Jan Darius Unterlauft

Pigment epithelium-derived factor released by Müller glial cells exerts neuroprotective effects on retinal ganglion cells.

Survival of retinal ganglion cells (RGC) is compromised in several vision-threatening disorders such as ischemic and hypertensive retinopathies and glaucoma. Pigment epithelium-derived factor (PEDF) is a naturally occurring pleiotropic secreted factor in the retina. PEDF produced by retinal glial (Müller) cells is suspected to be an essential component of neuron-glial interactions especially for RGC, as it can protect this neuronal type from ischemia-induced cell death. Here we show that PEDF treatment can directly affect RGC survival in vitro. Using Müller cell-RGC-co-cultures we observed that activity of Müller-cell derived soluble mediators can attenuate hypoxia-induced damage and RGC loss. Finally, neutralizing the activity of PEDF in glia-conditioned media partially abolished the neuroprotective effect of glia, leading to an increased neuronal death in hypoxic condition. Altogether our results suggest that PEDF is crucially involved in the neuroprotective process of reactive Müller cells towards RGC.

Enhanced survival of retinal ganglion cells is mediated by Müller glial cell-derived PEDF

The death of retinal ganglion cells (RGC) leads to visual impairment and blindness in ocular neurodegenerative diseases, primarily in glaucoma and diabetic retinopathy; hence, mechanisms that contribute to protecting RGC from ischemia/hypoxia are of great interest. We here address the role of retinal glial (Müller) cells and of pigment-epithelium-derived factor (PEDF), one of the main neuroprotectants released from the glial cells. We show that the hypoxia-induced loss in the viability of cultured purified RGC is due to apoptosis, but that the number of viable RGC increases when co-cultured with Müller glial cells suggesting that glial soluble mediators attenuate the death of RGC. When PEDF was ablated from Müller cells a significantly lower number of RGC survived in RGC-Müller cell co-cultures indicating that PEDF is a major survival factor allowing RGC to escape cell death. We further found that RGC express a PEDF receptor known as patatin-like phospholipase domain-containing protein 2 (PNPLA2) and that PEDF exposure, as well as the presence of Müller cells, leads to an activation of nuclear factor (NF)-κB in RGC. Furthermore, adding an NF-κB inhibitor (SN50) to PEDF-treated RGC cultures reduced the survival of RGC. These findings strongly suggest that NF-κB activation in RGC is critically involved in the pro-survival action of Müller-cell derived PEDF and plays an important role in maintaining neuronal survival.

A 10.0-mm posterior lamellar graft for bullous keratopathy in a buphthalmic eye.

Purpose: To report a case of Descemet stripping endothelial keratoplasty (DSEK) with a large posterior lamellar graft for the treatment of bullous keratopathy secondary to congenital glaucoma. Methods: Bullous keratopathy secondary to unilateral congenital glaucoma with buphthalmos in a 36-year-old man was treated with DSEK. A Descemet endothelium lamella of 10-mm diameter was excised by descemetorhexis. A regular sclerocorneal donor button of 12-mm diameter was manually split using the Melles technique, and a 10-mm diameter donor graft was punched. The graft was implanted as a folded “Taco” into the anterior chamber using forceps and fixed to the host bed using an intracameral air bubble. Results: Immediately after DSEK, the graft showed a small peripheral dehiscence of 1 × 3 mm, which resolved within 2 days. During 30 months of follow-up, the endothelial graft remained well centered, clear, and without any signs of graft rejection. Visual acuity improved from perception of hand movement before operation to 0.2 at 30 months after DSEK. Endothelial cell loss was 33% at 18 months, 44% at 24 months, and 47% at 30 months after operation. Maximum intraocular pressure was 15 mm Hg preoperatively and 16 mm Hg at the last follow-up. Conclusion: DSEK using a corneal graft of 10.0-mm diameter obtained from a normal-sized donor button can be performed safely and effectively in cases of unilateral buphthalmos and secondary corneal decompensation, where a large recipient cornea requires an equivalently sized graft and transplantation of large amounts of donor endothelium.

Müller glial cells inhibit proliferation of retinal endothelial cells via TGF‐β2 and Smad signaling

Neovascularization is a sight‐threatening complication of ischemic proliferative retinopathies. Transforming growth factor (TGF)‐β, a cytokine with multiple functions in the retina, participates in the control of pathological angiogenesis and neovascularization. Retinal glial (Müller) cells produce TGF‐β2 under physiological and post‐ischemic conditions. To characterize glial cell‐derived mediators of angiogenesis regulation in glial‐endothelial interactions in the retina, we co‐cultured primary Müller cells and bovine microvascular retinal endothelial cells (BRECs). Müller cell‐derived TGF‐β2 was bound by the BRECs, which were found to express serine/threonine kinase TGF‐β receptors, and stimulated TGF‐β‐dependent anti‐proliferative signaling pathways. The proliferation of BRECs was attenuated by exogenous TGF‐β2 as well as by the presence of Müller cell culture media. The following intracellular signaling mechanisms were found to be involved in the anti‐angiogenic action of Müller cell‐derived TGF‐β2: (i) binding of TGF‐β2 to BRECs is mediated by the type‐II TGF‐β receptor, leading to (ii) activation and phosphorylation of receptor‐activated Smads; (iii) Müller cell‐derived TGF‐β2 activates Smad2 and Smad3 to (iv) attenuate the phosphorylation state of the MAP kinases, extracellular signal‐regulated kinase (ERK)‐1/‐2. Neutralizing TGF‐β or TGF‐β type‐II receptor or blocking the activation of Smads partially abrogated the effect of Müller cell‐conditioned media on BRECs. Together, our data suggest that Müller cells release TGF‐β2, inhibiting the proliferation of retinal endothelial cells via activation of Smad2/Smad3 and attenuation of ERK signaling. Given the context‐dependent action of TGF‐β2 on angiogenesis, our results may have implications for understanding the pathogenesis of retinal angiopathies, such as diabetic retinopathy, and the anti‐angiogenic role of TGF‐β therein. GLIA 2014;62:1476–1485

Comparison of dynamic contour tonometry and Goldmann applanation tonometry in keratoconus.

Purpose: We performed a comparative study using Goldmann applanation tonometry (GAT) and dynamic contour tonometry (DCT) to measure intraocular pressure (IOP) in eyes with keratoconus. Methods: IOP was measured in 114 eyes of 75 patients with keratoconus (51 men and 24 women; mean age, 36.1 ± 11.2 years) using GAT and DCT in randomized order. Central corneal thickness (CCT), minimal corneal thickness (MCT), and corneal topography were recorded using the Pentacam. Four groups according to Amslers keratoconus classification were composed and analyzed for significant differences of CCT, MCT, GAT, and DCT results. Results: Mean CCT in the 114 keratoconus eyes was 481.1 ± 46.2 μm (range, 334-601 μm). Mean MCT was 453.3 ± 56.3 μm (range, 239-573 μm). Mean IOP measured using GAT was 13.1 ± 2.9 mm Hg, whereas mean IOP measured using DCT was 14.8 ± 2.6 mm Hg. Neither the results for GAT nor those for DCT showed a significant correlation with CCT (Pearson correlation: P < 0.05). Multifactorial analysis revealed that CCT and MCT, but not GAT and DCT, results were significantly different in corneas of varying curvatures. Conclusions: This study shows that DCT measures IOP higher than GAT in eyes with keratoconus. In keratoconus, both methods seem to be independent of CCT and therefore are equally, but not interchangeably, applicable when monitoring IOP. Further analysis revealed that CCT and MCT are significantly different in corneas of varying Amsler grade.

Laser peripheral iridotomy changes anterior chamber architecture.

Purpose The pressure gradient between anterior and posterior chamber in acute angle closure (AAC) and primary angle closure suspects is balanced by a sufficient laser peripheral iridotomy (LPI). The anterior chamber changes induced by LPI in patients with unilateral AAC were examined and compared to healthy eyes to define threshold values, which may help to discriminate between healthy and diseased eyes. Methods Using Scheimpflug photography, anterior chamber depth (ACD), anterior chamber volume (ACV), anterior chamber angle (ACA), and central corneal thickness (CCT) were measured before and after LPI in both eyes of unilateral AAC cases. These measurements were compared to a group of healthy control eyes to determine threshold values for ACD, ACV, and ACA. Results The ACD, ACV, and ACA increased significantly in the 25 AAC eyes after LPI. The ACD, ACV, ACA, and CCT values in the AAC eyes obtained before LPI were compared to a control group of 59 healthy eyes with wide open chamber angles. The cutoff values revealed by receiver operating characteristic analysis were 2.1 mm for ACD, 90.5 mm2 for ACV, and 27.25° for ACA. Conclusions Our results confirm the significant changes of the anterior segments architecture induced by LPI in AAC eyes. The found threshold values for ACD, ACV, and ACA may help in daily clinical routine to discriminate between healthy eyes and those in need for a prophylactic LPI.

[Firework-related eye trauma from 2005 to 2013].

PURPOSE Fireworks combusted during New Years Eve festivities can cause different eye traumas which often need complex reconstructive surgery. It was our aim to systematically analyse these eye trauma cases which were treated at our clinic during the last eight years. MATERIALS AND METHODS Age, gender, side, trauma mechanism, treatment methods and outcome were analysed for all eye trauma cases caused by fireworks during the New Years Eve celebrations from 2006 to 2013. For statistical analysis all trauma cases were divided into two groups of major and non-major eye trauma. RESULTS The total number of patients treated was 122 (28 women, 94 men, mean age 26.2±13.0 years) with 137 traumatised eyes (77 right, 60 left). 24.6% of patients were ≤18 years of age. 76.2% were bystanders. 50 eyes from 46 patients (37.7%) suffered from major eye trauma. 26 patients (21.3%) were hospitalised. 8 eyes (5.8%) suffered from a penetrating injury or globe rupture and underwent primary reconstructive surgery. Further 16 eyes (11.7%) suffered from major eye trauma without open globe injury. In the aftermath 11 eyes (8.0%) went blind (visual acuity<1/50). Gender, side and role of the patient were not significantly different between the two groups. Mean age was significantly higher in the major eye trauma group (p=0.01). CONCLUSION Young male bystanders have a high risk for suffering from eye trauma caused by fireworks. However older patients suffer from major eye trauma more often. More education and prophylaxis of eye trauma caused by fireworks is desirable.

Intraocular Pressure and Trabecular Meshwork Outflow Facility After Descemet Stripping Endothelial Keratoplasty.

Purpose:Increased intraocular pressure (IOP) is a frequent complication after penetrating keratoplasty and can be due to reduced trabecular meshwork outflow facility. Descemet stripping endothelial keratoplasty (DSEK) is a lamellar technique for replacing pathologic corneal endothelium and may be associated with a lower risk of postoperative IOP rise. In a prospective clinical study we studied IOP and outflow facility before and after DSEK. Methods:In 23 eyes of 23 patients before, 1 day, 6 weeks, and 3, 6, and 12 months after DSEK, IOP was measured using Goldmann applanation tonometry (GAT) and dynamic contour tonometry (DCT). Trabecular meshwork outflow facility (C-value) was assessed by impression tonography with the Schioetz tonometer. Central corneal thickness was measured by Haag-Streit pachymetry. Best spectacle corrected visual acuity, ocular surface fluorescein staining, and corneal sensation were also recorded. Results:Mean IOP showed a trend toward increase from preoperatively to 1 year postoperatively, which was not statistically significant (GAT: 13.5±3.3 to 15.3±4.7 mm Hg; DCT: 13.7±2.9 to 16.7±4.8 mm Hg; Schioetz: 12.4±2.8 to 15.3±2.9 mm Hg). Outflow facility increased significantly from 0.19±0.03 before to 0.29±0.05 mm3/&Dgr;mm Hg/min at 1 year after DSEK (P=0.002). Best spectacle corrected visual acuity increased significantly from 0.98±0.48 to 0.36±0.17 logMAR (P=0.0004). Corneal sensitivity was unchanged and corneal staining significantly decreased from the preoperative to 1 year postoperative period (P=0.01). Mean central corneal thickness changed significantly from 650±59 to 621±73 &mgr;m (P=0.002). Conclusions:IOP as measured by GAT, DCT, and Schioetz tends to increase during the first year after DSEK in eyes without previous glaucoma, whereas trabecular meshwork outflow facility as measured by Schioetz tonography improves. These findings are likely to be due to a progressive increase of corneal rigidity affecting transcorneal pressure measurements of both IOP and trabecular meshwork outflow facility.

1-Jahres-Ergebnisse nach posteriorer lamellärer Keratoplastik mit manuell disseziertem Spendermaterial

OBJECTIVE Posterior lamellar keratoplasty (PLK) is a reasonable alternative to penetrating keratoplasty (PK) for pathological changes of the corneal endothelium. The lamellar preparation of the donor tissue can be done in an automated fashion with a microkeratome, Descemet Stripping Automated Keratoplasty (DSAEK) or manually, Descemet Stripping Endothelial Keratoplasty (DSEK). Here, we describe our clinical results with one year follow-up using manually dissected donor lamellae for PLK. METHODS For 28 eyes (28 patients) best-corrected visual acuity, corneal topography, esthesiometry, pachymetry, as well as endothelial cell count were measured before, 1 day, 1 and 6 weeks, as well as 3, 6 and 12 months after surgery. RESULTS 3 of 28 grafts showed primary graft failure. For 19 eyes (no other vision-limiting diseases), the best-corrected visual acuity rose on average from 1.0 +/- 0.53 to 0.4 +/- 0.20 (logMAR) 1 year after surgery. The surgically induced astigmatism changed from 3.8 +/- 2.8 dpt preoperatively to 1.4 +/- 1.0 dpt 12 months after DSEK. The pachymetry measured by slit lamp showed an averaged thickness of 649 +/- 54 mm pre- and 776 +/- 75 mm one week and 636 +/- 79 mm 1 year after surgery was performed. The endothelial cell count of the grafts was 2615 +/- 156 cells/mm (2), after one year postoperatively the mean endothelial cell count was 2084 +/- 536 cells/mm (2). The esthesiometry showed a slight rise from 0.96 +/- 0.34 g/mm (2) pre- to 0.96 +/- 0.03 g/mm (2) one year post-surgery. CONCLUSIONS The postoperative course of our patients shows that improvement of visual acuity by PLK with manually dissected donor tissue is possible.

Firework-Related Eye Trauma in Germany

ABSTRACT Purpose: Firework devices cause high numbers of eye trauma cases each year worldwide. These can range from mild conjunctival irritation to devastating loss of all vision or the organ itself. A systematic 10-year retrospective monocentric case analysis was the main aim of this study. Materials and Methods: All firework-associated eye trauma patients treated in our clinic from 2007 to 2017 were grouped for trauma severity and analyzed for influencing factors like age, gender, laterality, final visual acuity, and ocular trauma score (OTS). Results: Between 2007 and 2017, 165 eyes of 149 patients were treated due to firework-associated eye trauma at our clinic. The mean patient age was 28.5 ± 14.4, 116 patients (78%) were male, 113 (75.8%) were bystanders, 94 right and 71 left eyes were treated, and final visual acuity was 0.26 ± 0.54 logMAR. The causative device were bangers in 98 cases (59%), rockets in 54 cases (33%), and sparklers in 13 cases (8%). Patients were significantly older (p = 0.026), final visual acuity was significantly lower (p < 0.01), and OTS was significantly higher (p < 0.01) in patients suffering from major eye trauma compared to minor trauma cases. Conclusions: Patients suffering from firework-associated eye trauma are mostly young, male, and bystanders. However, severe trauma is more frequent in higher age groups, leading to serious consequences. In Germany, more educational efforts and prophylaxis concerning eye trauma caused by firework devices are desirable.