Foveal regeneration after resolution of cystoid macular edema without and with internal limiting membrane detachment: presumed role of glial cells for foveal structure stabilization

Abstract

Aim: To document with spectral-domain optical coherence tomography the morphological regeneration of the fovea after resolution of cystoid macular edema (CME) without and with internal limiting membrane (ILM) detachment and to discuss the presumed role of the glial scaffold for foveal structure stabilization.

Methods: A retrospective case series of 38 eyes of 35 patients is described. Of these, 17 eyes of 16 patients displayed foveal regeneration after resolution of CME, and 6 eyes of 6 patients displayed CME with ILM detachment. Eleven eyes of 9 patients displayed other kinds of foveal and retinal disorders associated with ILM detachment.

Results: The pattern of edematous cyst distribution, with or without a large cyst in the foveola and preferred location of cysts in the inner nuclear layer or Henle fiber layer (HFL), may vary between different eyes with CME or in one eye during different CME episodes. Large cysts in the foveola may be associated with a tractional elevation of the inner foveal layers and the formation of a foveoschisis in the HFL. Edematous cysts are usually not formed in the ganglion cell layer. Eyes with CME and ILM detachment display a schisis between the detached ILM and nerve fiber layer (NFL) which is traversed by Müller cell trunks. ILM detachment was also found in single eyes with myopic traction maculopathy, macular pucker, full-thickness macular holes, outer lamellar holes, and glaucomatous parapapillary retinoschisis, and in 3 eyes with Müller cell sheen dystrophy (MCSD). As observed in eyes with MCSD, cellophane maculopathy, and macular pucker, respectively, fundus light reflections can be caused by different highly reflective membranes or layers: the thickened and tightened ILM which may or may not be detached from the NFL, the NFL, or idiopathic epiretinal membranes. In eyes with short single or multiple CME episodes, the central fovea regenerated either completely, which included the disappearance of irregularities of the photoreceptor layer lines and the reformation of a fovea externa, or with remaining irregularities of the photoreceptor layer lines.

Conclusion: The examples of a complete regeneration of the foveal morphology after transient CME show that the fovea may withstand even large tractional deformations and has a conspicuous capacity of structural regeneration as long as no cell degeneration occurs. It is suggested that the regenerative capacity depends on the integrity of the threedimensional glial scaffold for foveal structure stabilization composed of Müller cell and astrocyte processes. The glial scaffold may also maintain the retinal structure after loss of most retinal neurons as in late-stage MCSD.

Keywords: Müller cell sheen dystrophy; Müller glia; astrocytes; cystoid macular edema; fovea; internal limiting membrane detachment.

Figure 1. Regeneration of the foveal morphology after resolution of cystoid macular edema (CME)

The images show SD-OCT scans through the fovea and parafovea of 11 eyes of 10 patients. The months after the first visit (0) are indicated left of the images. A-G: Morphological regeneration of the fovea after resolution of CME in eyes of different patients. Arrowheads indicate adhesions of the partially detached posterior hyaloid at the para- and perifovea, respectively. H, I: Two eyes with CME with different patterns of edematous cyst distribution, characterized by the absence (H) and presence (I) of a large cyst in the foveola. H: The CME was likely induced by traction of the partially detached posterior hyaloid which adhered at the parafovea (arrowheads). I: Note that the stalk of the Müller cell cone is stretched and elongated. The arrowhead points to hyperreflective dots which represent light reflections at exudates in the inner nuclear layer (INL). J: Simultaneous CME in the foveas of the left (left side) and right eyes (right side) of a patient with uveitis which was treated with systemic prednisolone pulse therapy. The CME resolved rapidly during the subsequent systemic immunosuppressive therapy. Scale bars, 200 µm. ELM: External limiting membrane; EZ: Ellipsoid zone; GCL: Ganglion cell layer; HFL: Henle fiber layer; IPL: Inner plexiform layer; IZ: Interdigitation zone; NFL: Nerve fiber layer; ONL: Outer nuclear layer; OPL: Outer plexiform layer; RPE: Retinal pigment epithelium.

Figure 2. Regeneration of the foveal morphology after twofold (A-D) and multiple episodes (E, F) of cystoid macular edema (CME)

The images show SD-OCT scans through the fovea and parafovea of 6 eyes of 6 patients. The months after the first visit (0) are indicated left of the images. A: Twofold development and resolution of an edematous cyst in the foveola. The yellow arrowheads point to adhesion of the partially detached posterior hyaloid. The red arrowhead indicates the glial tissue membrane at the external limiting membrane (ELM) which keeps the central outer fovea together. B: The CME was likely associated with traction of the partially detached posterior hyaloid which adhered at the parafovea (arrowheads). C: Note the irregular reflection intensities of the central ellipsoid zone (EZ) and interdigitation zone (IZ) lines during both episodes of CME which were abrogated at the end of the examination period. D: An eye with different patterns of edematous cyst distribution in both episodes of CME. E: An eye with three CME episodes associated with a detachment of the central outer fovea from the RPE and subsequent regeneration of the foveal morphology. F: An eye with sixfold development of CME. The arrowheads point to foveal adhesions of the partially detached posterior hyaloid. Scale bars, 200 µm. GCL: Ganglion cell layer; HFL: Henle fiber layer; INL: Inner nuclear layer; IPL: Inner plexiform layer; NFL: Nerve fiber layer; ONL: Outer nuclear layer; OPL: Outer plexiform layer; RPE: Retinal pigment epithelium.

Figure 3. Detachment of the internal limiting membrane (ILM) from the nerve fiber layer (NFL) in different retinal disorders

The images show SD-OCT scans through the fovea and parafovea of 12 eyes of 12 patients. The months after the first visit (0) are indicated left of the images. A: Five eyes with cystoid macular edema (CME) and ILM detachment in the tissues at the right side. The images also display a foveoschisis between the outer plexiform layer (OPL) and Henle fiber layer (HFL), cystic cavities in the ganglion cell layer (GCL) and inner nuclear layer (INL), and in four eyes a detachment of the fovea from the retinal pigment epithelium (RPE). In three eyes, the GCL is degenerated. The tissues at the left side of three eyes show no abnormalities with the exception of a large foveoschisis in the HFL. B: An eye with two episodes of CME and ILM detachment. C: Enlargement of an outer lamellar hole (OLH) with ILM detachment and foveoschisis between the OPL and HFL in an eye with CME. D: Fovea of an eye with macular pucker with ILM detachment in the para- and perifovea at the right side. E: An eye with a full-thickness macular hole with ILM detachment in the foveal walls and parafovea. F: An eye with high myopia. The fovea (middle) and wide retinal areas are split by a schisis within the HFL. In addition, there is ILM detachment and schistic cavities in the GCL and INL of the inferior perifovea (right side). In the superior perifovea (left side), the edge of the thickened ILM and parts of the NFL are detached from the remaining NFL (arrowhead). G: An eye with glaucomatous parapapillary retinoschisis in the nasal retina. The image above shows a circumpapillary SD-OCT scan. The image below shows a horizontal SD-OCT scan through the excavated optic disc. H: Development of an OLH with inner and outer retinoschisis in an eye with myopic traction maculopathy. Scale bars, 200 µm. ELM: External limiting membrane; EZ: Ellipsoid zone; IPL: Inner plexiform layer; IZ: Interdigitation zone; ONL: Outer nuclear layer; PRS: Photoreceptor segments; RPE: Retinal pigment epithelium.

Figure 4. Müller cell sheen dystrophy (MCSD) is associated with cystoid macular edema (A, B) and internal limiting membrane (ILM) detachment (A-C)

The images show fundus images and SD-OCT scans through the fovea and parafovea of 5 eyes of 3 patients. The arrowheads with different colors in Ac, B, and Cb indicate corresponding light reflections in the fundus images and SD-OCT scans, suggesting that the light was reflected at the detached ILM and nerve fiber layer (NFL; left side in Cb). A: Fundus images (a) of the left (left side) and right eye (right side), and SD-OCT records (b-d) of a patient with late-stage MCSD. The images shown in c and d were recorded three weeks after recording of the images shown in a and b. a: The macular region of the right eye appears dark because of massive subretinal fluid. b: Circumpapillary SD-OCT scans of the left (above) and right eye (middle and below). The yellow arrows indicate vertical hyperreflective trunks which traverse the tissue from the detached ILM to the outer plexiform layer (OPL). c: Horizontal SD-OCT scans through the foveal center and the retina at two different distances from the fovea in the left eye. d: Composite SD-OCT image of the fovea (right side) and more peripheral retinal areas (left side) of the right eye. There was cystoid edema in the foveal tissue and a serous detachment of the fovea from the retinal pigment epithelium (RPE). The inset shows the mid-peripheral retina at two sites at higher magnification. The arrowheads indicate two hyperreflective trunks which spanned vertically between the detached ILM and the OPL. Note the light reflection at the crest of the ILM fold. B: Fundus images (above) and SD-OCT scans (below) of an eye with MCSD of another patient. The images were recorded at the first visit (left) and 1.5mo later (right). C: Fundus and SD-OCT images recorded in the right (a, b) and left eye (c) of a further patient with MCSD. The images in a and b were recorded at the first visit (0mo) and 46mo later. 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; ONL: Outer nuclear layer.

Figure 5. Fundus light reflections in eyes with cellophane maculopathy and macular pucker, respectively

A: Fundus (above) and SD-OCT images (below) of two eyes of two patients (left and right) with cellophane maculopathy. B: Fundus (above) and SD-OCT images (below) of two eyes of two patients (left and right) with macular pucker and fundus reflections. Left: There is also a macular pseudohole. The arrows indicate the directions of the retinal folds in the mid-peripheral retina. Right: Note that the light-reflecting part of the epiretinal membrane (ERM) is thicker than nonreflecting part. Scale bars, 200 µm. GCL: Ganglion cell layer; INL: Inner nuclear layer; IPL: Inner plexiform layer; NFL: Nerve fiber layer.

Figure 6. Foveal deformation caused by tractional cystoid macular edema

A: Perifoveal posterior vitreous detachment. The partially detached posterior hyaloid causes anterior traction which stretches the foveal center. B: The development of an edematous cyst in the central fovea results in a detachment of the inner Müller cell layer from the Henle fiber layer (HFL)/outer nuclear layer (ONL) in the foveola. This is associated with an elongation and subsequent disruption of the stalk of the Müller cell cone. Edematous cysts are also present in the inner nuclear layer (INL) of the foveal walls which are spanned by bundles of Müller and bipolar cell fibers. The enlargement of the cysts causes an anterior traction which is transmitted by the stretched and straightened Müller cells of the foveal walls from the inner to the outer foveal layers. This may cause abnormalities of the central photoreceptor layer and (when the elevation of the inner layers of the foveal walls exceeds the length of Müller cells and their capacity for cell stretching) a detachment of the fovea from the retinal pigment epithelium (RPE). Fluid accumulation in the subretinal space may impair the fluid clearance from the outer foveal layers through the RPE, resulting in the formation of edematous cysts in the HFL. ELM: External limiting membrane; EZ: Ellipsoid zone; GCL: Ganglion cell layer; IPL: Inner plexiform layer; IZ: Interdigitation zone; NFL: Nerve fiber layer; OPL: Outer plexiform layer.

Figure 7. Schematic representation of the glial cell network (red) which provides the mechanical stability of the normal fovea (left above) and of foveas with various kinds of tractional disorders

In foveal pseudocysts generated by anterior hyaloidal traction (left middle), the horizontal layer of the Müller cell cone is detached from the Henle fiber layer (HFL)/outer nuclear layer (ONL) in the foveola. In foveal pseudocysts generated by contractile idiopathic epiretinal membranes (ERM; left below), traction of ERM causes a drawbridge elevation of the inner layers [nerve fiber layer (NFL) to outer plexiform layer (OPL)] of the foveal walls and a foveoschisis between the OPL and HFL. A foveoschisis can also be found in tractional lamellar holes (TLH) and outer lamellar holes (OLH). In TLH, degenerative lamellar holes (DLH), and full-thickness macular holes (FTMH), the horizontal layer of the Müller cell cone in the foveola is disrupted. In OLH and FTMH, the external limiting membrane (ELM) is disrupted; this is also the case after a tractional disruption of the entire foveola. In cystoid macular edema (CME), foveal pseudocysts, and OLH, the vertical stalk of the Müller cell cone in the foveola may be disrupted while the horizontal layer of the Müller cell cone keeps the inner layers of the foveal walls together. GCL: Ganglion cell layer; EZ: Ellipsoid zone; INL: Inner nuclear layer; IPL: Inner plexiform layer; IZ: Interdigitation zone; RPE: Retinal pigment epithelium.