Chapter 61
Macular Holes and Epiretinal Macular Membranes
ALAN R. MARGHERIO and PAUL V. RAPHAELIAN
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MACULAR HOLES
RETINAL DETACHMENTS ASSOCIATED WITH MACULAR HOLES
EPIRETINAL MACULAR MEMBRANES
REFERENCES

MACULAR HOLES
Macular holes were considered rare, however, recent data have shown that macular holes are a common cause of unilateral visual loss.1 The first known reported case of a macular hole was by Knapp, in 1869.2 This was followed by reports from other investigators. These early reports were related to traumatic cases only. The first nontraumatic case was documented by Kuhnt.3 Results of pathologic studies followed with the classic paper by Coats in 1907.4 Some macular holes are associated with trauma or myopia, however, most are idiopathic. Idiopathic holes are most commonly seen in Caucasian women in the seventh decade of life who have no apparent predisposing conditions.5–8

DIFFERENTIAL DIAGNOSIS

Stage 1 and early stage 2 macular holes can be difficult to diagnose. They have often been confused with epiretinal macular membranes, pseudomacular holes, lamellar macular holes, macular cysts, cystoid macular edema, vitreomacular traction, adult vitelliform degeneration, bull's-eye maculopathy, and idiopathic juxtafoveal telangectasia.

Macular holes usually progress through several stages. A staging method for the development of idiopathic macular holes was originally described by Gass.9 In 1995, he refined his staging classification based on more recent surgical and pathologic data. A modified summary is presented here. Stage 1 occurs when the foveal depression is either decreased or absent, and a yellow ring or spot is present. Stage 2 is marked by early, full-thickness hole formation that is less than 400 μm in diameter. Stage 3 is reached when the hole is fully developed, greater than 400 μm in diameter without a Weiss ring. When the vitreous detaches and a Weiss ring is present, the hole is at stage 4.

Macular holes can resolve spontaneously. This most commonly occurs in stage 1 but has been reported for stage 2 holes as well. The resolution occurs when the posterior hyaloid separates. Traumatic macular holes have also been reported to resolve on their own. Because early holes and traumatic holes may resolve, many surgeons feel it is wise to observe them for a few months. If vision deteriorates or the hole progresses, vitreous surgery is indicated.

The visual acuity of patients with macular holes is variable. Typically, the acuity correlates with the stage of hole development. In stage 1 and early stage 2 holes, the acuity usually falls between 20/25 and 20/60. Late stage 2 and stage three holes fall between 20/70 and 20/200. Stage 4 holes and chronic macular holes (holes greater than 1 year's duration) have visual acuities between 20/400 and counting fingers.

Macular holes are most commonly unilateral.5 However, patients with unilateral macular holes, regardless of stage, should be informed that a hole can develop in their other eye. The incidence of hole formation in the fellow eye in patients with unilateral macular holes is 7%.5 Symptoms of impending holes should be explained to these patients. Symptoms include visual distortion, decreased visual acuity, and changes observed with home Amsler grid testing.

DIAGNOSIS

To diagnose a macular hole accurately, all available methods should be used to rule out other clinically similar conditions. First, the fundus should be examined carefully to determine if there appears to be a clinical posterior vitreous separation, if there is evidence of vitreomacular traction, or if an operculum is present. Next, using a very fine slit beam, the macula should be examined carefully to determine if there is any tissue bridging the apparent macular hole. Also, it should be noted if the edges of the hole are everted or irregular and if there are small, yellowish bodies near the base of the suspected hole. These signs lead to the diagnosis of a true macular hole rather than a pseudohole or other simulating lesion.10

Fundus photography and fluorescein angiography are useful tools in the diagnosis of a macular hole. Stereo color photography helps document the stage, size, and configuration of the hole so that any changes may be detected easily. However, it is important to obtain similar stereo images for serial comparison. Monochromatic photography with use of 490- to 610-nm filters is another useful tool. Monochromatic photos help identify subtle vitreoretinal interface changes.11 Fluorescein angiography, although useful in differentiating a true macular hole from a simulating lesion, can be misleading. The increased transmission of choroidal fluorescence that is associated with macular holes can reverse spontaneously.12 It may also reverse after successful surgical treatment.13

Functional testing has been used to help differentiate pseudoholes or other lesions from true macular holes. The Watzke-Allen sign was one of the first such functional tests.14 This test is performed by presenting a narrow slit beam over the suspected macular hole. The patient is then asked to describe what he or she perceives. If the patient describes a break in the line, a full thickness hole should be suspected (Fig. 1). Another method of performing this test is to pass the slit beam slowly over the macula from varying angles. If the patient perceives a break in the line, at any time, the test is considered to be positive (i.e., there is a full-thickness macular hole).

Fig. 1 A. Slit lamp light is focused on the retina using the widest possible slit that fits within margins of the macular cyst or hole. B. Appearances of slit beam when focused on macular cyst or hole of patient. (Margherio R, Trese MT, Margherio A, et al: Surgical management of vitreomacular traction syndromes. Ophthalmology 96:1437, 1989)

Another functional test may be performed by aiming the beam of the argon or dye laser. With visualization of the macular region, microperimetry is performed over the macular area. This is accomplished by presenting the 50-μm aiming beam, set at low intensity, to the area of the suspected macular hole and surrounding retina. Cases with full-thickness holes will demonstrate an absolute scotoma in the area of the hole. There will be a relative scotoma at the elevated rim of the neurosensory retina. With other lesions, either no scotoma or only a relative scotoma is seen. In describing the relative scotoma, the patient will usually say that the spot is “present, but different.” The Amsler grid has not been found to be of much value in differentiating true holes from pseudoholes because generally the absolute scotoma in patients with full-thickness macular holes is quite small.

The scanning laser ophthalmoscope (SLO) and the focal electroretinogram have been described as useful for differentiating true holes from other lesions.15–18 Laser biomicroscopy has also been used by some investigators to help demonstrate the fine retinal architecture at the fovea. With this technique, the vitreoretinal interface may be seen with greater detail. This is partly because of the enhanced illumination and the use of monochromatic green light.19,20 Also, some authors believe that a carefully performed B-mode ultrasound can help define the vitreoretinal relationships better than a clinical examination alone.

Optical coherence tomography or OCT is a relatively new tool used to diagnose macular lesions. It provides a unique view of the vitreoretinal architecture. OCT is particularly useful in diagnosing lamellar holes. With improvements in resolution and more widespread use, OCT will lead to new advances in the diagnosis and pathogenesis of macular holes (Fig. 2).

Fig. 2 Optical coherencd tomography of stage 2 macular hole with a visual acuity of 20/70.

PATHOGENESIS

The evidence incriminating vitreomacular traction in the pathogenesis of idiopathic macular holes is based on the correlation of clinical and surgical observations with known histopathology and OCT findings. Gass9 proposed that idiopathic macular holes begin from a tractional dehiscence of the umbo with minimal loss of photoreceptors. The tractional forces may be tangential, anteroposterior, or circumferential.21 These forces may resolve with a spontaneous vitreomacular separation22 but in the majority of cases the continuing tractional force will result in a full-thickness macular hole.

Early investigators focused on anteroposterior vitreomacular traction. Schepens,22 in 1955, was the first investigator to relate anteroposterior vitreous traction to the production of macular holes. Subsequently, other authors have made similar observations.6,23,24 Later studies indicated that in most cases, tangential traction plays a major role in the development of idiopathic full-thickness holes.13,25–27

On the basis of histopathologic studies, Foos28 demonstrated the presence of a vitreofoveal attachment that may be involved in the formation of macular holes. The opercula of macular holes obtained during vitrectomy for macular holes have been examined histologically. Macular hole opercula are rarely composed of true retinal tissue.29 The absence of cellular and fibrocellular fragments in the vitreous specimens obtained suggests that mechanisms other than cellular proliferation are important in the generation of the tractional forces required to create a macular hole.

Current theory, based on OCT, biomicroscopy, histology, and surgical experience, suggests that the posterior hyaloid applies traction to the foveola/umbo and causes it to go on stretch. The umbo dehisces because it is the thinnest point in the fovea. Then, according to the hydration theory proposed by Tornambe,30 the middle and inner retina absorbs vitreous fluid at the exposed edges of the hole and begins to swell. The hole enlarges because of a lateral extension of fluid into the outer plexiform layer. There is no mechanical loss of photoreceptors. Moreover, there is no microdetachment beyond the cuff of the hole. Once the inner retina is breached, the macular hole progresses from stage two to three by hydration of the fovea and perifoveal macula. Eventually, the posterior hyaloid separates completely and stage 4 is reached.

Additional support of the macular hole hydration theory may be derived from a report from Chung and Spaide,31 in which emulsified silicone oil migrated (or was absorbed) into the middle layers of the macula, around a successfully closed hole. The authors suggest that internal limiting membrane (ILM) peeling may have allowed the emulsified oil to infiltrate the retina into the macula at the exposed areas of the peel. However, the oil may have entered the middle retina layers through the exposed edges of the macular hole in a fashion similar to vitreous fluid proposed by the hydration theory.

TREATMENT

Stage 1: Impending Macular Holes

The role of vitrectomy for the prevention of full-thickness macular holes is still uncertain. The possible benefits of mechanically removing vitreous traction must be weighed against the known risks. These include retinal detachment, infection, nuclear sclerosis, and the creation of a full-thickness macular hole secondary to surgical manipulation.13,27,32,33 Surgical objectives for stage 1 macular holes consist of removing all tangential and anteroposterior vitreous traction on the foveal region. This must be accomplished without creating a full-thickness hole secondary to forces related to the surgical manipulation.

Some authors have commented on the importance of a posterior vitreous detachment in the pathogenesis of a macular hole.34,35 It is difficult to determine the vitreoretinal relationship preoperatively, even with careful slit-lamp evaluation. OCT testing can sometimes be helpful. However, the vitreomacular relationships are more accurately determined intraoperatively with use of oblique intraocular illumination and by noting the effect of gentle tractional forces on the macula during the vitrectomy. In some cases, what was thought to be a posterior vitreous separation preoperatively was actually found to be a large, optically empty space (Fig. 3).

Fig. 3 Large syneretic cavity simulating a complete posterior vitreous separation but with thin layer of posterior hyaloid still attached to posterior pole (arrow). (Margherio RR: Epiretinal macular membranes. In Albert R, Jakobiec EA, eds. Principles and Practice of Ophthalmology, Vol 2. Philadelphia: WB Saunders, 1993. Copyright 1990:919–925, S.W. Cochran)

Tissue surgically peeled from the macular region in cases of impending macular hole has been found to be clinically consistent with posterior hyaloid. This finding was supported by electron microscopic examination of the tissue (Fig. 4).13,36 This observation is supported by the work of Kishi and Shimizu.37 They noted a large, optically empty space that appeared to be a complete posterior vitreous detachment in eyes with advanced liquefaction of the vitreous. They termed this area the posterior precortical vitreous pocket (PPVP). They found this pocket in 48 of 84 eyes with either an incomplete or no posterior vitreous detachment, and in 19 of 36 eyes with a posterior vitreous detachment. They noted that in eyes with advanced liquefaction of the vitreous, a large PPVP appeared to be a complete posterior vitreous detachment. In all of their postmortem cases, the posterior layer of the PPVP was found to be a thin layer of cortical vitreous. The presence of this PPVP strengthens the hypothesis that contraction of remaining attached cortical vitreous causes tangential traction on the macula, which gives the clinical appearance of an idiopathic macular cyst or hole.13,25,26,38 These impending holes or cysts' have been noted to resolve with spontaneous or surgical stripping of the membranes.13,25

Fig. 4 Transmission electron micrograph shows folded collagen (arrowhead) conshstent with posterior hyaloid (morphologically type 2 collagen). Adherent to the denser posterior surface is a cellular pseudopod (double arrowheads). The cell body is not present in this grid. (Margherio R, Trese MT, Masgherio A, et al: Surgical management of vitreomacular traction syndromes. Ophthalmology 96:1437, 1989)

In the management of eyes considered to be at high risk for the development of full-thickness macular holes, emphasis must be placed on careful follow-up. Patients demonstrating these characteristics should be followed on a monthly or bimonthly basis. Of the patients followed in this manner, approximately one-third will develop a spontaneous vitreomacular separation with an improvement in symptoms. However, if the vision continues to deteriorate to the 20/50 to 20/70 level, surgical intervention should be considered because many of these eyes are likely to progress to full-thickness holes.39 Moreover, better visual acuity results can be achieved with early intervention.

Vitreous Surgery for Full-Thickness Holes

Prior to the landmark paper of Kelly and Wendel,40 full-thickness macular holes were considered to be untreatable. Because there appeared to be an irretrievable loss of foveal tissue, it was assumed that treatment would be of little or no benefit. Once they proved that full-thickness holes could be closed with subsequent improvement in vision, histopathology followed, with proof that photoreceptors were spared in macular hole formation.

Vitreous surgery for macular holes has been refined over the last few years. A standard three-port core vitrectomy is performed. The posterior hyaloid is detached from the retina with the vitrectomy instrument switched to suction mode, at a level of 200 mm Hg. The vitrector port is then placed near the nasal edge of the optic nerve and suction is applied. The posterior hyaloid is engaged and the vitrector tip is pulled anteriorly to promote a posterior hyaloidal separation. A hyaloidal separation is only achieved when a Weiss ring is visualized. After successful detachment of the posterior hyaloid, a more peripheral vitrectomy is performed to provide maximal space for gas tamponade.

An air–fluid exchange is performed with the aid of a soft-tipped cannula. Confirmation of posterior hyaloidal separation can be determined at this time. The soft-tipped cannula is placed near the optic nerve and suction is applied. If the tip engages residual hyaloid, it will bend toward the retina in a fishhook fashion. If residual hyaloid is noted, the vitreous cavity is refilled with fluid and another attempt is made to separate the posterior hyaloid. After the air fluid exchange is completed, 5 to 15 minutes are allowed to elapse for fluid reaccumulation resulting from surface tension. The residual fluid is removed with the soft-tipped cannula and the sclerotomies are trimmed free of vitreous and closed. The air in the vitreous cavity is exchanged with either 16% C3F8 or 20% SF6. The patient is instructed to remain in a face-down position for up to 14 days.

ILM peeling has been reported to be a beneficial adjunct to macular hole surgery. Many surgeons have reported high hole closure rates and excellent visual results.41,42 However, peeling the ILM is the most difficult maneuver in macular hole surgery. New instruments have been designed to aid the surgeon. Vital dyes such as indocyanine green and trypan blue have also been used to help identify the ILM for peeling.43,44

We have found that the ILM does not have to be peeled for surgical success in most cases.45 Moreover, in 2002, Spaide46 reported three cases of successful macular hole surgery with limited vitrectomy over the macular hole without ILM peeling. Similarly, in 2003, Dori et al.47 reported a 100% closure rate without ILM peeling in 50 eyes with stage 2 holes. Ninety-eight percent of these eyes had visual acuity results of 20/50 or better.

Additional complications may occur if ILM peeling is performed. ILM peeling-associated complications include phototoxicity, retinal hemorrhage, RPE defects, and nerve fiber layer defects. Moreover, several recent reports have suggested that indocyanine green, used as an adjunct to ILM peeling, may cause delayed photochemical damage to the RPE.48,49 Indocyanine green has been shown to be present in the fundus and optic disc for up to 12 months after use.50–52 Haritoglou et al.53 found that indocyanine green may alter the cleavage plane in the innermost layers of the retina that may result in less improvement in vision and unexpected visual field defects. Therefore, because of the increased potential for complications, we recommend ILM peeling only for stage 4 macular holes, chronic macular holes, previous surgical failures, and late reopened macular holes.

Laser

Photocoagulation has been used as an adjunct to help repair macular holes. Outpatient laser treatment, combined with fluid gas exchange has been used successfully to close macular holes after initial surgical failures. In 1998, Ohana and Blumenkrantz54 used slit-lamp–based yellow laser to close 13 of 15 holes. Ikuno et al.55 used one spot of argon green to the RPE at the base of the hole to close 12 of 13 holes. Intraoperative endolaser has also played a role in treating macular holes. Woog-Ki et al.56 used one spot of very light endolaser to the RPE at the base of the macular hole and closed 8 of 8 holes. Kwok et al.57 used endophotocoagulation to the base of the hole to help close macular holes in 3 of 4 associated with myopic retinal detachments.

We have reserved the use of endolaser to stage 4 holes, chronic holes, initial surgical failures, and late reopened holes in which the ILM is not peeled or is only partially peeled. We know from experience that these cases are likely to fail if the ILM is not peeled or an endolaser is not used. We use an argon green endolaser at very low power and short duration. A test spot is placed in the macula in a safe zone near an arcade vessel. Laser power is slowly increased until a faint grey blanching of the RPE is achieved. The probe is then placed over the hole and very close to the RPE to minimize the spot size. One spot is then applied to the RPE through the opening in the hole. We have had excellent success with this technique. The application of laser to the RPE at the base of the hole may stimulate the RPE to pump out the intraretinal fluid proposed by Tornambe's macular hole hydration theory.30

Complications

Complications associated with macular hole surgery, in addition to those that may occur with any intraocular procedure, include elevated intraocular pressure, peripheral retinal tears, retinal detachment, lens opacities, visual field defects, vitreous hemorrhage, and late reopenings.58 Some of these conditions will resolve spontaneously or with treatment; others may result in permanent loss of vision. Most of these eyes will develop visually significant nuclear sclerotic lens opacities within 1 year.58–61

CHRONIC MACULAR HOLES

Chronic macular holes are generally considered to be stage 3 or stage 4 holes that have been present for more than 1 year. These holes, possibly due to long-term intraretinal fluid accumulation, epiretinal membrane formation, and RPE atrophy are more difficult to close compared to acute macular holes. Fortunately, because of increased awareness of macular holes by the general ophthalmic community, chronic holes are becoming far more rare. Visual improvement may occur with successful hole closure. However, these improvements are generally not as pronounced as those seen with acute macular holes. Roth et al.62 were able to close 9 of 11 chronic holes in their series, with a mean postoperative vision of 20/100. ILM peeling, adjuvants, and endolaser may assist in macular hole closure in this challenging subgroup.

TRAUMATIC MACULAR HOLES

Traumatic macular holes are much less common than idiopathic macular holes. Most develop from significant blunt trauma to the eye. These holes are commonly preceded by Berlin's edema. Traumatic macular holes may close spontaneously,63,64 therefore, these holes should be observed for 3 to 6 months before surgery is contemplated. Surgical closure rates for traumatic holes are similar to idiopathic macular holes. Autologous plasmin enzyme has been used as an adjuvant to help close pediatric and adult cases.65,66 Adult traumatic holes have also been successfully closed without the use of adjuvants.67

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RETINAL DETACHMENTS ASSOCIATED WITH MACULAR HOLES
Retinal detachments secondary to macular holes are exceedingly rare, but they pose a challenging clinical problem. The incidence has been reported to range between 0.6% and 4%.68,69 Most rhegmatogenous detachments that appear to be the result of macular holes are actually secondary to peripheral holes. In the presence of a retinal detachment involving the macula, the normal thinning of the retina in the foveal region may give the appearance of a full-thickness macular hole when none is present. If a detachment involving a peripheral hole is combined with a suspected macular hole, the detachment can be treated in a standard fashion, ignoring the hole.68,70,71 In most cases, the suspected macular hole will close after successful retinal reattachment.

Retinal detachments associated with true macular holes are seen most frequently in highly myopic eyes.7,72 These detachments may only extend out from the macular hole to the major arcade vessels or slightly beyond. The association with high myopia probably accounts for the higher reported incidence of detachments caused by macular holes in Asians and other races with a large number of highly myopic people. Morita et al.,7 in a review of 209 eyes with retinal detachment secondary to macular holes, noted the factors relating to retinal detachment in macular holes to be: the degree of refractive error, the severity of myopic chorioretinal change, and the presence of posterior staphyloma.

Many methods for repairing detachments secondary to macular holes have been reported. These techniques can be categorized as either transscleral or transvitreal. The transscleral methods include macular diathermy or cryopexy, macular buckling, sling procedures, scleral resection, or some combination of these with equatorial scleral buckling.68,73–75 Transvitreal techniques include vitrectomy with gas tamponade, or vitrectomy with silicone tamponade.76–81

With the advent of vitreous surgery, membrane stripping, and long-acting gases, most methods of mechanically indenting the macula as the initial procedure of choice have been abandoned. Most of these mechanical methods caused complications because of the embarrassment of the retinal vasculature and physical damage to the optic nerve or its blood supply. Also, treatment in this region with diathermy or cryotherapy, in addition to causing extensive damage to retinal photoreceptors, could damage the optic nerve and adjacent structures. Kuriyama and colleagues82 evaluated the results obtained with both the transvitreal and transscleral methods in 250 eyes. They found that the initial results obtained with the transscleral methods were better (83% versus 56% for transvitreal methods), but that the final success rate of 95% was the same regardless of which approach was selected initially.

Today, most retinal surgeons choose pars plana vitrectomy and gas tamponade as the initial procedure to treat detachments associated with macular holes.76–81 This technique has the best visual prognosis. A careful and thorough peeling of the cortical vitreous and posterior hyaloid is accomplished with use of a soft-tipped cannula or vitrector. Any epiretinal membrane in the area should be peeled. Drainage of subretinal fluid can be accomplished through the existing macular hole or through a posterior retinotomy. A gas-fluid exchange is then performed with one of the long-acting gases. The patient is instructed to maintain a face-down position for 2 weeks. If a recurrence of the detachment occurs, the possible causes of the failure must be carefully evaluated. Endolaser to the RPE at the base of the hole in conjunction with repeat vitrectomy with gas fluid exchange has recently been shown to be effective in highly myopic, macular hole-related detachments.57

SUMMARY

Our identification, understanding, and treatment of macular holes has advanced tremendously since this chapter was first written. Optical coherence tomography has allowed us to examine macular holes in ways that were not possible just 10 years ago. We expect many more exciting advances to be made with OCT in the future as OCT technology improves and more macular holes are examined. The role of ILM peeling in the treatment of macular holes is still controversial, as is the use of indocyanine green dye. Vitreoretinal surgeons have demonstrated that all macular holes can be closed, with subsequent improvement in vision. Early macular holes have the best prognosis for 20/40 or better vision. With early diagnosis and prompt treatment, more patients will regain excellent vision.

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EPIRETINAL MACULAR MEMBRANES
Epiretinal membranes can be divided into those that are idiopathic and those that are secondary to another clinical condition. The proliferation of epiretinal membranes on the inner retinal surface along the internal limiting membrane was first described by Iwanoff in 1865.83 Epiretinal membranes are relatively common. In 1971, Roth and Foos84 reported that in a series of autopsy eyes, epiretinal membranes were present in 2% of patients at age 50 and in over 20% of patients at age 75. Clarkson et al.,85 in a review of some 1612 postmortem eyes, noted epiretinal membranes in 0.7% of eyes that had not undergone previous ocular surgery. Pearlstone86 reported an incidence of 6.4% in 1000 consecutive routine eye exams in patients older than age 50, with 20% being bilateral. Other authors report bilateral involvement in 10% to 20% of cases.87–89

The wrinkling of the retinal surface caused by epiretinal membranes in the macular region has been termed surface wrinkling retinopathy,84 macular pucker,90–92 cellophane maculopathy,24,93 wrinkling of the ILM,94 preretinal macular fibrosis,94,95 epiretinal macular membrane, primary retinal folds,96 internoretinal fibrosis,97 idiopathic preretinal macular gliosis,88,98,99 undetected central retinal vein occlusion,100 and silkscreen retinopathy. The term macular pucker has most frequently been applied to the condition when retinal surface wrinkling occurs after reattachment of a rhegmatogenous retinal detachment. This condition complicates 4% to 8% of otherwise successful primary retinal reattachments.101,102

The presence of epiretinal membranes in the macular region has been associated with numerous clinical conditions, including retinal tears and holes, previous retinal detachment repair, other intraocular surgery, cryopexy, photocoagulation, nonproliferative retinovascular disorders, trauma, ocular inflammatory disorders, certain proliferative retinopathies, vitreous hemorrhage, congenital disorders,103 as well as idiopathic or spontaneous development. The membranes develop as a result of the proliferation of cells and collagen on the surface of the retina. The clinical appearance depends to some degree on cell type, membrane thickness, and presence or absence of vessels. Vinores et al.104 found a correlation between the disease process and the amount of extracellular matrix, with proliferative vitreoretinopathy having a thicker membrane than post detachment macular pucker, which in turn was thicker than an idiopathic macular pucker. These ultrastructural findings correlate well with the clinical appearance of the various entities.

CLINICAL FEATURES

Patients with epiretinal membranes peripheral to the macula are generally asymptomatic. However, when the membranes involve the macula or are perimacular, the type and degree of symptoms experienced will vary. Symptoms depend on the membrane thickness, the degree of retinal distortion caused by the overlying membrane, the presence or absence of significant traction, which can cause a microdetachment of the posterior pole, and the presence or absence of edema in the macular and perimacular regions. Thin epiretinal membranes usually cause few symptoms. The condition appears to be relatively stable or slowly progressive, with only a small number (approximately 5%) obtaining a vision of 20/200 or worse.87,105,106 In more advanced cases there is a reduction in vision, micropsia, metamorphopsia, Amsler grid distortion, and occasionally monocular diplopia. Spontaneous separation of an epiretinal macular membrane, although uncommon, can occur. After separation, there is a general decrease in symptoms and a concomitant improvement in visual acuity.96,107–109

The clinical appearance is variable and may present as only a mild sheen or glint in the macular region that can best be seen with red-free or monochromatic green or blue light (Fig. 5). In more severe cases, there is increased vascular tortuosity and the perimacular vessels are seen to be pulled toward an epicenter, with striae and heterotopia of the macula. The superior and inferior arcuate vessels are also closer together and straighter than in an uninvolved eye. Other findings that may be present include small intraretinal hemorrhages, cystic changes in the macula, macular edema, and cotton-wool spots.110 Pseudoholes or macular cysts have been noted in up to 8% of idiopathic cases (Fig. 6).25,88 Thin membranes may be completely translucent, whereas thicker membranes are frequently opaque or pigmented and generally obscure details of the underlying fundus (Fig. 7).110–112 The thicker and occasionally pigmented membranes are often seen after retinal detachment surgery, severe inflammatory conditions, and trauma. An apparent posterior vitreous separation has been reported by most authors to exceed 75% in cases of idiopathic epiretinal membranes.84–88,93,104,105,113–117 It is sometimes difficult to accurately determine the vitreoretinal relationships preoperatively.

Fig. 5 A. An idiopathic epiretinal membrane in a 65-year-old man. Visual acuity was 20/25. B. Black-and-white fundus photograph taken with green 540-nm filter. Note increased definition of epiretinal membrane. (Margherio RR: Epiretinal macular membranes. In Albert R, Jakobidc EA, eds. Principles and Practice of Ophthalmology, Vol. 2. Philadelphia: WB Saunders, 1993:919–925)

Fig. 6 A. Idiopathic epiretinal membrane with macular pseudohole in a 35-year-old woman. B. Postoperative appearance with disappearance of macular pseudohole and improvement in vision from 20/100 to 20/40. (Margherio RR: Epiretinal macular membranes. In Albert R, Jakobiec EA, eds. Principles and Practice of Ophthalmology, Vol. 2. Philadelphia: WB Saunders, 1993:919–925)

Fig. 7 A. Preoperative appearance of thick epiretinal membrane in 10-year-old boy after trauma. B. Postoperative appearance after removal of epiretinal tissue. Vision improved from counting fingers to 20/100. (Margherio RR: Epiretinal macular membranes. In Albert R, Jakobiec EA, eds. Principles and Practice of Ophthalmology, Vol. 2. Philadelphia: WB Saunders, 1993:919–925)

Clinical testing, in addition to visual acuity, most commonly involves fluorescein angiography and ocular coherence tomography. Fluorescein angiography can show retinal vascular tortuosity, straightening, and leakage, as well as cystoid macular edema (Fig. 8). OCT typically demonstrates retinal folding, increased macular thickness, cystoid macular edema, traction macular retinal detachment, and both lamellar or macular hole formation (Figs. 9, 10, and 11). Sine Amsler chart testing may help quantify metamorphopsia in eyes with macular distortion.118 Abnormal macular function has been shown using both focal and multifocal electroretinography.119,120

Fig. 8 A. Black and white photograph taken with a green 540-nm filter, showing dragging and distortion of the macular vessels. B. Fluorescein angiogram. Note distortion of macula and vessels, with associated vascular leakage and cystoid macular edema.

Fig. 9 Optical coherence tomography of left macula with epiretinal membrane (arrow) and visual acuity of 20/100. Note retinal thickening and folding.

Fig. 10 Optical coherence tomography of left macula in eye with visual acuity of 20/40. Note epiretinal membrane with vitreous adherence (arrow), macular hole, and intraretinal edema around the hole.

Fig. 11 Optical coherence tomography of thickened and folded right macula in eye with 20/300 visual acuity. Note traction retinal detachment (small arrow) and posterior vitreous detachment with avulsed piece of epiretinal membrane (large arrows).

PATHOLOGY

The cellular origin of epiretinal membranes has long been debated, and almost every possibility has been considered. In 1865, Iwanoff83 implicated the endothelial cell in the formation of the membranes.83 Manschot,121 in 1958, thought that the membrane was an extension of the Müller cell processes, whereas Wolter122 considered the cells to originate from fibroblasts in the vascular connective tissue. Smith123 suggested that the cells in the membrane originated from the pigmented or nonpigmented cells of the pars ciliaris, retinal pigment epithelial (RPE) cells, mesodermal elements of the vascular system, normal vitreous cells, inflammatory cells within the vitreous, or retinal glial cells. In 1962, Kurz and Zimmerman124 believed that the cells originated from migration of RPE cells. Ashton125 later suggested that they originated from a transformation of vascular mesenchymal cells into fibroblasts, and in 1969, Von Gloor126 proposed that hyalocytes were the cells of origin.

The development of vitreous surgery has provided an opportunity to advance our understanding of the clinicopathologic relationships of epiretinal membranes. Constable127 reported on the histopathology of membranes obtained by open-sky vitrectomy. He found proliferating fibroblasts interspersed with extracellular material and clumps of pigment. Since then, numerous authors have attempted to characterize the cells of origin based on the suspected etiology of the membrane obtained by pars plana vitrectomy. The general consensus was that membranes in eyes that had retinal breaks or previous detachments were composed of cells of RPE origin, and that cells of glial origin predominated in the thin idiopathic epiretinal membranes.36,104,124–134 Some studies have demonstrated a high incidence of RPE type cells even in the idiopathic epiretinal membranes.135–138 This is supported by Vinores and colleagues,104 who studied the ultrastructural and electron immunocytochemical characterization of cells in epiretinal membranes. Their work suggests that both RPE cells and retinal glial cells are most likely to be the major participants in the pathogenesis of epiretinal membranes.104 Foos139 suggested that the glial cells found in the thin, idiopathic membranes were derived from the glial cells of the superficial retina, which had migrated through breaks in the internal limiting lamina to proliferate on the retinal surface. This hypothesis was subsequently supported by Bellhorn and associates.140 The dispersion of RPE cells on the retinal surface has been demonstrated clinically and experimentally in cases of retinal breaks and detachment.141–143 However, the finding of RPE cells in idiopathic membranes is more difficult to explain. Smiddy and colleagues136 suggest that the RPE cells gain access to the retinal surface by various methods, including migration through occult breaks, inactivation of developmental rests of RPE cells already on the surface of the retina, transformation from other cell types, and transretinal migration. Stern and co-workers144 suggested that the contractive forces of the membranes were related to their constituent cell types and were not dependent on intercellular collagen, as suggested by previous investigators.145

While the exact mechanism or combination of mechanisms is yet to be elucidated, recent studies have shed some light on the biochemical processes involved with epiretinal membrane proliferation. Armstrong and colleagues146 have demonstrated the presence of both vascular endothelial growth factor and tumor necrosis factor alpha in surgically excised membranes. Tissue-type plasminogen activator, plasminogen, and urokinase, which are involved in extracellular matrix breakdown, also have been found in epiretinal membranes.147,148 Recently, chemokine receptors mediating cell migration were shown to be expressed on both retinal pigment epithelium and epiretinal membranes.149 Consequently, the sequence of vascular endothelial growth factor-mediated activation of the signal transduction pathway, leading to extracellular matrix breakdown and RPE cell migration, may be involved in the formation and proliferation of some epiretinal membranes.

TREATMENT

The majority of patients with epiretinal macular membranes have symptoms that are mild and either nonprogressive or slowly progressive and treatment is rarely indicated. In a few cases, the membrane may spontaneously release, with a marked decrease in symptomatology and improvement in acuity. For patients with significant symptoms and substantially reduced visual acuity, bimanual vitrectomy with epiretinal membrane peeling can diminish the severity of the symptoms and improve acuity in 75% or more of cases.

There is no effective treatment available for mild forms of epiretinal macular membranes. In 1978, Machemer150 first reported on the surgical management of advanced cases of epiretinal macular membranes using the technique of pars plana vitrectomy. Subsequent authors reported on larger series and attempted to identify preoperative factors that appeared to influence the postoperative visual prognosis.25,113,114,133,134,151–171

A conventional three-port pars plana vitrectomy technique is now well-established in the removal of epiretinal membranes. Technique and instrumentation have improved over the years, almost eliminating complications such as iatrogenic retinal tears and detachments. The problems of membrane recurrence172 and accelerated nuclear sclerosis still remain unsolved. Also, although improvement in acuity is achieved in most cases, it may be less than expected, and it is rare to completely eliminate metamorphopsia. This appears to be especially true in eyes with relatively good preoperative vision.167,173 Therefore, when vision is better than 20/70, surgery should be approached with caution.

The surgical technique for removing epiretinal macular membranes includes first performing a pars plana vitrectomy (Fig. 12). After vitrectomy, the tip of a 20-gauge microvitreoretinal blade is bent approximately 80 degrees. (Alternatively, a 23-gauge 1.5-inch needle can be bent toward its lumen. The needle is then attached to a tuberculin syringe and filled with balanced salt solution in order to prevent the introduction of air bubbles into the vitreous.) Dissection is preferentially carried out with the tip of the blade facing the light source to avoid working in a shadow (Fig. 13). If there is an obvious edge to the membrane, the tip of the blade can be slid under it and the membrane can be removed (Fig. 14). This should be done with tangential rather than anteroposterior force. As the membrane is lifted off the surface of the neurosensory retina, great care must be used to avoid creating retinal tears. This is particularly true when peeling the membrane off the fovea. After the membrane has been lifted off the posterior pole, it can be removed from the eye by use of vitreous forceps or a vitrector.

Fig. 12 A pars plana vitrectomy is completed. (Margherio RR: Epiretinal macular membranes. In Albert R, Jakobiec EA, eds: Principles and Practice of Ophthalmology, Vol. 2. Philadelphia: WB Saunders, 1993:919–925)

Fig. 13 By keeping the blade directed toward source of endoillumination, working in the “shadow” is avoided and visualization improved during dissection of epiretinal membrane. (Margherio RR: Epiretinal macular membranes. In Albert R, Jakobiec EA, eds. Principles and Practice of Ophthalmology, Vol. 2. Philadelphia: WB Saunders, 1993:919–925)

Fig. 14 In cases with an obvious edge, the tip of the bent 20-gauge microvitreoretinal blade or 23-gauge needle engages the membrane and gently peels it from the retinal surface. (Margherio RR: Epiretinal macular membranes. In Albert R, Jakobiec EA, eds. Principles and Practice of Ophthalmology, Vol. 2. Philadelphia: WB Saunders, 1993:919–925)

For eyes in which there is no obvious edge to the epiretinal membrane, the oblique illumination of the light pipe may be used to cast a “shadow” of the retinal vessels on the retinal pigment epithelium. This will readily enable identification of the area of maximum elevation of the neurosensory retina. The bent blade is then used over a small retinal vessel in that area to open a small hole in the membrane. It can then be removed as previously described (Fig. 15).

Fig. 15 Opening is created in epiretinal membrane with tip of bent blade. Dissection is performed over small retinal vessel to guard against creating a retinal hole. Arrow shows area of maximum vascular shadowing, which identifies area of greatest elevation of the neurosensory retina from the retinal pigment epithelium. (Margherio RR: Epiretinal macular membranes. In Albert R, Jakobiec EA, eds. Principles and Practice of Ophthalmology, Vol. 2. Philadelphia: WB Saunders, 1993:919–925)

Recently, trypan blue has been used to help intraoperative visualization of epiretinal membranes and the ILM.44,174,175 A concentration of 0.06% trypan blue was found to be a safe intravitreal dose for staining membranes in a study by Veckeneer and colleagues,176 and 0.2% in a study by Teba and associates.177 Unlike trypan blue, indocyanine green selectively stains the ILM, not epiretinal membranes.178 Various preparations, concentrations, and exposure times of indocyanine green have been used, either with a balanced salt solution-filled eye or under air, to improve epiretinal membrane visualization and peeling by staining the adjacent uncovered internal limiting membrane.

After initial removal of the membrane, an attempt should be made to determine whether a multilayered membrane is present. Membrane staining may be helpful in this regard. Additional layers must be sequentially peeled, or the expected visual and anatomic results will be compromised. Incomplete removal of a multilayered membrane can sometimes be confused with a recurrence. After complete removal of the membrane, the peripheral retina is inspected for tears and/or detachments, which, if present, can be subsequently repaired.

RESULTS

After surgical removal of epiretinal macular membranes, there is a tendency toward normalization of the appearance of the retina in most cases, although there is almost never a complete resolution of the vascular tortuosity and retinal striae. Similarly, vision is improved in most eyes, but a return to normal acuity is rare even in eyes without previous underlying pathology. In Margherio's25 series of 328 eyes, there was an overall improvement of at least two lines in 74%, with 24% being unchanged and 2% becoming worse. In light of absent preexisting macular pathology, better visual results were generally found in the 184 idiopathic cases. Other series, however, report greater improvement in nonidiopathic than in idiopathic cases.173

Numerous authors have attempted to define prognostic indicators of postoperative vision in vitrectomy for treatment of epiretinal membranes of the macula. Indicators that have been mentioned include preoperative visual acuity, duration of diminished acuity prior to surgery, the presence of preoperative cystoid macular edema, age of the patient, thickness of the epiretinal membrane, idiopathic versus nonidiopathic epiretinal membranes, and the presence of RPE window defects on fluorescein angiography. Trese et al.171 reported that transparent membranes had a better visual prognosis than did opaque membranes. They also believed that the presence of cystoid macular edema was a poor prognostic sign. Rice and colleagues,173 however, found that eyes with thin, transparent membranes had a poorer prognosis than eyes with thicker membranes. McDonald and Aaberg159 found no association between the transparency of the membrane and the final postoperative vision. Ferencz and associates,153 in a study of 167 cases of idiopathic epiretinal membranes, found no association between the transparency of the membrane and the final visual outcome. Likewise, they found no association between the presence or absence of cystoid macular edema or a RPE defect and the final visual outcome. Only preoperative vision had a predictive value with regard to the ultimate visual prognosis.153 Maguire and colleagues179 reviewed the preoperative fluorescein angiographic features of 229 cases of idiopathic epiretinal membranes. They found that postoperative visual improvement was greatest in eyes with the most severe degree of macular edema. No such association was noted with the degree of retinal vascular distortion or contraction of the foveal avascular zone.179 Other studies have suggested that the presence of cystoid macular edema is a poor prognostic sign.114,114,160,163,171,173,180 However, larger series have shown no relationship between the presence of preoperative cystoid macular edema and the ultimate visual prognosis.25,153,158,167 There has been recent discussion as to whether it is necessary to additionally peel the ILM. Park and associates181 compared short-term results for a total of 44 eyes with idiopathic macular pucker undergoing epiretinal membrane peeling either with or without associated peeling of the internal limiting membrane. Staining of membranes was not utilized, and a statistically significant visual acuity benefit between the two groups was not demonstrated. Intraoperative staining of epiretinal and ILMs can facilitate membrane visualization and removal. Histologic specimens of peeled epiretinal membranes stained with trypan blue have both included174 and lacked44 ILM. No added visual benefit from the use of trypan blue has yet been demonstrated, and its long-term safety is unknown.

Similar to trypan blue, indocyanine green allows improved visibility of the internal limiting membrane, and consequently overlying epiretinal membrane. Sorcinelli,182 in a series of 28 eyes with idiopathic and secondary epiretinal membranes, used indocyanine green to stain the membranes during vitrectomy. He reports that the membrane was stained in all cases, and visual acuity at a mean 6-month follow-up was improved an average of two lines, without clinical evidence of indocyanine green toxicity.182 However, there are reports of potential RPE toxicity and traumatic retinal damage with its use. Sippy and associates183 found that cultured RPE cell enzymatic activity was reduced when exposed to indocyanine green. A subsequent study by Engelbrecht49 demonstrated RPE atrophy at the site of previous macular holes in eyes that underwent vitrectomy and internal limiting membrane peeling with the aid of indocyanine green. Recently, Tadayoni and associates52 have shown persistence of indocyanine green fluorescence of the optic disc and macula up to 7 months after assisted peeling of the ILM for macular holes. However, macular fluorescence was not present after the peeling of epiretinal membranes not associated with a macular hole. Possibly the intact retina provides a barrier against indocyanine green-related RPE cell toxicity.52 Paques and co-workers,184 using a rabbit model, suggest that retrograde diffusion of indocyanine green in retinal ganglion cells is a causative mechanism for optic disc fluorescence.

Trauma to the retina after indocyanine green-stained membrane peeling also can occur. All 10 ILM specimens peeled with the aid of indocyanine green by Gandorfer and colleagues,185 and examined by transmission electron microscopy, contained parts of Müller cells. Haritoglou and co-workers53 also had similar histologic results in a recent study, with unstained membranes having fewer retinal elements compared to stained membranes. In their series, indocyanine green was used for 20 of 48 consecutive eyes with idiopathic macular pucker undergoing vitrectomy. Visual acuity did not improve statistically in the eyes which were exposed to indocyanine green, unlike in eyes undergoing membrane peeling without staining, and visual field deficits were documented.53 Consequently, it is unclear at this time whether the intraoperative use of either trypan blue or indocyanine green to assist membrane visualization and peeling is visually beneficial.

COMPLICATIONS

The most frequently occurring intraoperative complications with pars plana vitrectomy for epiretinal membrane surgery include vitreous hemorrhage and peripheral or posterior iatrogenic retinal breaks. The vitreous hemorrhage is generally small and is easily removed with the vitrectomy instrument. Posterior breaks are rare and occur in less than 1% of cases in most series.25,114,152,156,164 In some series, however, the occurrence of posterior breaks has been as high as 9%.168 The retinal tears are treated with photocoagulation or transscleral cryosurgery.

Postoperative complications can include the development of accelerated nuclear sclerosis, retinal tears or detachment, rubeosis iridis, and endophthalmitis. Retinal detachments can generally be repaired without further loss of vision. Rubeosis and endophthalmitis have occurred in less than 0.5% of cases.25,134 The most troublesome postoperative complication has been the development of accelerated nuclear sclerosis, which has ranged from 12% to over 60%.25,134,160,163,167,168 The reasons for this are unclear, but possible factors are the influence of the operating microscope light or endoilluminator, the chemical composition of infusion fluid, infusion via an anterior infusion port, and/or change in intraocular temperature.25,186

The membrane recurs in less than 5% of idiopathic cases. In eyes with membranes from known etiologies, recurrence is much higher, approaching 100% in eyes of young patients who develop epimacular membranes after trauma or inflammatory disease.25,172

SUMMARY

Epiretinal membranes are relatively common. They occur in 2% to 6% of patients. The incidence of idiopathic membranes increases with age and may approach 20% by age 70.

Many cell types have been implicated in the origin of epiretinal macular membranes. RPE cells and retinal glial cells are most likely the major participants in the pathogenesis of epiretinal membranes. The epidemiology of the membranes includes proliferative diseases, trauma, inflammation, and retinal surgery, as well as those membranes that are idiopathic. The clinical appearance is variable and depends on cell type, membrane thickness, presence of vessels, and etiology. In most cases, the condition is relatively stable or slowly progressive, with only 5% progressing to 20/200 or worse. Membranes involving the macular or perimacular regions can cause a reduction in vision, metamorphopsia, micropsia, or occasionally monocular diplopia. The contractile forces of the membranes appear to be more closely related to their cellular constituents than to the extracellular collagen matrix. The contraction of epiretinal membranes may be implicated in the development of macular cysts and/or holes. Occasionally, the membrane may spontaneously separate with relief of symptoms.

Bimanual pars plana vitrectomy surgery can successfully remove epiretinal macular membranes in virtually all advanced cases. After surgical removal, vision improves in approximately 75% of cases. However, a return to normal vision is unlikely. Postoperatively, retinal complications such as tears and detachment are rare in the idiopathic cases but are somewhat more common in cases associated with other etiologies. The most frequent postoperative complication is the development of accelerated nuclear sclerosis, which occurs in 12% to 68% of cases. The reasons for this have yet to be defined. Epiretinal membranes recur in approximately 5% of cases.

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