**2. Epidemiology and pathophysiology**

Idiopathic membranes and membranes associated with RD or retinal tears, as well as their management, are the most prevalent clinical phenotypes of ERM proliferation [10]. The prevalence of iERM in the general population is estimated to be approximately 6 to 7% [11], with the disease's prevalence increasing significantly with age. Specifically, according to epidemiologic studies, the prevalence of ERM formation is increasing from 2% under the age of 60 years to 12 to 20% beyond the age of 70 [2, 10], while it is bilateral in 10 to 30% of cases [11-12]. Nevertheless, lower prevalence rates have been recorded in Chinese populations [13]. Moreover, histopathological findings suggest the presence of iERMs in 1.7 to 3.5% of autopsied eyes [12-14]. Regarding secondary ERMs, the disease incidence is 4 to 8% following surgical management of rhegmatogenous RD [15-16] and 1 to 2% following precautionary treatment of peripheral retinal breaks [17].

The proposed theories regarding the underlying pathophysiology of ERM formation have been controversial; furthermore, the exact origin and type of cells that make up different types of ERMs remains an area of debate [14, 18]. Nevertheless, the general consensus is that the primary cell component in iERMs is of glial origin, more recently called laminocytes, while

secondary ERMs predominantly consist of different cell types that do not originate in the neuroretina, such as retinal pigment epithelial (RPE) cells, macrophages, myofibroblasts and fibrocytes, depending on the causative ocular pathology [19-20]. Posterior vitreous detachment (PVD), complete as well as partial, seems to play an important role in ERM pathogenesis. Specifically, it is well documented that PVD is present in up to 90% of eyes with iERMs and in fact, in all eyes with ERM formation associated with RD or retinal breaks [21]. It is therefore believed that glial cells from the neuroretina migrate through breaks in the ILM occurring during the PVD process and start to proliferate on the inner retinal surface, resulting in the formation of iERMs [18]. According to another theory, residual vitreous on the retinal surface following PVD may be related to the development of iERMs [22]. Nevertheless, iERM forma‐ tion is also known to take place in eyes without PVD. In these cases, different theories have been proposed, including the migration of cells of glial origin through pre-existing ILM breaks or due to ILM thinning [23]; additionally, the vitreous traction theory proposes that astrocytic gliosis, commonly triggered by ischaemia and vitreous traction, can also occur in cases with partial or anomalous PVD (vitreoschisis), or even in the absence of PVD due to the coexistence of vitreous-retina attachment (complete or partial) with simultaneous vitreous movement, which is facilitated by the natural liquefying process of the vitreous, ultimately generating active vitreous traction and therefore, astrocytic gliosis [24]. On the other hand, the formation of secondary ERMs that develop in association with retinal breaks, RD, cryopexy and laser photocoagulation, most likely represents a form of mild PVR caused by the release of RPE cells into the vitreous cavity and their subsequent proliferation on the retinal surface [25]. In their recent work, Snead and colleagues [26], using surgically peeled membrane specimens and normal cadaver globes, determined the principal cell populations that characterize different types of ERMs, thus allowing for a clinical classification of ERMs based on their histopatho‐ logical characteristics, which reflect different aetiologies. Specifically, they concluded that idiopathic ERMs are characterized by laminocytes and ILM, while the presence of laminocytes both on the ILM surface and the posterior hyaloid membrane (PHM) in cases of PVD raised the hypothesis that separation can likely occur due to the cellular activity of pre-existing laminocytes at the vitreoretinal interface. In ERMs, secondary to RD, retinal tears, PVR, trauma or intraocular inflammation, RPE cells, macrophages, lymphocytes and collagen were the primary cell components indicating that these ERMs most likely represent a tissue repair reaction. Furthermore, ERMs, secondary to PDR and vasoproliferative tumours, consisted mainly of capillaries and acellular stromal tissue, and were therefore characterized as neovas‐ cular ERMs, with hypoxia likely being the main stimulus for their formation.

ties and as a result, leads to variable visual symptoms and visual impairments, primarily due to the mechanical distortion of the macular area. The condition's variable effect on vision is determined primarily by the severity of the retinal distortion and the location of the membrane. ERMs can be classified according to their underlying aetiology into: a) primary or idiopathic ERMs (iERMs) [2], when no underlying causative factor or ocular pathology can be associated with the membrane formation; b) secondary ERMs, which are commonly found in association with retinal breaks and retinal detachment (RD), RD surgical repair, laser photocoagulation, retinal cryopexy, proliferative vitreoretinopathy (PVR), retinal vascular diseases, intraocular inflammation and ocular trauma [3-7]. Additionally, international literature describes rare cases of secondary ERM formation associated with type-2 neurofibromatosis [8]. In addition to the etiological classification, Gass proposed a clinical classification of ERMs based on biomicroscopical findings [9], according to which ERMs can be differentiated into three grades: **a.** Grade 0 membranes or cellophane maculopathy. Translucent membranes not associated

**b.** Grade 1 membranes or crinkled cellophane maculopathy. Membranes causing an irregular wrinkling of the inner retinal surface due to the contraction of the overlying membrane. Increased vascular tortuosity and perimacular vessels being pulled toward

**c.** Grade 2 membranes or macular puckers. Opaque and thick membranes that cause profound retinal distortion and tractional phenomena. Cystic macular oedema, intrareti‐ nal haemorrhages, exudates, foveal ectopia and shallow localized retinal detachment can

Idiopathic membranes and membranes associated with RD or retinal tears, as well as their management, are the most prevalent clinical phenotypes of ERM proliferation [10]. The prevalence of iERM in the general population is estimated to be approximately 6 to 7% [11], with the disease's prevalence increasing significantly with age. Specifically, according to epidemiologic studies, the prevalence of ERM formation is increasing from 2% under the age of 60 years to 12 to 20% beyond the age of 70 [2, 10], while it is bilateral in 10 to 30% of cases [11-12]. Nevertheless, lower prevalence rates have been recorded in Chinese populations [13]. Moreover, histopathological findings suggest the presence of iERMs in 1.7 to 3.5% of autopsied eyes [12-14]. Regarding secondary ERMs, the disease incidence is 4 to 8% following surgical management of rhegmatogenous RD [15-16] and 1 to 2% following precautionary treatment

The proposed theories regarding the underlying pathophysiology of ERM formation have been controversial; furthermore, the exact origin and type of cells that make up different types of ERMs remains an area of debate [14, 18]. Nevertheless, the general consensus is that the primary cell component in iERMs is of glial origin, more recently called laminocytes, while

with retinal or visual distortion.

116 Advances in Eye Surgery

the fovea are common findings.

be accompanying findings in biomicroscopy.

**2. Epidemiology and pathophysiology**

of peripheral retinal breaks [17].

In addition, recent studies implementing novel immunohistochemistry and proteomics techniques have attempted to elucidate the role of inflammatory cytokines and trophic factors in ERM development and proliferation. Basic fibroblast growth factor (bFGF) supports the survival and proliferation of glial cells and may play an important role in the ERM pathogen‐ esis [27]. Harada et al. [28] encountered increased reactivity and expression of the bFGF in the majority of iERM and PDR-associated ERM cases studied. In accordance, similar results were reported by Chen et al. [29]. Other studies stressed the role of the nerve growth factor (NGF) and the transforming growth factors β1 and β2 (TGFβ1 and TGFβ2) in iERM formation and their subsequent contraction [30-31]. Authors suggested that these trophic factors possibly induce the differentiation of glial cells into myofibroblasts, granting ERMs their contractile properties [30-31]. Increased expression of the vascular endothelial growth factor (VEGF) has also been reported in iERMs, though its exact role in the disease pathogenesis still remains unknown [29, 32-33]. Furthermore, proteins such as apolipoprotein A-1, transthyretin, αantitrypsin, serum albumin and interleukin-6 have also been proposed to participate in the pathogenesis of the disease [27, 34].
