Morphology of partial-thickness macular defects: presumed roles of Müller cells and tissue layer interfaces of low mechanical stability

Abstract

Background: The pathogenesis of partial-thickness macular defects and the role of Müller glial cells in the development of such defects are not well understood. We document the morphological characteristics of various types of partial-thickness macular defects using spectral-domain optical coherence tomography, with the focus on tractional and degenerative lamellar holes, and discuss possible pathogenic mechanisms.

Methods: A retrospective case series of 61 eyes of 61 patients with different types of partial-thickness macular defects is described.

Results: Partial-thickness macular defects are caused by anteroposterior or tangential traction onto the fovea exerted by the partially detached posterior hyaloid and epiretinal membranes, respectively. Tractional elevation of the inner Müller cell layer of the foveola-without (outer lamellar holes, foveal pseudocysts) or with a disruption of this layer (tractional lamellar holes, macular pseudoholes)-produces an elevation of the inner layers of the foveal walls (nerve fiber layer to outer plexiform layer [OPL]) and a schisis between the OPL and Henle fiber layer (HFL). With the exception of outer lamellar holes, the (outer part of the) central outer nuclear layer and the external limiting membrane remain nondisrupted in the various types of partial-thickness defects. Degenerative lamellar holes are characterized by cavitations between the inner plexiform layer and HFL of the foveal walls; many cases have lamellar hole-associated epiretinal proliferation (LHEP). Proliferating cells of the disrupted Müller cell cone may contribute to the development of LHEP and fill the spaces left by degenerated photoreceptors in the foveal center.

Conclusions: It is suggested that morphological characteristics of partial-thickness macular defects can be explained by the disruption of the (stalk of the) Müller cell cone in the foveola and the location of tissue layer interfaces with low mechanical stability: the boundary with no cellular connections between both Müller cell populations in the foveola, and the interface between the OPL and HFL in the foveal walls and parafovea. We propose that the development of the cavitations in degenerative lamellar holes is initiated by traction which produces a schisis between the OPL and HFL, and enlarged by a slow and chronic degeneration of Henle fibers and bipolar cells.Trial registration retrospectively registered, #143/20-ek, 04/03/2020.

Keywords: Epiretinal membrane; Fovea; Lamellar hole; Macular defect; Müller glia; Vitreofoveal traction.

Fig. 1

Schistic splitting of the foveal walls between the outer plexiform layer (OPL) and Henle fiber layer (HFL) as a characteristic of tractional lamellar holes. The images show SD-OCT scans through the fovea and parafovea of 5 eyes of 5 patients. In c, e, f the months after the first visit (0) are indicated left of the images. a The presence of an operculum (arrowhead) may suggest that traction exerted by the posterior hyaloid removed the inner Müller cell layer from the foveola. The tissue of the foveal walls splitted between the OPL and HFL. b The scans were recorded at and 85 months after the first visit. The orientations of the scans are shown at the left side. The arrowhead indicates a tissue band with medium reflectivity extending from the center of the foveola to the edge of the elevated dorsal foveal wall. c Development of a tractional lamellar hole from a macular pseudohole. The orientations of the scans are shown above. Note the presence of epiretinal membranes (ERM) which bridged deep retinal folds in the fovea and parafovea. Note also that the fovea externa was not disrupted. d Circumpapillary scans recorded in the same eye 34.5 months after the first visit. The right image shows a part of the image at higher magnification. Note the schistic splitting between the OPL and ONL at various sites of the peripapillary retina which was associated with a disappearance of the ellipsoid zone (EZ) line. e Development of a lamellar hole by tractional detachment of the foveola from the retinal pigment epithelium (RPE) and subsequent disruption of the junction between the inner layer of the foveola and the nasal foveal wall. The disruption allowed a reattachment of the central outer nuclear layer (ONL) at the RPE and was associated with a schistic splitting of the foveal walls between the OPL and HFL. An ERM was present in the nasal parafovea. f Development of a tractional lamellar hole after disruption of the Müller cell cone. Scale bars, 200 µm. ELM: external limiting membrane; GCL: ganglion cell layer; ELM: external limiting membrane; INL: inner nuclear layer; IPL: inner plexiform layer; IZ: interdigitation zone; NFL: nerve fiber layer

Fig. 2

Schistic splitting of the foveal walls between the outer plexiform layer (OPL) and Henle fiber layer (HFL) in foveal pseudocysts (a‒e), outer lamellar holes (f–h), and macular pseudoholes (j, k). The images show linear SD-OCT scans through the fovea and parafovea of 24 eyes of 24 patients. a Foveal pseudocysts which were likely produced by tangential traction exerted by epiretinal membranes (ERM). b‒e Foveal pseudocysts which were produced by anteroposterior traction exerted by the partially detached posterior hyaloid. c Tractional development of a foveal pseudocyst. The months after the first visit (0) are indicated left of the images. Note the hyperreflectivity of the inner Müller cell layer of the foveola. d, e Regeneration of the foveal shape after relief of the vitreofoveal traction. f‒h The outer lamellar holes were produced by vitreomacular traction exerted by the posterior hyaloid attached to the foveola. In f, the orientations of the scans are shown above. i‒k Macular pseudoholes without (i) and with (j, k) a schistic splitting of the foveal walls. The scans in k were recorded at the first visit (0) and 6 months later. Pars plana vitrectomy with internal limiting membrane and ERM peeling was performed 2.5 months after the first visit. Scale bars, 200 µm. ELM: external limiting membrane; EZ: ellipsoid zone; GCL: ganglion cell layer; INL: inner nuclear layer; IPL: inner plexiform layer; IZ: interdigitation zone; NFL: nerve fiber layer; ONL: outer nuclear layer; RPE: retinal pigment epithelium

Fig. 3

Cavitations of the foveal pit in the lower foveal walls as a characteristic of degenerative lamellar macular holes in 6 eyes of 6 patients. The months after the first visit (0) are indicated above or left of the images. Yellow and pink arrowheads indicate lamellar hole-associated epiretinal proliferation (LHEP). The arrows indicate tissue bands of medium reflectivity which connect glial cells in the center of the foveola with LHEP at the inner surface of the foveal walls. a–d Radial scans of four cases of a degenerative lamellar macular hole. The orientations of the SD-OCT scans are shown at the left side. The blue arrowhead in a indicates the adherence of a membrane to the temporal parafovea. e Development of a degenerative lamellar hole. f Development of a full-thickness macular hole from a lamellar hole. Scale bars, 200 µm. ELM, external limiting membrane; EZ, ellipsoid zone; GCL, ganglion cell layer; HFL, Henle fiber layer; INL, inner nuclear layer; IPL, inner plexiform layer; IZ, interdigitation zone; NFL, nerve fiber layer; ONL, outer nuclear layer; OPL, outer plexiform layer; RPE, retinal pigment epithelium

Fig. 4

In degenerative lamellar holes, Müller cells in the foveola are connected to the middle part of lamellar macular hole-associated epiretinal proliferation (LHEP) at the inner surface of the foveal walls. The images show SD-OCT scans through the fovea and parafovea of 6 eyes of 6 patients. The orientations of the scans are shown at the left side. The blue arrowheads indicate LHEP. The yellow arrowheads indicate vitreomacular adhesions. In the smaller images at the right side, the middle part of LHEP is indicated by yellow color, cells of the Müller cell cone are indicated by green color, and the posterior hyaloid is indicated by pink color. Scale bars, 200 µm. ELM, external limiting membrane; ERM: epiretinal membrane; EZ: ellipsoid zone; GCL: ganglion cell layer; HFL: Henle fiber layer; INL: inner nuclear layer; IPL: inner plexiform layer; IZ: interdigitation zone; NFL: nerve fiber layer; ONL: outer nuclear layer; OPL: outer plexiform layer; RPE: retinal pigment epithelium

Fig. 5

The connection between Müller cells in the foveola and the middle part of lamellar macular hole-associated epiretinal proliferation (LHEP) at the inner surface of the foveal walls is visible only in certain orientations of SD-OCT scans. The images show radial scans through the fovea and parafovea in the left eye of a 77 year-old man. The orientations of the scans are shown at the left side. The arrowheads indicate LHEP. In the smaller images at the right side, the middle part of LHEP is indicated by yellow color, and cells of the Müller cell cone are indicated by green color. Note that there are no connections between Müller cells in the foveola and LHEP in the scans which show cavitations of the foveal pit into the lower foveal walls (scans 1‒3 and 6) whereas in the scans 4 and 5, foveal walls without cavitations display such connections. Scale bars, 200 µm. ELM: external limiting membrane; EZ: ellipsoid zone; GCL: ganglion cell layer; HFL: Henle fiber layer; INL: inner nuclear layer; IPL: inner plexiform layer; IZ: interdigitation zone; NFL: nerve fiber layer; ONL: outer nuclear layer; OPL: outer plexiform layer; RPE: retinal pigment epithelium

Fig. 6

Example of a full-thickness macular hole with lamellar macular hole-associated epiretinal proliferation (LHEP) at the inner surface of the foveal walls. The images show SD-OCT scans through the fovea and parafovea of the right eye of a 76 year-old man. The orientations of the scans are shown at the left side. The arrowheads indicate LHEP. In the smaller images at the right side, the middle part of LHEP is indicated by yellow color, and cells of the Müller cell cone are indicated by green color. Scale bars, 200 µm. ELM: external limiting membrane; ERM: epiretinal membrane; EZ: ellipsoid zone; GCL: ganglion cell layer; HFL: Henle fiber layer; INL: inner nuclear layer; IPL: inner plexiform layer; IZ: interdigitation zone; NFL: nerve fiber layer; ONL: outer nuclear layer; OPL: outer plexiform layer; RPE: retinal pigment epithelium

Fig. 7

Comparison of schistic and degenerative cavitations in tractional and degenerative lamellar holes, respectively. The images show linear SD-OCT scans through the fovea of 18 eyes of 18 patients. a Tractional lamellar holes. b Degenerative lamellar holes. The arrows indicate the levels of the widest lateral extensions of schistic (a) and degenerative cavitations (b). The arrowheads indicate morphological connections between Müller cells in the foveola and lamellar macular hole-associated epiretinal proliferation. Scale bars, 200 µm. ELM: external limiting membrane; ERM: epiretinal membrane; EZ: ellipsoid zone; GCL: ganglion cell layer; HFL: Henle fiber layer; INL: inner nuclear layer; IPL: inner plexiform layer; IZ: interdigitation zone; NFL: nerve fiber layer; ONL: outer nuclear layer; OPL: outer plexiform layer; RPE: retinal pigment epithelium

Fig. 8

Hypothetical mechanisms of the development of partial- and full-thickness macular defects. a Schematic section through a fovea. The Müller cell cone in the foveola is shown in pink. The tissue layer interfaces of low mechanical stability are indicated by red lines: the boundary between the Müller cell cone and the Henle fiber layer (HFL)/outer nuclear layer (ONL) in the foveola, and the interface between the outer plexiform layer (OPL) and HFL in the foveal walls and parafovea. In addition, the vertical stalk of the Müller cell cone in the center of the foveola has a low mechanical stability. b The horizontal layer of the Müller cell cone keeps the inner layers of the foveal walls (nerve fiber layer [NFL] to OPL) together. Normally, the stalk of the Müller cell cone prevents the elevation of the inner layers of the foveal walls. When anteroposterior or tangential tractions exerted by the posterior hyaloid or epiretinal membranes (ERM) disrupt the stalk, foveal pseudocysts associated with an elevation of the inner layers of the foveal walls may develop. The elevation of the inner layers of the foveal walls disrupts the tissue between the OPL and HFL resulting in the formation of schistic cavities which are obliquely traversed by Henle fiber bundles. c, d Anteroposterior or tangential traction may cause a disruption of the connection between the Müller cell cone and the foveal walls, resulting in an elevation of the inner layers of the walls. This may produce a schisis between the OPL and HFL in the foveal walls (c) which may develop to degenerative cavitations of the foveal pit into the lower foveal walls (d). Bundles of Henle fibers composed of photoreceptor axons and the outer processes of Müller cells of the foveal walls keep the schistic cavities together (c). The degenerative cavitations may be enlarged by a degeneration of Henle fibers (d). The formation of a degenerative lamellar hole is often associated with a disruption of the fovea externa (d). Macular pigment-containing cells of the Müller cell cone may contribute to the development of the lamellar hole-associated epiretinal proliferation (LHEP), likely by the formation of a tissue bridge between the foveola and the inner surface of the foveal walls (d). e Anteroposterior traction may cause the formation of an outer lamellar hole characterized by a large pseudocyst in the foveola, schistic splitting of the foveal walls between the OPL and HFL, cystic cavities in the inner nuclear layer (INL), and a gap in the whole central outer retina including the ELM. A disruption of the Müller cell cone produces a full-thickness macular hole (FTMH) from an outer lamellar hole. f Fluid accumulation in the foveal walls may produce edematous cysts between the OPL and HFL, and in the INL. Enlargement of the cysts causes a large elevation of the inner layers of the walls; the Müller cells are obliquely stretched and straightened, and transmit the tension to the outer retina. This produces a detachment and a centrifugal displacement of the central ONL and photoreceptors resulting in an enlargement of the FTMH. g Schematic summary of pathogenic steps which mediate the development of partial-thickness macular defects and FTMH. h Pathogenic events which may be implicated in the development of degenerative cavitations of the foveal pit into the lower foveal walls. EZ: ellipsoid zone; GCL: ganglion cell layer; IPL: inner plexiform layer; IZ: interdigitation zone; NFL: nerve fiber layer; PVD: posterior vitreous detachment; RPE: retinal pigment epithelium; VMA: vitreomacular adhesion; VMT: vitreomacular traction