Epidemiologic considerations and terminology

Idiopathic, primary epimacular membranes are a quite common finding, especially in elder people. The prevalence ranges between 2 and 20% in patients aged 70–80 years¹. It is hypothesized that this type of epimacular membrane is the result of glial cell migration and proliferation through small breaks of the internal limiting membrane (ILM), which represent a sequelae of posterior vitreous detachment². Other, secondary, pathomechanisms include retinal breaks, laser coagulation or cryotherapy of the retina, inflammation, and vascular diseases³. An association with macular holes has been described⁴.

A variety of names are used to describe this entity, mainly based on the heterogeneous clinical appearance: cellophane maculopathy, surface wrinkling retinopathy, macular pucker, or premacular gliosis. However, there is no standardized nomenclature and therefore the term epimacular membrane is used, as it covers all types of epiretinal proliferations over the macula.

Clinical features, diagnosis, and differential diagnoses

The diagnosis of epimacular membranes can be very well established using clinical examination techniques such as slit-lamp biomicroscopy with a 78 or 90 diopter lens to assess the macula. As mentioned above, the clinical features and findings can vary considerably and are dependent on the extent of the epimacular proliferation. Using biomicroscopy one may see a translucent, glistening reflex over the macula, wrinkles of the retinal surface potentially associated with a distortion of the adjacent vasculature in more pronounced cases of traction, or even an opaque sheet of tissue covering the retinal surface associated with full-thickness retinal folds and localized tractional retinal detachment (Fig. 65.1). The contraction of such membranes forming a macular pseudohole may be misinterpreted as a full-thickness macular hole in some cases. Secondary tissue alterations are the result of tractional forces and include macular edema, which can also be noted during fluorescein angiography, and small retinal hemorrhages.

Fig. 65.1 Clinical features of epimacular membranes: (A) Grey epimacular membrane with significant traction as seen by the retinal folds and distortion of blood vessels. (B) Epimacular membrane forming a macular pseudohole (photographed in red-free light). (C) Vitreomacular traction syndrome with focal retinal elevation.

New and high resolution imaging techniques such as optical coherence tomography (OCT) allow for a better insight into the morphological retinal changes due to localized tractional forces and the interaction of the vitreous with the retinal surface in this disease. OCT can be of great value to detect anomalous posterior vitreous detachment (PVD) such as vitreoschisis before surgery and differentiate epimacular membranes from vitreomacular traction syndromes. The latter is sometimes difficult to diagnose by using biomicroscopy alone.

Anatomical considerations

The most common cellular components of epimacular membranes are fibrous astrocytes, retinal pigment epithelial cells, fibrocytes, myofibroblasts, and macrophages. Myofibroblasts were also identified as the predominant cell type in vitreomacular traction syndrome⁵. The predominance of myofibroblasts may help to explain the high prevalence of cystoid macular edema and progressive vitreomacular traction characteristic of this disorder. Müller cells may also play a relevant role. A very important aspect of the pathogenesis of epimacular membranes is the anomalous PVD or splitting of the vitreous cortex (vitreoschisis) where collagen fibers are left adherent to the inner surface of the retina. These collagen fibers serve as a scaffold for cellular proliferations. Histological studies revealed that the cellular layers, which may vary from single cells to single sheet or multi-sheet layers, may grow either directly on the ILM or on a collagen layer being interspersed between the ILM and the cellular proliferation⁶ (Fig. 65.2). Similar observations were made in patients with vitreomacular traction syndrome⁵, where two distinct clinicopathologic features were identified suggesting different forms of epiretinal fibrocellular proliferation, with epiretinal membranes being interposed in native vitreous collagen and single cells or a cellular monolayer proliferating directly on the ILM. These histological findings have implications for surgery, as in one type the vitreoretinal surgeon will remove fragments of the ILM along with the epiretinal proliferation in many cases, whereas in the other type the epiretinal proliferation will be removed without the ILM, as the plane of dissection is within the collagen layer. As a consequence, parts of the collagen fibers and the ILM will remain in place. The surgeon needs to consider that in the first type only one membrane is to be removed, whereas in the second type two are to be removed.

Fig. 65.2 Histological features of epiretinal proliferations: Note that the epiretinal cellular layer can either be located directly on the vitreal side of the ILM (A) or may rest on a layer of collagen which is interspersed between the cellular proliferation and the ILM (B).

These findings also indicate the important role of the ILM in the treatment of epimacular membranes. The understanding of the clinical relevance of the ILM for macular surgery emerged in the 1980s, when histopathological examinations of removed epiretinal membranes disclosed fragments of the ILM to be a common feature of these membranes and no functional deficits were noted in these patients^7,8. It took years to transfer these findings into clinical consequences. The topic of intentional ILM removal returned to the focus of attention following the presentation of the Gass’ classification of macular holes coinciding with the first report on successful vitrectomy for macular hole closure by Kelly and Wendel in 1991^9,10. Intentional ILM removal was then first described by Morris et al. in patients with Terson syndrome where ILM peeling led to excellent functional results even in the long term; as a consequence, ILM peeling was then suggested for other ‘traction maculopathies’¹¹.

Fundamental principles and goals of surgery

Obviously, the fundamental principle of surgery is to relieve the tractional force in the area of the macula and prevent a recurrence of the disease. The tractional force can be removed by inducing a PVD in cases of vitreomacular traction syndrome and to remove the visible epimacular membrane. The prevention of recurrences is related to the removal of the ILM during surgery, as clinical trials have shown, with less reproliferations having been seen in patients in whom the ILM had been removed^12,13. Therefore, ILM peeling has become a widely accepted and important step for successful surgery for epimacular membranes and vitreomacular traction syndromes, despite single reports on potential negative effects¹⁴.

Indications for surgery

The indication for surgery is not well defined and needs to be carefully discussed with the patient. The patient’s symptoms and complaints should be assessed prior to surgery. A thorough clinical examination including measurement of best corrected near and distance visual acuity has to be performed. The documentation of metamorphopsia, micropsia, or macropsia, if present, is also of relevance. Interestingly, patients are mainly bothered by metamorphopsia and to a lesser extent by a deterioration of visual acuity. Assessments of visual quality of life before and after surgery have shown that especially the reduction of metamorphopsia is considered a success after macular surgery by the patient. In general, surgery could be considered in patients presenting with a best corrected visual acuity of less than 20/40 with or without disturbing metamorphopsia. If the patient presents with a visual acuity of better than 20/40, disturbing metamorphopsia should be present. It is important to tell the patient before surgery, that the improvement of visual acuity may take weeks to months, whereas the regression of metamorphopsia usually occurs earlier. However, epimacular membrane formation is a quite benign and slowly progressive disease and surgery should not be forced on the patient given the well-known complications of any vitreoretinal surgery. The indication should be based on the patient’s needs and expectations. In addition, the best corrected visual acuity of the fellow eye should be taken into account. If you feel that the patient is reluctant to undergo surgery, the decision can be postponed in nearly all cases and a further visit can be scheduled after a period of 3 months.

Preoperative assessment

A complete preoperative assessment includes a thorough clinical examination with measurement of best corrected distance and near visual acuity, intraocular pressure, and assessment of the lens (in phakic patients showing cataract, combined surgery with pars plana vitrectomy and cataract extraction and intracapsular lens implantation may be considered). Slit-lamp biomicroscopy using a 78 or 90 diopter lens to assess the macular is mandatory, as well as a careful examination of the retinal periphery, in order to detect potential retinal breaks or other pathologies.

Imaging techniques such as OCT or fluorescein angiography may provide additional useful information, but especially the latter is not considered a standard diagnostic tool for this condition. OCT is of relevance to assess vitreoretinal adhesions, retinal thickness, and morphological alterations of the different retinal layers.

Anesthesia

Vitreoretinal surgery for the treatment of epimacular membranes and vitreomacular traction syndrome may be performed in general or local retrobulbar or parabulbar anesthesia, with the letter being the most frequent form. If available, the addition of hyaluronidase to the local anaesthetic for retrobulbar anesthesia may enhance the safety of the surgical procedure due to more complete akinesia and quicker onset of complete anesthesia¹⁵. If the surgery is performed in general anesthesia, an additional preoperative retrobulbar injection of a local anesthetic may significantly reduce postoperative pain¹⁶. This concept of ‘pre-emptive analgesia’ is based on the idea that analgesia initiated before a nociceptive event will be more effective than analgesia commenced afterwards.

Operation techniques

Today, small gauge sutureless (23- or 25-gauge) instruments and systems appear to be the most appropriate tools for vitrectomy in epimacular membrane and vitreomacular traction cases, as postoperative discomfort is significantly reduced. If peripheral pathologies need to be approached, less flexible 23- or 20-gauge systems (compared with 25-gauge) may be preferred¹⁷. During surgery, there are actually three relevant target structures for a successful surgery in epimacular membrane and vitremacular traction syndrome: the vitreous cortex, the epimacular cellular proliferation, and the ILM.

Removal of epimacular membranes

Following the removal of the posterior hyaloid, the actual epimacular membrane can be approached. This should be done using a high resolution macular contact lens as a viewing system. The membrane can extend over large areas and it is helpful to find the edge of the membrane to start its removal. In cases where no such edge can be detected, an opening can be created using a microvitreal blade or a bent-tip needle. The removal of the membrane is then performed using a forceps from the periphery to the center. The tip should be moved tangentially to the retinal surface and it may be necessary to engage the membrane from different directions in order to prevent a fragmentation of the tissue and tearing of the retina. Similar to capsulorrhexis in cataract surgery, the membrane should be removed in a circumferential fashion, always observing the fovea. The selection of the instrument is usually based on the surgeon’s preference. End-gripping forceps or spatula-like instruments can be used. Whatever forceps is used, the separation and removal of the membrane should be performed carefully as strong adherences with the underlying structures may be present and retinal breaks may be caused.

The epimacular membrane could be visualized using trypan blue^19,20. Trypan blue is a vital dye with a high biocompatibility^21,22 and is commercially available for the application in the posterior segment in a concentration of 0.15%. It is especially helpful to visualize the edges of the membrane, so that the surgeon can easier determine where to start the peeling (Fig. 65.3). The main drawback of trypan blue for vitreoretinal surgery is that a fluid–air exchange is required before injecting the dye in order to achieve high enough concentrations on the retinal surface and prevent a diffusion of the dye though the vitreous cavity. To avoid the need for a fluid–air exchange it was suggested combining the dye with glucose (heavy trypan blue). By eliminating the need for a fluid–air exchange, repeated applications of the dye can easily be carried out²³. The removal of the epimacular membrane is often followed by an intentional peeling of the ILM, or of the ILM fragments still present.

Fig. 65.3 Peeling of an epimacular membrane stained with trypan blue 0.15%.

Peeling of the internal limiting membrane (ILM)

This technique opened the possibility for better functional and anatomic results of macular surgery. The ILM is a very delicate structure, less than 3 µm thick and nearly invisible. Consequently, it is quite difficult to identify the ILM during macular surgery and to determine whether the structure removed is really ILM. However, there are a few signs that might be of assistance. Clinically, the ILM gives the retina a shiny appearance, especially in younger patients. Intraoperatively, this shiny reflex helps the surgeon to identify areas of peeled retinal surface with a slight whitening of the surface as a sign of removed ILM, in contrast to areas where the ILM is still present with the surface still having a glistening appearance. Peeled ILM specimens usually appear clear, smooth, sharp edged and shiny, while specimens of epiretinal membranes are more opaque with an irregular surface and border and not reflective. Regarding the surgical technique including the instruments and the motion performed, ILM peeling can be performed similar to the removal of epimacular membranes, as mentioned above.

However, ILM peeling represents a challenging surgical technique, even for the experienced vitreoretinal surgeon, so effort, were made to develop a technique to visualize the ILM. The introduction of vital dyes to assist vitreoretinal surgery was greeted with great enthusiasm as this difficult surgical maneuver suddenly appeared to be – at least in theory – easier, safer, and more controlled. Staining of the ILM allowed even less experienced surgeons to follow the principle of ILM peeling and opened the possibility to better functional and anatomic results of macular surgery.

Indocyanine green (ICG) was the first dye introduced for ILM staining²⁴. ICG is a hydrophilic tricarbocyanine dye, first introduced in 1956. Since then ICG has been used for a variety of diagnostic purposes^25,26 including the imaging of choroidal perfusion during angiography²⁷. While the intravenous application of the dye in humans is considered very safe, the ‘off label’ intravitreal application of ICG has become a subject of ongoing discussion as toxic effects of the dye leading to functional impairment of the patients cannot be ruled out^28–32. The main advantage of ICG is the good contrast provided at the level of the ILM and its selective staining properties. If applied, ICG should be injected into the fluid filled globe and then washed out immediately. The dye concentration used today varies between 0.05 to 0.5%.

Brilliant blue G (BBG) is a triarylmethane dye introduced in 2006 by Enaida and co-workers for ILM staining^33,34. Meanwhile BBG is commercially available in a concentration of 0.025% for use in vitreoretinal surgery. Similar to ICG, BBG selectively stains the ILM but provides a weaker contrast, which is still enough to visualize the ILM and allow for its controlled removal. There is no clinical and experimental evidence so far indicating adverse effects of BBG on functional outcome as seen for ICG^35,36. BBG can be injected into either the fluid filled globe or the air filled globe, but should be washed out immediately.

However, in the presence of epimacular membranes, any dye selectively staining the ILM has no access to the ILM and the formation of epimacular membranes may impair sufficient staining and visualization of the ILM. Poor staining may result in an incomplete removal of the ILM associated with residual ILM fragments, with an indefinite amount of cells and collagen remnants at the vitreal side of the ILM. Therefore, different approaches could be considered to achieve the best possible result. First, the ILM-dye is injected prior to the removal of the epimacular membrane. This will allow for a demarcation of the membrane due to the ‘negative’ staining of the epimacular tissue (Fig. 65.4). The removal can be initiated in an area of stained ILM and both tissue sheets may be removed together. Second, the surgeon may remove the unstained epiretinal membrane first, followed by an injection of the ILM dye. This will allow for an identification of ILM remnants after epimacular membrane peeling. Third, trypan blue is injected first, to stain and remove the epimacular membrane, followed by an ILM dye injection (double staining technique)³⁷. However, with respect to potential toxic effects it is recommended to limit the application of any dye, exposure times, and concentrations.

Fig. 65.4 ‘Negative staining’ of an epimacular membrane using brilliant blue. Brilliant blue selectively stains the ILM, but not epimacular membranes. After dye injection the unstained epimacular membrane and its edge can be seen surrounded by stained ILM.

Intraoperative complications

During the removal of epimacular membranes posterior tears of the retina can occur if the surgeon grasps too much tissue using the forceps, or moves the forceps not in a tangential fashion along the retinal surface but in a more perpendicular fashion resulting in anterior–posterior tractional forces. Breaks may also be the result of excessive traction during the induction of a PVD. Macular holes may occur if the fovea has been involved. Posterior breaks require endolaser coagulation and fluid/air or air/gas exchange only if the macula is affected. At the end of surgery, the surgeon should inspect also the peripheral retina to identify peripheral breaks. Should the surgeon notice any breaks with elevated rims, fluid/air exchange followed by air/gas exchange and endolaser coagulation should be considered. If the edges of the peripheral break are not elevated, laser coagulation alone may be sufficient.

Small superficial retinal hemorrhages may be seen as a result of membrane and ILM peeling in areas of strong adhesions of the tissue.

Postoperative care

Postoperatively the patient should be treated with anti-inflammatory and antibiotic eyedrops. While the antibiotic eyedrops can be discontinued after 3–4 days, anti-inflammatory treatment should be reduced slowly. Measurement of intraocular pressure is mandatory in the postoperative phase and IOP rises should be treated accordingly. Lower postoperative intraocular pressure can be seen following transconjunctival sutureless small gauge vitrectomy. If very low IOP lasts longer than 1–2 days, a suture should be placed over the sclerotomy sites.

Postoperative complications

In general the surgical complication rate after surgery for epimacular membrane and vitreomacular traction syndrome is low. Posterior retinal breaks may occur in approximately 5% but should be lower using staining techniques. Peripheral retinal breaks are mostly related to traction at the vitreous base during vitreous removal, instrument introduction forces, or incarceration of vitreous in the sclerotomies. The rate of retinal detachment after surgery is 1–5%. The retinal periphery should be carefully inspected during surgery; high cut rates and low suction are recommended when approaching the retina.

Recurrences of the epimacular membrane can be reduced by a meticulous removal of the ILM^12,13, as the ILM serves as a scaffold for cellular proliferation. There is a significant difference when comparing recurrences in ILM-peeled and non-ILM-peeled eyes.

Cataract formation is the most common complication in the postoperative course and is not related to epimacular membrane or ILM removal but to vitrectomy itself. The incidence of the development of nuclear sclerosis is correlated with the age of the patient and the use of an intraocular tamponade. Rates as high as 50–75% have been reported³⁸. The development of cataract is the most frequent cause for a deterioration of visual acuity following vitreoretinal surgery. With this background many surgeons try to avoid tamponades in these surgeries unless required for other reasons such as retinal breaks.

Other postoperative complications, such as asymptomatic paracentral scotomata, may be related to a mechanical trauma of the nerve fiber layer following ILM peeling³⁹.

The use of adjuvants such as vital dyes, especially ICG, may result in visual field defects or peculiar alterations of the retinal pigment epithelium^28,29, which may be associated with less favourable functional outcome.