{55 ,​ 56 ,​ 57} Several pathology studies have demonstrated the presence of vitreous collagen interposed between the retina and ERM, ^{33 ,​ 58 ,​ 59 ,​ 60} strongly suggesting a role for vitreous gel in ERM formation. The theory proposes that during the course of PVD, the posterior vitreous cortex splits and thin cortical remnants remain adherent to the ILM. This splitting has come to be known as “vitreoschisis” and occurs because of the well-documented lamellar structure of the posterior vitreous cortex (Fig. 18-6). ^{40 ,​ 56 ,​ 61 ,​ 62 ,​ 63} The key cellular element responsible for ERM formation is thought to be the hyalocyte. Hyalocytes, which are embedded in the posterior vitreous cortex ⁶⁴ (Fig. 18-7), are capable not only of secreting collagen (the main structural component of ERMs) but also of transdifferentiation into myofibroblasts. ^{65 ,​ 66 ,​ 67} This would explain the ability of ERMs to contract and form the characteristic retinal wrinkling of macular pucker.

Although most authorities now believe that vitreoschisis is a critical step in the formation of ERMs, this theory is not accepted by all retinal specialists and investigators. Some studies have failed to show colocalization between areas of retained vitreous cortex following PVD and subsequent ERM formation. ⁶⁸ Regardless of whether ERMs form due to retinal microbreaks or remnant hyalocyte proliferation, both theories emphasize the importance of PVD in the development of this disorder.

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