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Purpose: To describe evolution and progression of a lamellar macular hole (LMH) with "lamellar hole-associated epiretinal proliferation (LHEP)" using spectral-domain optical coherence tomography and fundus autofluorescence., Methods: Observational case report., Results: We report on a 63-year-old male patient demonstrating a complete history of LMH development with LHEP occurring during a follow-up period of 8 years. Presenting with a normal foveal contour and attached posterior vitreous at first visit, an LMH developed shortly after incomplete posterior vitreous detachment with vitreopapillary adhesion. On spectral-domain optical coherence tomography images, progression of the LMH including enlargement of the intraretinal cavitation and decrease in the retinal thickness were documented. An increase of LHEP was first documented 6 months after LMH evolution. One month after cataract surgery and 6 years after the first visit, a full-thickness macular hole developed that closed spontaneously after 4 weeks. Localization of LHEP had moved into the foveal defect toward the outer retinal layers. Thereafter, the LMH was stable, and the patient presented with a visual acuity of 20/25., Conclusion: Proper follow-up time is important for studying eyes with an LMH. Epimacular cell proliferation shows progression over time that appears to be associated with morphologic changes of the LMH including shape of the lamellar defect, amount of LHEP, and contractive properties of epiretinal tissue. The presence of LHEP was documented shortly after posterior vitreous detachment.

Withanolides are steroidal lactones widespread in Nightshade plants with often potent antiproliferative activities. Additionally, the structural diversity of this compound class holds much potential for the discovery of novel biological activity. Here, we report two newly characterised withanolides, named irinans, from Physalis peruviana with highly unusual truncated backbones that resemble mammalian androstane sex hormones. Based on biomimetic chemical reactions, we propose a model that links these compounds to withanolide biosynthesis. Irinans have potent antiproliferative activities, that are however lower than those of 4ß-hydroxywithanolide E. Our work establishes androwithanolides as a new subclass of withanolides.

Pharmacological vitreolysis with ocriplasmin is an effective treatment option for eyes with vitreomacular traction. Pre-marketing and post-marketing clinical studies revealed an improvement of visual function in ocriplasmin treated eyes and showed a release of traction in up to 78% of cases. Treatment success is related to patient selection based on positive predictive factors. Adverse events, such as visual acuity loss, dyschromatopsia or photopsia are known to be self-limited in the majority of eyes. Structural outer retinal layer changes, such as ellipsoid zone disturbances or subretinal fluid accumulation on SD-OCT analysis, as well as ERG abnormalities, are transient and correlated to VMT release. Surgical outcomes in patients with a prior history of ocriplasmin injection have been shown to be comparable with patients who proceeded directly to surgery without ocriplasmin treatment., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: To describe the morphologic characteristics of the vitreomacular interface in intermediate age-related macular degeneration associated with tangential traction due to premacular membrane formation and to correlate with optical coherence tomography (OCT) findings and clinical data., Methods: Premacular membrane specimens were removed sequentially with the internal limiting membrane from 27 eyes of 26 patients with intermediate age-related macular degeneration during standard vitrectomy. Specimens were processed for immunocytochemical staining of epiretinal cells and extracellular matrix components. Ultrastructural analysis was performed using transmission electron microscopy. Spectral domain optical coherence tomography images and patient charts were evaluated in retrospect., Results: Immunocytochemistry revealed hyalocytes and myofibroblasts as predominant cell types. Ultrastructural analysis demonstrated evidence of vitreoschisis in all eyes. Myofibroblasts with contractile properties were observed to span between folds of the internal limiting membrane and vitreous cortex collagen. Retinal pigment epithelial cells or inflammatory cells were not detected. Mean visual acuity (Snellen) showed significant improvement from 20/72 ± 20/36 to 20/41 ± 20/32 (P < 0.001) after a mean follow-up period of 19 months (median, 17 months). During this period, none of the eyes required anti-vascular endothelial growth factor therapy., Conclusion: Fibrocellular premacular proliferation in intermediate age-related macular degeneration predominantly consists of vitreous collagen, hyalocytes, and myofibroblasts with contractile properties. Vitreoschisis and vitreous-derived cells appear to play an important role in traction formation of this subgroup of eyes. In patients with intermediate age-related macular degeneration and contractile premacular membrane, release of traction by vitrectomy with internal limiting membrane peeling results in significantly functional and anatomical improvement.

Purpose: To report on progression of lamellar hole-associated epiretinal proliferation (LHEP) in eyes with lamellar macular holes (LMH) using spectral-domain optical coherence tomography (SD-OCT), and to correlate with intraretinal changes and visual function., Methods: From a retrospectively reviewed series of 167 eyes with non-full-thickness macular holes, we exclusively included a subgroup of 34 eyes with LMH and LHEP by SD-OCT evaluation. In these eyes, area of LHEP, intraretinal changes of defect diameter, central retinal thickness, defects of the ellipsoid zone and occurrence of a contractive epiretinal membrane were analysed. Additionally, clinical data were documented., Results: Area of LHEP significantly increased during a mean follow-up period of 40.5 months (median 52 months). Analysing intraretinal changes, a significant enlargement of minimum and maximum horizontal lamellar hole diameter was found that correlated with the area of LHEP. Defects of the ellipsoid zone were seen in 65% of the eyes at baseline and in 85% at the end of follow-up. Increase of maximum horizontal hole diameter and ellipsoid zone defects correlated with a decline of visual acuity. Fifty per cent of patients with LMH and LHEP also demonstrated extrafoveal typical contractive epiretinal membranes with retinal folds., Conclusions: Long-term follow-up revealed an increase of the area of LHEP in eyes with LMH that correlated with the enlargement of lamellar hole diameter and ellipsoid zone defects. Our data delineate the progression of intraretinal changes in association with a decline of visual function in this subgroup of LMH eyes., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Purpose: To assess treatment effects following intravitreal injection of ocriplasmin for vitreomacular traction (VMT), with or without full-thickness macular hole (FTMH), in real-life setting., Methods: This is a monocentric, retrospective, consecutive series of 82 eyes from 82 patients who underwent ocriplasmin treatment between July 2013 and December 2016. We included 57 eyes with pure VMT, 17 eyes with small FTMHs, and eight eyes with medium FTMHs. Primary outcome measures were VMT release and MH closure rates. Secondary outcomes were visual acuity (VA), morphological changes, and subjective visual impairment after 1, 3, and 6 months and at last follow-up., Results: After a median follow-up of 10 months, VMT release was achieved by pharmacologic vitreolysis in 57% of all eyes, whereas the macular hole closure rate was 32%. In those presenting with five or more positive prognostic factors (PPF), eyes with pure VMT showed nonsurgical traction release in 88%, and FTMHs were released in 93%, with a closure rate of 20%. Small FTMHs closed in 41% and medium FTMHs in 13%. The mean change in VA (LogMAR) was -0.07 ± 0.24 (median - 0.10) in all eyes. Subretinal fluid accumulation and ellipsoid zone changes were seen in 31% and 37% of all eyes, respectively. They were more frequent in eyes with traction release, but were self-limited., Conclusions: In a real-life setting, release of VMT by ocriplasmin injection can be achieved in the majority of eyes, relying on a strict patient selection. Closure of FTMHs rather correlates with hole diameter than with presence of PPF, and remains a rare finding in medium FTMHs.

Purpose: To introduce a human cell culture technique for investigating in-vitro behavior of primary epiretinal cells and membrane contraction of fibrocellular tissue surgically removed from eyes with idiopathic macular pucker., Methods: Human epiretinal membranes were harvested from ten eyes with idiopathic macular pucker during standard vitrectomy. Specimens were fixed on cell culture plastic using small entomological pins to apply horizontal stress to the tissue, and then transferred to standard cell culture conditions. Cell behavior of 400 epiretinal cells from 10 epiretinal membranes was observed in time-lapse microscopy and analyzed in terms of cell migration, cell velocity, and membrane contraction. Immunocytochemistry was performed for cell type-specific antigens., Results: Cell specific differences in migration behavior were observed comprising two phenotypes: (PT1) epiretinal cells moving fast, less directly, with small round phenotype and (PT2) epiretinal cells moving slowly, directly, with elongated large phenotype. No mitosis, no outgrowth and no migration onto the plastic were seen. Horizontal contraction measurements showed variation between specimens. Masses of epiretinal cells with a myofibroblast-like phenotype expressed cytoplasmatic α-SMA stress fibers and correlated with cell behavior characteristics (PT2). Fast moving epiretinal cells (PT1) were identified as microglia by immunostaining., Conclusions: This in-vitro technique using traction application allows for culturing surgically removed epiretinal membranes from eyes with idiopathic macular pucker, demonstrating cell behavior and membrane contraction of primary human epiretinal cells. Our findings emphasize the abundance of myofibroblasts, the presence of microglia and specific differences of cell behavior in these membranes. This technique has the potential to improve the understanding of pathologies at the vitreomacular interface and might be helpful in establishing anti-fibrotic treatment strategies.

Purpose: To describe ultrastructure and immunocytochemistry of internal limiting membrane peelings after unsuccessful treatment with ocriplasmin, to compare with untreated eyes, and to correlate with clinical imaging data., Design: Interventional comparative case series., Methods: Internal limiting membrane specimens were removed from 10 eyes with small macular holes and vitreomacular traction during vitrectomy after intravitreal ocriplasmin injection without release of traction or closure of macular holes during follow-up. Based on optical coherence tomography analysis, specimens from 10 other eyes without ocriplasmin treatment served as controls. All specimens were processed as flat mounts for phase-contrast microscopy followed by immunolabeling for fluorescence microscopy and embedding in epoxy resin with serial sectioning for transmission electron microscopy., Results: Despite the absence of contractive epiretinal membranes on optical coherence tomography, we found epiretinal cells and vitreous collagen fibrils on the internal limiting membrane in specimens removed from eyes with and without previous pharmacologic vitreolysis. Immunolabeling revealed glial cells and hyalocytes in macular holes, whereas myofibroblasts were predominant in vitreomacular traction. There was no apparent damage of the vitreoretinal interface after unsuccessful pharmacologic vitreolysis compared to untreated controls., Conclusions: Epiretinal cell proliferation and vitreous collagen fibrils with close adhesions to the internal limiting membrane are not always detectable by optical coherence tomography or may not have been recognized. Since they are associated with unsuccessful ocriplasmin treatment, presence and topography of epiretinal cells and vitreous collagen remnants on the internal limiting membrane should be further elucidated in order to refine criteria and indications for case selection in pharmacologic vitreolysis., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To compare immunocytochemical and ultrastructural characteristics of "lamellar hole-associated epiretinal proliferation" in lamellar macular holes with "conventional epiretinal membrane" in macular pseudoholes., Design: A consecutive observational case series, laboratory investigation., Methods: We analyzed surgically excised flat-mounted internal limiting membrane specimens and epiretinal membrane specimens removed from 25 eyes of 25 patients with lamellar macular holes (11 eyes) and macular pseudoholes (14 eyes) using interference and phase-contrast microscopy, immunocytochemistry, and transmission electron microscopy. By spectral-domain optical coherence tomography, epiretinal material of homogenous reflectivity without contractive properties was categorized as lamellar hole-associated epiretinal proliferation, whereas tractional epiretinal membranes presenting contractive properties were termed conventional epiretinal membrane., Results: Lamellar hole-associated epiretinal proliferation was seen in 73% of eyes with lamellar macular hole. Eyes with macular pseudohole presented with conventional epiretinal membrane. In lamellar hole-associated epiretinal proliferation, positive immunoreactivity for anti-glial fibrillary acidic protein, hyalocyte markers, and anti-collagen type I and III was seen. In contrast, specimens of macular pseudoholes were positive for α-smooth muscle actin and anti-glial fibrillary acidic protein, predominantly. Cellular ultrastructure showed that lamellar hole-associated epiretinal proliferation of lamellar macular holes mainly consisted of fibroblasts and hyalocytes, whereas myofibroblasts dominated in conventional epiretinal membranes of macular pseudoholes., Conclusions: Cells within lamellar hole-associated epiretinal proliferation appear to originate from vitreous and possess less contractive properties than cells of conventional epiretinal membranes. Our findings point to differences in pathogenesis in a subgroup of lamellar macular holes presenting lamellar hole-associated epiretinal proliferation on the retinal surface., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To report on epiretinal membrane (ERM) characteristics and photoreceptor layer integrity of lamellar macular holes (LMHs) and macular pseudoholes (MPHs), and to compare with clinical course in operated and untreated eyes., Methods: We consecutively reviewed the charts of patients with LMH and MPH between 2003 and 2013. For clinical analysis, we included 87 eyes (48 with LMH, 39 with MPH) with a minimum follow-up of 6 months. Of these, we included 64 eyes (37 with LMH, 27 with MPH) for high-resolution spectral domain optical coherence tomography analysis with examinations fulfilling the required resolution and quality of optical coherence tomography images. Epiretinal membranes were termed "typical tractional ERM" if presenting with contractive properties, or "atypical epiretinal tissue" if presenting as epiretinal material of homogeneous medium reflectivity without contractive properties. Integrity or discontinuity of the inner and outer segment (IS/OS) and the external limiting membrane (ELM) was evaluated by differentiating between "defect present" and "defect absent.", Results: In eyes with LMH, atypical epiretinal tissue presented in 29%, typical tractional ERMs were seen in 57%, and a combination of both in 14%. In contrast, eyes with MPH rarely presented atypical epiretinal tissue, and typical tractional ERMs were found in 89%. Comparing cases with LMH, eyes with atypical epiretinal tissue showed significantly more defects of the IS/OS and the ELM than eyes with typical tractional ERM. Both IS/OS and ELM defects correlated with a significant lower best-corrected visual acuity. Defects of the IS/OS were seen in 41% of LMH and 11% of MPH. Defects of the ELM revealed in 27% of LMH and in 11% of MPH. Operated eyes with disrupted IS/OS but intact ELM had significant better best-corrected visual acuity than eyes with defects in both layers., Conclusion: Atypical epiretinal tissue is related to the presence of photoreceptor layer defects and to poor visual acuity. It seems that integrity of the ELM is most important for functional recovery after surgery in both LMH and MPH. The presence of atypical epiretinal tissue in eyes with LMH may represent differences in the pathogenesis compared with MPH, and might have therapeutic implications for the proceeding with macular surgery in selected cases.

Purpose. To describe morphology of lamellar hole-associated epiretinal proliferation (LHEP) removed from eyes with lamellar macular holes (LMH). Methods. Based on optical coherence tomography data, 10 specimens of LHEP were removed from 10 eyes with LMH during standard vitrectomy. Specimens were prepared for correlative light and electron microscopy (CLEM) using an immunonanogold particle of 1.4 nm diameter that was combined with a fluorescein moiety, both having been attached to a single antibody fragment. As primary antibodies, we used antiglial fibrillary acidic protein (GFAP), anti-CD45, anti-CD64, anti-α-smooth muscle actin (α-SMA), and anticollagen type I and type II. Results. In LHEP, GFAP-positive cells possess ultrastructural characteristics of fibroblasts and hyalocytes. They represent the major cell types and were densely packed in cell agglomerations on vitreous collagen strands. Epiretinal cells of LHEP rarely demonstrated contractive properties as α-SMA-positive myofibroblasts were an infrequent finding. Conclusion. CLEM indicates that epiretinal cells in LHEP might originate from the vitreous and that remodelling processes of vitreous collagen may play an important role in pathogenesis of eyes with LMH.

Purpose. To assess functional and morphological alterations following video-documented surgery for epiretinal membranes. Methods. Forty-two patients underwent video-documented 23-gauge vitrectomy with peeling of epiretinal (ERM) and inner limiting membrane (ILM). Patient assessment was performed before and 3 and 6 months including best corrected visual acuity (BCVA), slit lamp biomicroscopy, SD-OCT, and central 2° and 18° microperimetry. In addition, all video-documented areas of peeling on the retinal surface were evaluated postoperatively using an additional focal 2° microperimetry. Retinal sensitivity and BCVA were correlated with morphological changes (EZ and ELM) in the foveal region and in regions of membrane peeling. Results. Overall, BCVA increased from 0.6 (±0.2) to 0.2 (±0.2) logMAR after 6 months with an increase in retinal sensitivity (17.9 ± 2.7 dB to 26.8 ± 3.1 dB, p < 0.01). We observed a significant correlation between the integrity of the EZ but not of the ELM and the retinal sensitivity, overall and in peeling areas (p < 0.05). However, no significant correlation between alterations in the area of peeling and overall retinal sensitivity regarding visual acuity gain could be observed after 6 months (p > 0.05). In contrast, overall postoperative retinal sensitivity was significantly decreased in patients with a visual acuity gain lower than 2 lines (p < 0.05) correlating with EZ defects seen in OCT. Conclusions. Mechanical trauma of epiretinal membrane and ILM peeling due to the use of intraocular forceps may affect the outer retinal structure. Nevertheless, these changes seem to have no significant impact on postoperative functional outcome.