Epiretinal Membrane

Abstract

Epiretinal membrane (ERM) is formed at the vitreoretinal interface that leads to a myriad of visual disturbances includes decrease in visual acuity (VA), stereopsis, contrast sensitivity and metamorphopsia. Most common etiology of ERM is posterior vitreous detachment (PVD) and is usually labeled as idiopathic. Secondary ERMs arise from several causes including cataract surgery, retinal tears and detachment, diabetic retinopathy, uveitis etc. Multiple cell lines, cytokines, proteins, and genes play a role in the formation and progression of ERMs. In this chapter, we aim to summarize the current evidence related to etiology, pathophysiology, and management of ERM.

1. Introduction

Epiretinal membrane (ERM) is formed as a result of proliferative process involving myofibroblasts and extracellular matrix (ECM). There are many etiological pathways that eventually result in formation of ERM. Optical coherence tomography (OCT) is the most widely used investigative modality to diagnose, grade and plan intervention for ERMs but lacks the ability to classify according to histopathological variations that suggest it’s multifactorial origin. In this chapter, we discuss the current evidence about the etiology, investigations and management of ERMs.

2. Epidemiology

The Blue Mountain Eye Study (BMES) and the Beaver Dam Eye Study (BDES) reported the initial prevalence of idiopathic ERMs (iERMs) as 7% and 11.8% respectively in large population-based analysis. This observation was based in colored retinal and macular photography showing cumulative 5-year incidence of 5.3% [1, 2]. iERMS were found to be bilateral in up to 31% with a 13.5% incidence of other eye involvement within 5 years [1, 3]. Later on, OCT was used in a 20-year follow-up of BDES that showed an overall prevalence of 34.1% which was significantly higher than that showed by retinal photography [4]. Therefore, now OCT is the most desirable investigation to detect the presence of ERM [5].

According to the published literature, there is significant ethnic variation in the prevalence of ERM. Care should be exercised when interpreting the results of ethnic variation due to possible confounders (reading methodology, imaging modalities, various differing OCT based imaging tools) and probable etiology (pigmentation may affect the ability to detect ERM on retinal photography) [6]. Various ethnic reported prevalence rates include 2.9% in Korean National Health and Nutrition Examination Study [7], 4.0% in Hisayama Study from Japan [8], 12.1% in Singapore Epidemiology of Eye Disease Study (SEED) [6], 7.6% in Singapore Indian Eye Study [9], 7.9% in Singapore Malay Eye Study [10], 2.2% in Beijing Eye Study from China [11], 11.8% in BDES from United States [2], 18.7% in Los Angeles Latino Eye Study [12] and 7% in BMES from Australia [1].

Another significant and consistent risk factor is age. BMES study showed increasing incidence from 1.9% (<60 years) to 7.2% (60–69 years) to 11.6% (70–79 years) and Melbourne Collaborative Cohort Study (MCCS) found further increasing incidence of 17% in population above 80 years [1, 13].

Gender does not play a major role as a risk fact although refractive errors have shown to play some inconsistent role where hyperopia [7] and myopia [5] have likelihood of increased ERM incidence.

3. Cellular architecture of ERM

3.1 Proteomic basis of ERM pathogenesis

Our knowledge of pathogenesis of iERMs and secondary ERM (sERM) have greatly improved in the last two decades due to advances in modern imaging coupled with new proteomic techniques and immunohistochemistry [14]. It has been shown in many literature reports that multiple genes and growth factors influence the formation of ERMs [15]. There is also a great range of cell types involved in the pathogenesis and formation of ERMs [16, 17].

3.2 Cellular basis of ERM pathogenesis

ERM is composed of an inner and an outer layer overlying the internal limiting membrane (ILM). The inner layer is composed of cellular sheets whereas the outer layer is a non-cellular protein constituting ECM and arranged in random orientation. With the progression in ERM, its contractile properties are further increased because of accumulation of further ECM and myofibroblasts [18]. The origin of myofibroblasts has been debated but now there is enough evidence from immunohistochemical studies that hyalocytes, retinal pigment epithelial (RPE) cells, fibroblasts and retinal glial cells, all contribute to formation of myofibroblasts [19, 20, 21].

There are three basic proposed mechanisms which explain the migration of ERM precursor cells to retinal surface. The earliest mechanism was proposed by Foos who theorized that precursor cells especially retinal glial cell travel to surface of retina after posterior vitreous detachment (PVD) leaving behind microdefects on retinal surface [22, 23]. This has been widely superseded by a more popular theory stating that hyalocytes left behind on retinal surface after PVD undergo metaplasia to form ERM [24]. However, ERMs do occur in the absence of PVD and there is possibility of precursor cells migrating to retinal surface through the retinal tissue and defects in ILM. Metaplasia of these cells then happens on the retinal surface [20]. Due to limitations in the process of ERM mechanism in all these theories, currently we do not have a consensus on this subject.

RPE cells are the most frequently found precursor cells of ERM occurring with a retinal detachment or retinal tears. These cells are not frequently found in iERMs [25]. Although the process of transretinal migration is still unclear, they can deposit on the surface of retina while migrating through retinal breaks in cases of rhegmatogenous retinal detachment. Once deposited on the retinal surface, they undergo transdifferentiation into myofibroblasts under stimulation of Transforming growth factor – beta (TGF-β) [26, 27].

The origin of fibroblasts as precursors of ERM is also not fully elucidated but they are found in ERMs associated with diabetic retinal disease [28]. Fibroblasts secrete ECM and can produce collagen fibers that can ultimately result in tractional retinal detachment [29]. Fibroblasts and myofibroblasts are responsible for the contractile properties of ERM and this happens with the expression of alpha smooth muscle actin protein. A-SMA is also responsible for production of collagen from fibroblasts and generation of contractile forces in ERM [30].

Müller cells can be activated to contribute in the formation of ERM by factors such as retinal ischemia, hyperglycemia, mechanical stress and by various growth factors and cytokines [31]. Traction on the macular surface can be a potential activator of Müller cells that can lead to reactive gliosis and differentiation into myofibroblasts [30].

Laminocytes and hyalocytes also contribute to the formation of iERMs. These are present in eye with PVD and in the cortical vitreous remnants [32]. TGF-β is produced and activated by both hyalocytes and Müllers cells that is involved in the formation of iERMs [33, 34].

Retinal microglia are now known to be found more frequently in the ERMs and PVR than once believed. They also have the capability to secrete TGF-B that aids in differentiation of epithelial cells to myofibroblasts [35]. Retinal astrocytes are flat cell body cells that are known to act as a scaffold for collagen production and fibroblast differentiation [21, 22]. These cell types are predominantly implicated in vitreomacular traction, lamellar macular holes, diabetic retinopathy associated ERMs and myopic traction maculopathies. Their role in formation of iERMs is not so consistent [36, 37, 38].

Macrophages have more role to play in secondary ERMs associated with vitreous hemorrhage [39]. They have an unclear role in iERMs formation, but they secrete TGF-β, insulin like growth factor − 1 (IGF-1), fibroblast growth factor (FGF) and platelet derived growth factor (PDGF) that are known to contribute in myofibroblastic transformation [40].

Hyalocytes are predominantly found in the vitreous base and posterior cortex [41]. At the posterior pole, they are positioned at 20–50 μm from ILM in a widely spaced single layer [24]. The presence of hyalocytes has been established in ERMs with their long fibers nested next to fibroblasts in cellular agglomerations [24, 42]. Studies have shown that hyalocytes display strong contractile properties in response to TGF-β2 stimulation that may have a role in enhancing the contractile properties of ERM [43]. It has been proposed that vitreoschisis can occur in the event of an anomalous PVD. The level of split in posterior vitreous (anterior or posterior to hyalocytes layer) determines the eventual role of hyalocytes in the contractile activity of ERMs [24]. Various studies have also proved the role of myofibroblastic differentiation from these cells in ERMs, vitreomacular traction syndrome (VMTS), lamellar macular hole (LM) and other proliferative vitreoretinopathies [44, 45].

Non cellular ECM forms the framework that promotes the proliferation and adhesion of epiretinal cells [46]. ECM is formed by the glial cells, RPE cells and myofibroblasts [47]. ECM is mainly composed of type I, II, III, IV and VI collagen [48]. Type I, II, and III are known to be newly formed collagen whereas type II and IV are native vitreous collagen present adjacent to ILM [49, 50]. Type VI collagen is known form the fine fibrillar network of ECM and interacts with type IV collagen of outer ILM boundaries of ECM to account for the biomechanical stability when removing surgically [16]. A summary of the cell types and their role in ERM formation are given in Table 1.

Cell type	Role in pathogenesis of ERM
RPE	iERM and sERM (PVR, PDR)
Müller cells	iERM and sERM
Hyalocytes	iERM and sERM (PVR, PDR)
Glial cells	iERM and sERM (PVR, PDR)
Laminocytes	iERM
Fibroblasts	iERM and sERM (PDR)
Astrocytes	iERM
Endothelial cells	ERM formation
Macrophages	iERM and sERM (PVR)
Myofibroblasts	iERM and sERM (PVR, PDR)

Table 1.

Common cell types and their role in ERM formation.

iERM, idiopathic epiretinal membrane; sERM, secondary epiretinal membrane; PVR, proliferative vitreoretinopathy; PDR, proliferative diabetic retinopathy; RPE, retinal pigment epithelium.

3.3 Genes involved in ERM pathogenesis

There has been keen interest to understand the role of genes in pathogenesis of ERM. A total of 52 genes are upregulated in PVR or sERM. Four genes in particular, PARP8, ZNF713, FN1 and MALAT1 are significantly upregulated in ERMs [51]. Out of these genes, MALAT1 is associated with progression of sERM such as PVR associated ERM. It also plays a role in activation of genes involved in metastasis and motility at the transcription level [52]. Other important genes involved in the pathogenesis of iERMs include RELA, tenscin C, glial fibrillary acidic protein and other cytokine encoding genes like TGF-β2, IL6 and VEGF-A [53]. PPM1D encodes wild type p53-induced phosphatase 1 (Wip1) that has been reported in PDR associated ERM formation. Another gene associated with encoding angiogenesis related factors in PDR associated ERM is SP1. It regulates expression of genes such as TGF-β, VEGF and many matrix genes [54].

3.4 Role of cytokines and growth factors in formation of ERMs

Cytokines and growth factors play their role in formation, growth and contraction of ERMs. Contraction and growth of ERMs is regulated by these molecules and their role is implicated in both iERMs and sERMs [55, 56].

3.4.1 The transforming growth factor-β family

The TGF-β family is involved in mediating the myofibroblast differentiation and inflammatory response. These are also involved in upregulation of ECM production. The retinal Müller cells and hyalocytes are involved in production and activation of TGF-β. This in return, leads to the process of Müller cell proliferation, transdifferentiation and migration [57, 58]. Both, TGF-β 1 and TGF-β2 are upregulated in ERMs and vitreous humor. Their expression seems to be secondary in cases of ERM although there is evidence, they may be involved in the initiation of iERM [17]. As studies have shown that there are differences in the levels of TGB-β1 and β2 in vitreous and that levels of the later are raised in vitreous in cases of iERMs, it is now believed that the role of TBF-β1 may be minimal in the pathogenesis of iERMs. This observed predominance of TGF-β2 in iERMs makes this a potential target for therapeutic agents targeted to control or limit/inhibit the formation of iERMs [14, 59].

3.4.2 Vascular endothelial growth factor (VEGF)

VEGF is known to contribute in development of iERMs. This is evidenced with high levels of VEGF in vitreous in patients of iERMs and retinal neovascularization leading to sERMs. Also, the VEGF-A gene is overexpressed in this clinical scenario [60, 61].

3.4.3 Nerve growth factor (NGF)

NGF is highly expressed and utilized in the formation of iERM through modulating intracellular signaling and there may play a part in the formation if iERMs [17].

3.4.4 Insulin like growth factor (IGF)

IGF has been shown to contribute to the growth, progression and contraction of ERM especially secondary to PDR [62, 63].

3.4.5 Platelet derived growth factor (PDGF)

RPE cells are known to stimulate the production of PDGF. As a result, PDGF enhances the interaction between RPE and glial cells after former have migrated to the retinal surface or vitreous [64]. This is most notably evidenced in ERM secondary to PVR [65, 66]. PDGF also stimulates other cells that lead to proliferation of ERM [66].

3.5 Proteins involved in pathogenesis of ERM

There are over 300 proteins that have been known to play a role in pathogenesis of iERMs and have been localized in aqueous fluid (AF) and vitreous fluid (VF) [32]. Out of these, 8 proteins are overexpressed in VF and 4 proteins are overexpressed in AF and rest of them are non-differentially expressed both in AF and VF. Of these, fibrinogen A is the most significant overexpressed protein in VF that plays a critical role in pathogenesis of iERMs [67].

4. Etiology of iERMs and sERMs

Traditionally, ERMs are classified based on their causative factors and associated ocular conditions. A PVD is present in up to 95% of all iERMs and therefore suggest the role of PVD in iERM pathogenesis. 5% patients do not have PVD and still have iERM (Figure 1) [68, 69]. sERMs are found to coexist with other ocular conditions most common of which is recent cataract surgery, followed by diabetic retinopathy and retinal vein occlusion [70, 71, 72]. Common causes of iERMS and sERMs are listed in the Table 2 above.

Figure 1.

Epiretinal membrane with no posterior vitreous detachment.

Idiopathic ERM; No known pathology Posterior vitreous detachment

Secondary ERM; Uveitis Retinal detachment Retinal tears Post cataract surgery Retinal laser Retinal cryotherapy Retinal surgery – vitrectomy Diabetic retinopathy Retinal vein occlusion Radiation retinopathy Sickle cell disease Retinal artery macroaneurysm Coats disease Retinal telangiectasia Trauma Pathological myopia Intraocular tumors Macular hole Vitreomacular traction syndrome Retinitis pigmentosa Age related macular degeneration

Table 2.

Etiology of idiopathic and secondary epiretinal membrane.

5. Signs and symptoms

Most common presenting complaints of patients with ERMs include decreased visual acuity (VA), hazy vision, anisokonia, micropsia, macropsia and reduced stereopsis. Binocular interference happens when the patient closes the involved eye to see better from the other eye in the absence of strabismus or diplopia. This symptom significantly reduces the quality of life [73, 74].

Clinical signs of ERM range from mild glistening of macular reflex to inner retinal distortion, disturbed vascular architecture, cystoid macular oedema (CMO), displaced fovea and full thickness or lamellar macular hole [75].

6. Clinical classification of ERMs

With the introduction of OCT, our understanding about the architecture, evaluation and prognosis of ERM has been revised. Original classification of ERM was from Gass who described ERM in terms of cellophane maculopathy (Grade 0), crinkled cellophane maculopathy (Grade 1), macular pucker (Grade 2) and pseudohole [76, 77].

7. Investigations

7.1 Optical coherence tomography

Various OCT based classifications of ERM have been proposed in the literature. Hwang et al. described ERMs based on their involvement of fovea and used multifocal electroretinogram (mfERG) to assess retinal function based on this classification [78]. Stevenson introduced an additional classification taking into account the presence or absence of PVD along with foveal involvement or sparing [79]. Konidaris et al. also proposed a complex classification of ERM while describing nine categories based on retinal architecture and PVD [80].

More recently, a simple classification proposed by Govetto et al. has gained attraction due to its simplicity and ease of application in clinical scenarios. It is a four-stage classification based on presence (Figure 2) or absence of foveal pit (Figure 3), ectopic inner foveal layers (Figure 4), and disorganization of retinal layers (Figure 5)[81]. Ectopic inner foveal layer is a continuous band extending form inner nuclear and plexiform layers across fovea [82]. Recent literature has validated the prognostic value of this staging with higher stage associated with poorer pre- and post-operative visual outcomes [83, 84].

Figure 2.

Intact foveal pit with identifiable retinal layers. Reproduced with permission [81].

Figure 3.

Loss of foveal pit with identifiable retinal layers. Reproduced with permission [81].

Figure 4.

Loss of foveal pit with identifiable ectopic inner retinal layers. Reproduced with permission [81].

Figure 5.

Loss of foveal pit with disorganized inner retinal layers. Reproduced with permission [81].

Additional signs manifested and described in recent literature include cotton ball sign and center bouquet. The cotton ball sign is a round and reflective lesion at the center of fovea between ellipsoid zone (EZ) and cone outer segment termination (COST) line [85]. It has been suggested that cotton ball sign is a sign of chronic traction and may predict the severity of ERM. Based on the cotton ball sign, a central bouquet is an advancement of cotton ball sign and is described in 3 clinical variants according to their level of chronicity and severity of traction: cotton ball sign (Figure 6), acquired vitelliform lesion and central foveolar detachment (Figure 7) [86].

Figure 6.

Cotton ball sign visible at the center of fovea between ellipsoid zone and cone outer segment termination line.

Figure 7.

Epiretinal membrane with vitreomacular traction syndrome and foveal elevation.

The eyes with cotton ball sign have better visual outcomes as compared to acquired vitelliform lesions and foveolar detachment [86].

OCT changes in ERMs are also being used as prognostic markers for visual outcomes and to the exact timing of intervention in ERM cases. OCT markers predicting better visual outcomes after surgery include absence of ectopic inner retinal foveal layer, inner retinal irregularity, CMO, acquired vitelliform lesion, normal EZ and COST [87, 88, 89, 90, 91]. There has been recent shift to the pathologies located in inner retinal layers in predicating the outcomes after intervention. This includes the presence or absence of ectopic inner foveal layer and surgeries performed before the formation of this layer carry better visual prognosis [92]. Another marker on OCT is the ratio of the length of inner plexiform layer to RPE in a 3 mm zone center on fovea. This marker is also significantly associated with predicting visual outcomes after surgical intervention [93]. Most of these studies have been done in cases of iERMs. It is difficult to deduce prognostic OCT markers in cases of sERMs. This is because the vision may be affected due to the primary disease process more than due to ERM and this acts as a confounder. Nevertheless, earlier intervention in cases of sERMs is favorable due to overall worse visual prognosis when compared to iERMs [94].

7.2 Angiography

Angiography can be helpful in accurately diagnosing the secondary causes of ERM and hence can be useful preoperatively [95]. Advanced ERMs can lead to alterations in foveal avascular zone because of displacement and stretching of superficial and deep capillary plexus as has been shown by OCT angiography (OCT-A). It has also been shown that there is reduced vascular density of superficial capillary plexus and increase in the density of deep vascular plexus after ERM surgery which may impact the post-operative visual function [96, 97, 98].

7.3 Microperimetry

It can be very useful to assess the subclinical abnormalities in visual function when other regular visual function tests are equivocal [99]. This has also clarified the role of additional ILM peeling in cases of ERMs that may at times lead to decreased retinal sensitivity and micro scotomas as shown by findings of microperimetry [100, 101].

7.4 Electroretinography (ERG)

Although ERG is not routinely used as an investigative tool for ERM management, several findings explain its novel role for research and investigative purpose. One such clinical finding is lower mfERG responses (P1) in cases of ERM with increased subfield retinal thickness [102]. Whereas some studies have shown decreased responses of dual peeling on microperimetry, mfERG has shown improved responses with this technique that shows improved retinal ganglion cell function [103, 104, 105]. mfERG also has predictive value as decreased pre-operative P1 values often signifies poorer post-operative results [106].

7.5 Artificial intelligence (AI)

There is a promising role of AI in detecting ERMs without human intervention as some studies have successfully identified ERMs based on OCT scans with high sensitivity (98.7%) and specificity (98%) [107, 108].

8. Management

8.1 Observation

It has been shown in natural history studies that ERMs progress very slowly. In the landmark BMES study, it was shown that only 10% of eyes with ERM progressed to pre retinal fibrosis over a follow up of 5 years [1]. Once we observe lamellar macular hole in presence of ERM, it is also a sign of long-term clinical stability and does not require intervention unless there is progressive decrease in VA [109].

8.2 Surgical management

There is no definitive medical management of ERMs and surgery is usually indicated when there is decline in visual functions. The optimal timing of surgery is still a question of debate but recently there has been preference to intervene before the formation of ectopic inner foveal layer. Often the surgery is reserved for cases where vision is <20/60 but modern-day surgery has decreased this threshold even further. Following surgery, there can be a prolonged period of up to 6–12 months over which the vision keeps on getting better. Studies have shown that up to 85% of patients achieve 2 or more lines of vision improvement and up to 55% of patients achieving vision >20/50 [110, 111]. Contrast sensitivity also improves significantly after ERM surgery even when vision does not improve, and this correlates well with Quality of Life measures and represents a better measure of surgical advantages [112, 113]. Stereopsis is another visual functional that improves after ERM surgery and it has been shown that stereopsis is worse in patients with ERM as compared with controls [114, 115, 116].

Often double peel is employed to ensure more complete removal of ERM and to ensure there are lesser chances of ERM recurrence [117, 118]. On the contrary, ILM peeling is associated with inner retinal dimpling, micro scotomas and has no impact on final VA. Therefore, some surgeons may reserve this for recurrent ERMs [119].

In modern day vitrectomy, the use of small gauge instruments has improved the surgical outcomes and post-operative rehabilitation after ERM surgery. Some studies have shown better outcome with 27-gauge vitrectomy plat form whereas others have shown equivocal results [120]. The surgery starts with core vitrectomy followed by check for PVD facilitated with triamcinolone acetonide. If PVD is not present, then induction of PVD is carried out. There has been recent interest in non vitrectemozing surgery with newer small gauge instruments. This technique potentially reduces the chances of post-operative cataract and retinal tears, but the general adaptation of this technique has been limited due to persistent presence of floaters due to vitreous debris [121, 122]. ERM peel is facilitated by chromovitrectomy. The vital dyes used for ERM staining include trypan blue (TB) and for ILM, brilliant blue G (BBG) and indocyanine green (ICG) have been extensively used [123]. More recently, combinations of TB and BBG have been made available to facilitate dual membrane staining. The use of ICG has become less popular now because of purported macular toxicity [123]. This has been more pronounced in cases of macular hole and studies have shown no difference in macular toxicity in cases of ERM surgery [124, 125]. ICG has better binding with ILM as compared to ERM and a negative staining technique can also be used to peel ERM where ERM can be visualized as an area with no staining surrounded by clearly visible ILM [126, 127]. A number of studies reporting ICG toxicity have been published with varying incubation times, osmolarity, and concentrations. In general, RPE toxicity has been more commonly demonstrated with a solution that has an osmolarity of <270 mOsm, a concentration above 0.5%, and incubation time > 30 seconds. Additional factors that may be associated with RPE toxicity include application technique and duration of light exposure [128].

Usual application time of vital dyes to effectively stain the ERM and ILM range from 1 to 3 minutes. Once the staining of membranes is complete, there are a number of techniques to peel the ERM. Once way is to identify the edge of ERM and lift it with help of end grasping forceps. In cases where edge is not clearly visible, it can be created with bent picks or bent micro vitreo retinal (MVR) blades, flex loops or diamond dusted scrapers [129]. Peeling of ERM and ILM can also be facilitated with traditional pinch and peel technique using high magnification with contact or indirect posterior segment viewing systems. ILM peeling or end grasping forceps are used for peeling the membranes in a circular manner centered on the fovea and ranging up to the vascular arcades [130]. Peeling of secondary membranes employs similar techniques except that some additional maneuvers may be required to address the cause of sERMs. These may include laser or cryopexy for retinal tears or detachment, laser photocoagulation for PDR and retinal vein occlusions, anti VEGF treatment for neovessels arising from retina or choroid and intravitreal or preocular steroids of ERMs secondary to uveitis [131].

8.3 Surgical complications

As with any other vitrectomy surgery, ERM surgery is also associated with complications such as retinal detachment and tears, cataract formation, infection, and vitreous hemorrhage. With the advancements in OCT, certain particular complications of ERM surgery have surfaced which require additional discussion [132].

8.3.1 Swelling of arcuate nerve fiber layer (SANFL)

This is a temporary complication (lasts 3 months) which at times is followed by focal RNFL thinning in the temporal macula [133]. It is postulated that ILM peeling during ERM surgery causes swelling of arcuate nerve fiber layers especially in the papillomacular bundle (Figure 8). This may be caused by either damage to the Müller cell foot plates or direct retinal nerve fiber layer (RNFL) damage. It is noted as swelling of RNFL on OCT [134].

Figure 8.

Blue arrow shows swelling of arcuate nerve fiber layer and yellow arrow shows dissociated optic nerve fiber layer.

8.3.2 Nasal displacement of fovea

This condition arises after ERM peeling surgery when there is imbalance between the temporal and nasal mechanical forces due to release of traction caused by ERM [135]. If there is a difference in the retinal thinning between temporal and nasal retina (temporal retinal thinning is more pronounced than nasal retina) after ERM surgery, then the chances of nasal displacement are higher [135].

8.3.3 Dissociated optic nerve fiber layer (DONFL)

Another name of DONFL is “inner retinal dimpling” proposed by Spaide who reclassified this condition in OCT scan (Figure 8). One hypothesis is that it represents changes secondary to regeneration of damaged Müller cells [136, 137].

8.3.4 Full thickness paracentral macular hole

There can be a full thickness paracentral macular hole that occurs at the point of start of ILM peel or where the ILM peel ends. These are asymptomatic and no intervention is usually needed [138].

8.4 Post-operative functional results

There is usually a 2-line improvement after ERM surgery. In the absence of vision improvement, there is improvement in metamorphopsia [139]. Post-operative vision can keep on improving for next 3 years. This is because of continued resolution of macular edema and near normal organization of retinal layers [140].

9. Conclusion

The main risk factors the precedes the formation of iERMs is PVD and occurs in 2% of the population [1, 13, 68, 69]. One of the major associations of PVD is age [13]. With the advent of new diagnostic tools and molecular analysis methods, we now better understand the progressive and sequential processes that lead to formation of iERMs and sERMs [17]. Currently, we do not have the biochemical or diagnostic tools to predict the formation of ERMs but with improving knowledge about the cellular processes (proteins, cytokines, cellular lines), it is hoped that we may identify biochemical or genetic markers for the development and progression of ERMs. With advancements in the clinical classification of ERM severity, some simple and practical guidelines and grading systems have evolved in last decade that helps us understand the optimal timing for intervention and predicting functional outcomes after surgery [78, 79, 80, 81, 82, 83, 84]. We, currently do not have any prophylactic treatment of ERMs. With current small gauge instruments, our threshold to address ERMs has considerably decreased with safe outcomes and quick post-operative functional recovery [112, 113].

Conflict of interest

The author declares no conflict of interest.