The vitreoretinal interface and its role in the pathogenesis of vitreomaculopathies

Transcription

1 English version of "Die vitreoretinale Grenzfläche und ihre Rolle in der Pathogenese vitreomakulärer Erkrankungen" DOI /s Springer-Verlag Berlin Heidelberg 2015 J. Sebag VMR Institute for Vitreous Macula Retina, Huntington Beach The vitreoretinal interface and its role in the pathogenesis of vitreomaculopathies The vitreous body is the largest structure of the human eye. It consists mostly of water and the structural components collagen and hyaluronan. The vitreous body is a clear and solid gel in youth (. Fig. 1). With aging, there are molecular changes that alter the gel structure, inducing fiber formation [1] and liquefaction. These destabilize the vitreous body and promote collapse, with separation from the retina if there is concurrent weakening of vitreoretinal adhesion. The result is an innocuous posterior vitreous detachment (PVD), a phenomenon that occurs in more than two-thirds of elderly individuals. There are, however, many instances when PVD is not innocuous and causes visual dysfunction at times severe. The primary reasons for this anomaly relate to the nature of the vitreoretinal interface. The current article reviews the anatomy of the vitreoretinal interface, the pathophysiology of anomalous PVD and vitreoschisis, as well as the role these play in the pathogenesis of vitreomaculopathies. Vitreoretinal anatomy The limiting membrane of the retina is formed by the contiguous basement membranes of Müller cells. The limiting membrane of the vitreous is formed by the posterior vitreous cortex, a structure composed of densely packed vitreous collagen fibrils [2]. Between the two is an interdigitating extracellular matrix (ECM) that contains elements of each, described by Heegaard as the vitreoretinal border region [3]. Inner limiting membrane The inner limiting membrane (ILM) like all other basement membranes (BMs) is transparent, very thin, and difficult to visualize by conventional histology. The ILM can, however, be readily detected by either immunocytochemistry using antibodies specific to BM proteins or transmission electron microscopy (TEM;. Fig. 2). High-resolution TEM of fetal human eyes shows the ILM to be an ECM sheet with a thickness of less than 100 nm. The fetal human ILM can be subdivided into an outer lamina lucida layer that faces the ECM of the vitreoretinal border region, a central electron-dense lamina densa, and a second inner lamina lucida that faces the endfeet of the retinal Müller glia cells [3, 4]. By adulthood, these clearly distinct layers are no longer apparent within the ILM: nevertheless there are potential cleavage planes at these locations, both during posterior vitreous detachment and during surgical membrane peeling [4]. As studied by TEM, the ILM is thickest in the macular region [3]. However, TEM requires chemical fixation and dehydration of tissues, resulting in artifacts. The massive shrinkage of the ILM after dehydration is due to the loss of water that is tightly bound by the glycosaminoglycans of the abundant proteoglycans. Recently, atomic force microscopy (AFM) has been introduced to examine the morphology and biomechanical properties of isolated and flat-mounted BMs [5, 6], including measurements of ILM thickness. AFM examination revealed that the thickness of embryonic chick and adult human ILMs is two- to four-times greater than previously measured by TEM [5, 6]. AFM demonstrates that water is the most abundant (50%) component of the ILM mass, tightly bound by proteoglycans. This is important because the hydration status determines the rigidity of the ILM, which influences the ease of surgical peeling. Topographic variations In the entire fundus, the anterior border of the ILM has a smooth appearance (. Fig. 2). However, the posterior border of the ILM varies in structure depending on location within the eye: in the periphery, the posterior border of the ILM is smooth and resembles the anterior border; at the posterior pole (. Fig. 2), the posterior border of ILM undulates in an irregular configuration, filling the crevices between underlying retinal glia and nerve fibers. Immunostaining for collagen IV or laminin in ILM whole mounts detects that the foveal ILM is a distinct circular area. AFM measurements showed that the foveal ILM has a thickness of approximately 100 nm, whereas the parafoveal ILM has a thickness of up to 3 µm [7], consistent with earlier TEM reports [8]. The very thin ILM at the fovea and the proximity of large blood vessels in the nerve fiber layer [9] suggest that both areas are possible exit points for migrating retinal cells, Excerpted in part from: Vitreous in Health and Disease (J. Sebag, editor). Springer, New York, (Vitreous/ ). 1

2 Fig. 1 8 Human vitreous. This eye was obtained during autopsy of a 9-month-old girl. The sclera, choroid, and retina were dissected off the vitreous body, which is still attached to the anterior segment. Owing to the young age of the donor, the vitreous body maintains a solid gel consistency, which does not lose its shape despite being situated on a surgical towel at room temperature. (From [1], reproduced with kind permission) Fig. 2 8 Vitreoretinal Interface. Transmission electron micrograph of the vitreoretinal interface showing the inner limiting membrane (ILM; arrowheads) and the transition (arrow) from the undulations of the posterior border of the ILM in the posterior pole (lower right hand corner of the image), to the straight configuration of the posterior border of the ILM in the peripheral fundus (upper left hand corner of the image). (Courtesy of Professor Christos Haritoglou; original magnification =4800:1) which then proliferate and form premacular membranes (see below). Origin and resynthesis of the inner limiting membrane All BM proteins are multidomain molecules that polymerize (laminin, collagen type IV), crosslink (collagen type IV), or bind to each other (laminin, agrin, nidogen/entactin, perlecan, collagen type IV; 2 Der Ophthalmologe 2015 [4]). The cell receptors required for BM assembly are members of the integrin family and dystroglycan. The presence of the ILM adjacent to the endfeet of the Müller glial cells suggests the retina, specifically the Müller cells, as the major source of ILM proteins. Surprisingly however, with the exception of the mrna for agrin, ILM protein mrnas are not detected in the neural retina [10, 11, 12, 13]. In situ hybridization experiments have rather suggested that ILM proteins are secreted into the vitreous body by the lens and ciliary body, and that these diffuse to the retinal surface where they assemble into the ILM [4]. This hypothesis further proposes that the role of the retina is to provide the cell surface receptors of the neuroepithelial cells for ILM assembly. Current data suggest that the ILM is primarily assembled during embryonic and neonatal stages of development, and that this activity is greatly reduced in the adult [11, 14]. However, it has recently been shown that Müller cells can synthesize ILM collagens in vitro [15]. Furthermore, studies in primates found that ILM peeling is followed by resynthesis of the ILM over the course of several months [16]. Since ILM peeling is a very common microsurgical intervention for macular hole closure and treatment of other tractional vitreomaculopathies, it is important to understand that it is effective because it assures removal of the entire outer vitreous cortex and the proliferating cells lying on the ILM; however, in light of the available experimental studies, it must also be recognized that in most cases, only a partial inner layer of the ILM is removed certainly in successful cases. Removing the ILM in its entire thickness can damage the inner retinal cells, reducing vision. Aging of the inner limiting membrane The most obvious age-related change of the human ILM is an increase in thickness with progressing age. During fetal stages, the ILM has a thickness of less than 100 nm and the classical trilamellar structure of BMs. With aging, the ILM becomes thicker and loses its trilaminar structure to become amorphous. However, these lamella remain potential cleavage planes an observation that offers an important explanation for why ILM peeling does not injure the supporting Müller cells, since only the inner layer of the ILM is peeled, not the entire ILM.» With aging, the inner limiting membrane becomes thicker A systematic analysis of ILMs from over 20 patients shows a progressive increase in ILM thickness with advancing age [17]. The continued age-related increase in ILM thickness indicates that ILM protein synthesis occurs in the adult human eye over the entire life span, but probably at reduced levels compared to earlier developmental stages. Increases in ILM thickness have only been recorded for the long-lived humans and primates, and not reported in any short-lived animal species [17]. In addition to an increase in thickness, the ILM also becomes more rigid with advancing age [4, 6]. Posterior vitreous cortex The posterior vitreous cortex is μm thick [18, 19] and consists of densely packed collagen fibrils ([18, 19, 20],. Fig. 3). Within the posterior vitreous there is lamellar organization of vitreous collagen fibrils resulting in the appearance of sheets on immunohistochemistry (. Fig. 4). These too are important potential cleavage planes, both as sites of tissue separation during posterior vitreous detachment and as potential cleavage planes during membrane peel surgery. Because of vitreoschisis, many experienced surgeons have peeled what was thought to represent full-thickness posterior vitreous cortex with pathologic membranes, only to find additional membranes still attached to the macula. Hyalocytes Hyalocytes are mononuclear phagocytes embedded in the posterior vitreous cortex (. Fig. 5), widely spread apart in a single layer situated μm from the ILM in the posterior pole, and adjacent to the basal lamina of the ciliary body epithelium at the pars plana and vitreous base. Balazs previously proposed that hyalo-

3 Abstract cytes are remnants of the adventitia of the hyaloid blood vessels that fill the vitreous body early during embryogenesis. However, recent studies identified that rodent hyalocytes contain macrophage cell surface markers, that these cells are derived from bone marrow, and that they are replaced every 7 months. Quantitative studies of cell density in bovine [21] and rabbit [22] vitreous found the highest density of hyalocytes in the region of the vitreous base, followed by the posterior pole, with the lowest density at the equator. In response to inducting stimuli and inflammation, hyalocytes may become phagocytic, as well as stimulatory for monocyte recruitment from the circulation, thus beginning the cascade of events associated with inflammation and wound repair [21, 22, 23, 24, 25]. It is also important to consider that hyalocytes are the first cells to be exposed to any migratory or mitogenic stimuli. Therefore, hyalocytes play an important role in the pathophysiology of proliferative disorders at the vitreoretinal interface, particularly proliferative vitreoretinopathy (PVR) and premacular membrane formation. Hyalocytes capacity to synthesize collagen was first demonstrated by Newsome and colleagues [26]. This, as well as their ability to respond to various growth factors by inducing contractile forces via the collagen matrix, renders hyalocytes key cells in the development and contraction of membranes that are attached to the retina in various proliferative vitreoretinal disorders, such as PVR and macular pucker.» Hyalocytes play an important role in the pathophysiology of proliferative disorders at the vitreoretinal interface Anomalous posterior vitreous detachment Posterior vitreous detachment (PVD) is a separation between the posterior vitreous cortex and the ILM of the retina. PVD can be localized, partial, or total; i.e., throughout the entire posterior pole up to the posterior border of the vitreous base [1, 27, 28]. For PVD to occur without complications, two different processes must develop to similar extents: F weakening of vitreoretinal adhesion F vitreous liquefaction English version of "Die vitreoretinale Grenzfläche und ihre Rolle in der Pathogenese vitreomakulärer Erkrankungen" DOI /s Springer-Verlag Berlin Heidelberg 2015 J. Sebag The vitreoretinal interface and its role in the pathogenesis of vitreomaculopathies Abstract The vitreoretinal interface consists of the inner limiting membrane of the retina, the posterior vitreous cortex, and an intervening extracellular matrix. Hyalocytes are mononuclear phagocytes embedded in the posterior vitreous cortex, in a single layer of sparse density. At the macula, anomalous posterior vitreous detachment (PVD) results in either fullthickness vitreous cortex adhesion with vitreomacular traction syndrome, or partialthickness adhesion due to vitreoschisis, a split in the posterior vitreous cortex. Anomalous PVD with vitreoschisis splitting behind the level of the monolayer of hyalocytes leaves a relatively thin hypocellular membrane attached to the macula. Vitreoschisis anterior to the level of the hyalocytes leaves a thicker cellular membrane. Persistent vitreopapillary adhesion promotes outward (from the fovea) tangential traction and is therefore associated with macular holes. Inward (centripetal) tangential traction results in macular pucker, almost always in the absence of persistent vitreopapillary adhesion. Keywords Vitreous body Vitreoretinal interface Posterior vitreous cortex Vitreoschisis Macular hole Macular pucker Vitreomacular traction Vitreopapillary adhesion An innocuous PVD occurs when a critical amount of liquefaction has formed and there is enough weakening of vitreoretinal adhesion to allow the collapsing vitreous to separate away from the retina. Such a PVD occurs without untoward consequences [28, 29, 30, 31]. However, it is known that during youth, there is strong adhesion between the posterior vitreous cortex and the ILM, primarily at the vitreous base and the posterior pole. In some unfortunate individuals, this strong adhesion persists throughout life; e.g., at sites of retinal lattice. In other unfortunate individuals there is precocious gel liquefaction and the posterior vitreous collapses away from the retina before there has been enough weakening of vitreoretinal adhesion. Peripherally, the adhesion appears to be focal; while vitreoretinal adhesion at the posterior pole is fascial, encompassing the disc, macula, and retinal blood vessels [32]. Focal adherence in the periphery contributes to retinal tears and detachments. Fascial adherence in the posterior pole (. Fig. 6) predisposes to vitreomaculopathies that are typically membranous in character. Anomalous PVD occurs when there is insufficient weakening of vitreoretinal adhesion and gel liquefaction exceeds the degree of weakening of vitreoretinal adherence, thus exerting traction at the vitreoretinal interface [27, 29, 33]. There are various possible consequences of anomalous PVD, depending upon where the gel is most liquefied and where the posterior vitreous cortex is most firmly adhered to the retina (. Fig. 7). If the degree of vitreoretinal dehiscence is sufficient to allow syneresis (collapse), the vitreous body pulls away from the retina without untoward sequelae. When there is insufficient vitreoretinal dehiscence, the destabilized liquefied vitreous cannot pull away cleanly, resulting in anomalous PVD. This process can occur as full-thickness anomalous PVD, when the entire posterior vitreous cortex stays attached to an area of retina, or partial thickness when there is splitting of the posterior vitreous cortex between the lamellae described above (. Fig. 4). Vitreomacular traction Vitreomacular traction (VMT) is defined as vitreomacular adhesion with structural alteration of the underlying neural retina [34]. There is often perifoveal vitreous cortex detachment from the retinal surface, with persistent adhesion of the vitreous cortex within a 3-mm radius of the fovea. VMT can be classified by the size of the vitreous attachment (focal if less than 1500 μm; broad if greater than 1500 μm), associated with intraretinal structural changes and/or elevation of the fovea above the retinal pigment epi- 3

4 Fig. 3 8 Human posterior vitreous cortex. Scanning electron micrograph of the posterior aspect of the human posterior vitreous cortex after peeling off the retina. The appearance of the dense collagen matrix is exaggerated by specimen fixation (dehydration), but in situ, the posterior vitreous cortex has the highest density of collagen fibrils in the vitreous body. (From [4], reproduced with kind permission) Fig. 4 8 Primate vitreoretinal interface. Immunohistochemistry using anti-aba fluorescent antibodies shows the inner limiting membrane (ILM; arrowheads) at the interface between the retina (above) and vitreous (below). Just anterior to (beneath) the ILM is the posterior vitreous cortex. A lamellar structure can be readily seen. Between the lamellae are potential cleavage planes during anomalous posterior vitreous detachment, which would result in vitreoschisis; or which during membrane peel surgery, would result in persistent adherence of pathologic vitreous membranes to the retina ILM. (From [50], reproduced with kind permission) thelium (RPE), but no full-thickness interruption of all retinal layers [34, 35]. Recently, an international panel of experts, the International Vitreomacular Traction Study (IVTS) Group, convened to develop a new classification system of vitreomacular traction based upon anatomic criteria alone primarily on the findings of optical coherence tomography (OCT) evaluation [34]. Determining the presence of VMT requires that the following anatomic criteria be evident on at least one B- mode OCT scan: F perifoveal vitreous cortex detachment from retinal surface, F macular attachment of the vitreous cortex within a 3-mm radius of the fovea, and F association of attachment with distortion of the foveal surface, intraretinal structural changes, elevation of the fovea above the RPE, or a combination thereof. While vitreomacular adhesion/traction can be a primary cause of vision disturbance, it can also be a contributing factor to a variety of other macular disorders. Age-related macular degeneration Full-thickness vitreomacular adhesion/ traction may be important in patients with age-related macular degeneration 4 Der Ophthalmologe 2015 (AMD). Recent studies have identified that true PVD is protective against progression toward a neovascular form of AMD, while anomalous PVD with persistent VMT may promote choroidal neovascularization.» Anomalous PVD was determined to be a risk factor for the development of exudative AMD Krebs et al. investigated the state of the posterior vitreous using ultrasound and OCT in exudative AMD, compared to nonexudative AMD eyes and controls. Eyes with exudative AMD had significantly lower rates of detached vitreous compared to the nonexudative eyes and controls [36]. OCT found significantly higher rates of vitreomacular adhesion in exudative AMD. These findings were confirmed by Robison et al. [37], who reported similar findings in a study that also ruled out genetic and environmental factors. Anomalous PVD was determined to be a risk factor for the development of exudative AMD and several hypothetical mechanisms have been proposed [37, 38, 39]. Cystoid macular edema and macular cysts Cystoid macular edema (CME) can be associated with VMT and occur in cases of unifocal vitreofoveal traction arising from anomalous PVD [40]. Broad areas of attachment with traction can cause generalized thickening of the macula, vascular leakage on fluorescein angiography, macular schisis, and CME. Macular cysts that result from chronic edema need to be distinguished from the cystoid spaces created by vitreous traction in macular holes (lamellar and full-thickness) and macular pucker with vitreopapillary adhesion [41]. The presence of macular traction cysts is usually associated with decreased visual acuity and distortion, but generally resolves quickly after the release of traction with little remaining visual deficit [42]. Diabetic macular edema Systemic conditions such as diabetes induce biochemical [43] and structural [44] alterations in vitreous. The result is diabetic vitreopathy [45], an important contributor to the pathobiology of proliferative diabetic vitreoretinopathy. Histopathological findings showed that retinal traction caused by shrinking of the vitreous body may result in a combination of retinoschisis and retinal detachment. Ultrasound [46] and histopathologic [47] stud-

5 Fig. 5 8 Human hyalocytes. a Posterior aspect of human vitreous body with retina dissected off the posterior vitreous cortex imaged by dark-field slit illumination. The many highly refractile points represent cells embedded within the posterior vitreous cortex. b Phase contrast microscopy of human posterior vitreous cortex demonstrates the presence of mononuclear cells. c Transmission electron microscopy of human hyalocyte. A mononuclear cell is seen embedded within the dense collagen fibril network of the vitreous cortex (black C). The lobulated nucleus (N) contains dense marginal chromatin (white C). In the cytoplasm there are mitochondria (M), dense granules (arrows), vacuoles (V), and microvilli (Mi). (Magnification 1670:1. From [1], reproduced with kind permission. Courtesy of JL Craft and DM Albert, Harvard Medical School, Boston) Fig. 6 8 Posterior vitreous in a 14-year-old boy. Postmortem dark-field slit microscopy of the posterior vitreous body reveals a foveal imprint (white arrow) and linear branching structures that resemble the pattern of the retinal vasculature (black arrows) emanating from a hole corresponding to the prepapillary in the posterior vitreous cortex. (From [32], reproduced with kind permission) ies have shown that patients with proliferative diabetic retinopathy very often have clear evidence of vitreoschisis. OCT studies have also found vitreoschisis in diabetic macular edema [48], the most common cause of vision loss in diabetic patients. Vitreoschisis PVD is associated with vitreous cortex remnants at the fovea in 44% of human eyes studied at autopsy with scanning electron microscopy [49]. When these remnants are a layer or sheet of posterior vitreous cortex, the term vitreoschisis is employed [50]. Proliferation of hyalocytes and migration of glial cells can result in a cellular membrane at the vitreoretinal interface. Although previously called an epiretinal membrane (ERM), this membrane is best referred to as a premacular membrane (PMM). The term ERM is incorrect because of the following reasons: epiretinal means adjacent to the retina, which could refer to a subretinal membrane; however, the membranes in question are always anterior to the macula, which is a more precise term than retina. Furthermore, the spatial relationship to the macula plays an important role. Therefore, a far more accurate and preferable term is premacular membrane or PMM. The term macular pucker should be used to refer to distortion or puckering of the macula induced by a PMM (see below). On clinical examination, the inner wall of the vitreoschisis cavity may be confused with a PVD when the posterior layer of the split vitreous cortex remains attached to the ILM of the retina. Ultrasonography can, at times, detect the split layers in vitreoschisis, as has been detected by ultrasound in 20% of eyes with proliferative diabetic retinopathy [46]. OCT detected vitreoschisis in about half of patients with macular pucker and macular holes [50]. Vitreoschisis can have varying effects at the vitreoretinal interface, depending upon the level of the split (. Fig. 8) and whether or not there is persistent vitreopapillary adhesion [41, 51]. Concerning the level of vitreoschisis, the split can occur at various levels within the posterior vitreous cortex, since this tissue is composed of multiple layers or lamellae (see above;. Fig. 4). Furthermore, as described above, the posterior vitreous cortex contains mononuclear phagocytes called hyalocytes, which are embedded in a monolayer approximately μm anterior to the ILM of the retina. If the vitreoschisis split occurs anterior to the level of the hyalocytes, vitreoschisis leaves a relatively thick, cellular membrane attached to the macula. Inward (centripetal to the fovea) contraction of this membrane induces macular pucker. A vitreoschisis split posterior to the hyalocytes leaves a relatively thin and hypocellular premacular membrane. Outward (centrifugal from 5

6 PATHOPHYSIOLOGY OF ANOMALOUS PVD Anomalous Aging and Disease Gel Vitreous and Vitreo-Retinal Adhesion Normal Aging Liquefaction without Vitreo- Retinal Dehiscence Liquefaction with Vitreo-Retinal Dehiscence Innocuous PVD Some cases of macular hole may not have VS Anomalous PVD No vitreoschisis (VS) splitting Vitreoschisis (VS) splits the posterior vitreous cortex partial thickness vitreo-macular adhesion Full thickness vitreous cortex but PVD is only partial Split posterior to hyalocytes thin hypocellular Macular Hole Premacular Membrane membrane Tangential Traction + VPA Centrifugal (outward) tangential contraction Macular Pucker Split anterior to hyalocytes thicker hypercellular membrane on macula + No VPA Centripetal (inward) tangential contraction Vitreo-Papillary Adhesion (VPA)/Traction Peripheral Separation, but Posterior Adhesion Axial Traction Vitreo-Macular Traction (VMT) Exudative AMD Posterior Separation, but Peripheral Traction Retinal Tears Retinal Detachment Fig. 7 9 Anomalous posterior vitreous detachment. Schematic diagram demonstrating the various potential consequences of vitreous gel liquefaction without vitreoretinal dehiscence. PVD posterior vitreous detachment VS vitreoschisis, VPA vitreopapillary adhesion, VMT vitreomacular traction, AMD age-related macular degeneration. (From [33], reproduced with kind permission) the fovea) tangential traction can induce a macular hole, particularly in the presence of vitreopapillary adhesion, as found in nearly 90% of cases [41, 51]. Macular hole Full-thickness macular hole (FTMH) is defined as a foveal lesion with interruption of all retinal layers from the ILM to the RPE, which is usually detected by OCT. There have been various theories of FTMH pathogenesis, such as primary (vitreous traction) or secondary causes (trauma, foveal degeneration, high myopia, exudative AMD, and involutional thinning with PVD). Recently, the IVTS Group differentiated FTMHs based on diameter (small 250 μm; medium μm; large 400 μm), status of vitreous (with or without vitreomacular adhesion), and associated conditions (primary or secondary) [34]. This classification is important, as hole size and the presence or absence of vitreomacular adhesion are of predictive value in terms of anatomical and functional outcomes after pharmacologic or surgical treatment [35].» Hole size and the presence or absence of vitreomacular traction are of predictive value in terms of anatomical and functional outcomes It is clear from recent surgical experience [52, 53] that anomalous PVD is the cause of FTMH. Johnson and Gass [54] originally formulated the tangential traction theory by suggesting that shrinkage of the prefoveal vitreous induces FTMH formation in four stages. However, many cases do not progress through each of these stages. Additionally, not all cases are due to the same cause(s), as there are three possible mechanisms of tangential vitreous traction: fluid vitreous movements and countercurrents, cellular remodeling of cortical vitreous, and contraction of a cellular membrane on the tapered cortical vitreous after vitreoschisis [27, 33]. While the Gass classification has had some utility in the past, OCT-based data have added much to our understanding of the pathogenesis and the progression of FTMH and thus form the basis of the IVTS classification of macular holes [34]. As previously mentioned, the level of splitting in vitreoschisis can vary. If the split occurs posterior to the level of the hyalocytes, a relatively thin hypocellular membrane remains adherent to the pos- 6 Der Ophthalmologe 2015

7 Fig. 8 8 Vitreoschisis. Two potential planes of cleavage during anomalous posterior vitreous detachment with vitreoschisis are demonstrated. A vitreoschisis split anterior to the level of hyalocytes likely plays an important role in macular pucker, while a split posterior to the level of hyalocytes may be important in macular hole pathogenesis. Black C mononuclear cell embedded within the dense collagen fibril network of the vitreous cortex, ILM inner limiting membrane Mi microvilli, N nucleus, white C chromatin, M mitochondria, V vacuoles, and arrows dense granules. (From [33], with kind permission) terior pole (. Fig. 8). OCT-scanning laser ophthalmoscope (SLO) imaging found vitreoschisis in 50% of eyes with FTMH [50]; however, the level of resolution of OCT has been unable to reliably detect the thickness of this tissue or the presence or absence of cells to date. In the remaining 50% of cases, it is plausible that there is full-thickness separation of vitreous from the retina peripherally, with persistent adhesion of full-thickness vitreous cortex posteriorly exerting traction on the macula. In an ultrastructural study of premacular tissue removed during vitrectomy for impending macular holes, Smiddy et al. [55] observed cortical vitreous in all eyes. Vitreopapillary adhesion Vitreopapillary adhesion (VPA) may play an important role in the pathogenesis of certain vitreomaculopathies, as this is present in 88.2% of FTMH eyes with a macular hole. VPA is also prevalent in eyes with intraretinal cystoid spaces in both lamellar macular holes and macular pucker [41, 51]. These cystoid spaces are not the result of exudation, but the consequence of tangential traction; therefore, they are cystoid spaces and not cysts. VPA influences the vector of tangential forces on the macula and induces outward (centrifugal) traction, opening a central dehiscence. As indicated in. Fig. 7, there may be cases of FTMH that do not involve vitreoschisis. It is nonetheless likely that these cases have vitreopapillary adhesion influencing the vector of forces at play during and following anomalous PVD. Macular pucker It was previously held that the cellularity of premacular membranes inducing macular pucker is due to breaks in the inner retina that allow cells to migrate into the vitreoretinal interface. However, there have been no studies to prove this hypothesis. An alternate hypothesis is that vitreoschisis plays an important role in the pathogenesis of macular pucker [56]. If a vitreoschisis split occurs anterior to the level of hyalocytes, these cells remain attached to the macula in a relatively thick premacular membrane. Hyalocytes have the ability to stimulate the migration of monocytes from the circulation, as well as RPE cells and glial cells from the retina. Hyalocytes have also been shown to initiate contraction of premacular membranes under the influence of connective tissue growth factor [57, 58]. Following anomalous PVD with vitreoschisis, premacular membranes can contract and cause significant visual impairment and metamorphopsia, sometimes necessitating surgical intervention. Studies of excised tissue have demonstrated the presence of astrocytes and RPE cells, but there can likely be other cells that can have similar appearances such as hyalocytes. Zhao et al. [52] examined surgically obtained histologic ILM specimens from 79 eyes with macular pucker or vitreomacular traction syndrome and found that hyalocytes constitute one of the major cell types of premacular membranes. It has also been shown that nearly half of all eyes with macular pucker have more than one site of retinal contraction [59]. There is a higher incidence of intraretinal cysts and significantly more macular thickening with three or four foci of retinal contraction, as compared to one or two foci [59]. Finally, in macular pucker there is usually no vitreopapillary adhesion and the vector of tangential traction is inward (centripetal), causing the usual rippling of the inner retina and distortion of the outer retina with inner segment/ outer segment (IS/OS) disruption that is typically seen in macular pucker [56, 60]. Conclusion for clinical practice F The physiological interactions between the vitreous body and the retina are complex. F Anomalous PVD with partial separation of the posterior vitreous cortex from the ILM of the retina may be related to various diseases of the vitreoretinal interface, such as macular holes and premacular membrane formation with macular pucker. F Pathological interactions of the posterior vitreous and the retina also contribute to the pathogenesis of other macular diseases, such as diabetic macular edema and age-related macular degeneration. 7

8 Corresponding address J. Sebag VMR Institute for Vitreous Macula Retina 7677 Center Avenue, suite 400, Huntington Beach California USA Compliance with ethical guidelines Conflict of interest. J. Sebag states that there are no conflicts of interest. In this review there were no human or animal studies. References 1. Sebag J (1989) The vitreous structure, function, and pathobiology. Springer-Verlag, New York 2. Salzmann as cited by Hogan MJ, Alvarado JA, Weddel JE (1971) Histology of the human eye: an atlas and textbook. WB Saunders, Philadelphia, p Heegaard S (1997) Morphology of the vitreoretinal border region. Acta Ophthalmol Scand Suppl 222: Halfter W, Sebag J, Cunningham E (2014) Vitreoretinal interface and inner limiting membrane. In: Sebag J (ed) Vitreous in health and disease. Springer, New York 5. Candiello J, Balasubramani M, Schreiber EM et al (2007) Biomechanical properties of native basement membranes. FEBS J 274: (PMID: ) 6. 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