Raffael Liegl

Central serous chorioretinopathy

The pathogenesis of central serous chorioretinopathy (CSC) is still not fully understood. The involvement of corticosteroids is undisputed, although their exact role has not been clarified; other parts of the underlying mechanism of CSC have been mainly elucidated by imaging techniques such as fluorescein and indocyanine green angiography. Even though most cases of CSC are self-limiting, severe as well as recurrent courses exist, and for these patients only a limited number of treatment options are available: laser photocoagulation, with a risk of scotoma and choroidal neovascularization, and photodynamic therapy. In this review article, we give an overview of its epidemiology, the current understanding of its pathogenesis as well as systemic and ocular risk factors. We illuminate modern diagnostic tools as well as current treatment options in the context of CSC, particularly in the light of a better understanding of corticosteroids and their receptors involved in its pathogenesis.

Cytoprotective effects of a blue light–filtering intraocular lens on human retinal pigment epithelium by reducing phototoxic effects on vascular endothelial growth factor-α, Bax, and Bcl-2 expression

PURPOSE: To compare the possible protective effects of the ultraviolet (UV)‐filtering and blue light–filtering SN60AT intraocular lens (IOL) and the untinted UV‐filtering SA60AT IOL with regard to light‐induced stress on human retinal pigment epithelium (RPE). SETTING: Department of Ophthalmology, Ludwig‐Maximilians‐University, Munich, Germany. METHODS: Primary human RPE cells were exposed to white light, and a tinted or untinted IOL was placed in the light beam. After 15 to 60 minutes of irradiation, cell viability was determined by a colorimetric test (tetrazolium dye‐reduction assay) and a microscopic live/dead assay. The expression of vascular endothelial growth factor‐α (VEGF‐α), Bax, and Bcl‐2 and their mRNA was determined by reverse‐transcription polymerase chain reaction (RT‐PCR) and Western blotting. RESULTS: Without an IOL, white‐light exposure decreased cell viability compared with the decrease with the nonirradiated control in a time‐dependent manner. Light‐induced cell death was significantly reduced by both the tinted IOL and untinted IOL. The combined UV and blue‐light filtering attenuated light‐induced cell damage significantly more than UV filtering alone. Results of RT‐PCR and Western blotting showed a significant time‐dependent decrease in Bcl‐2 and increase in Bax and VEGF‐α that were significantly less with the tinted IOL than with the untinted IOL. CONCLUSIONS: Both IOLs reduced light‐induced RPE damage. The UV‐ and blue light–filtering IOL reduced damage more than the conventional IOL. This supports the hypothesis that blue light–filtering IOLs may prevent retinal damage in clinical use.

Pain and accuracy of focal laser treatment for diabetic macular edema using a retinal navigated laser (Navilas

Aim To investigate treatment-related pain and the accuracy of navigated laser photocoagulation in the treatment of clinically significant macular edema. Methods Focal laser treatment of diabetic macular edema in 54 consecutive patients was digitally planned on fundus images and performed using the navigated laser photocoagulation system Navilas® (OD-OS GmbH, Teltow, Germany). Treatment-related pain was quantified on a visual analog scale directly after treatment and compared with a matched control group who received conventional laser treatment (n = 46). In addition, for Navilas-treated patients, the accuracy of spot placement on color images was analyzed 1 month after treatment. Results In total, 5423 laser spots (mean 100 per eye) were analyzed. With navigated treatment, 90% of laser spots were visible on color images, of which 96% were within 100 μm from the target. Eighty percent of the laser spots were placed and visible within the 100 μm target on an intention-to-treat basis for color imaging. Optical coherence topography confirmed that laser effects were limited to the outer retina. Treatment-related pain following navigated laser photocoagulation was significantly lower than that of conventional laser treatment (1.6 vs 4.4 on a visual analog scale, P < 0.001). Conclusion Navigated laser effects could be visualized to a high percentage on post-treatment color images, and their location showed a high concordance to targeted areas. Patients reported that treatment-related pain following Navilas laser photocoagulation was significantly lower than pain following conventional laser treatment.

Functional and morphological changes in diabetic macular edema over the course of anti-vascular endothelial growth factor treatment

Purpose: To evaluate macular morphology and function in diabetic macular edema (DME) over the course of intravitreal anti‐vascular endothelial growth factor (VEGF) treatment with Ranibizumab.

Navigated macular laser decreases retreatment rate for diabetic macular edema: a comparison with conventional macular laser

Background The purpose of this study was to evaluate and compare clinical outcomes and retreatment rates using navigated macular laser versus conventional laser for the treatment of diabetic macular edema (DME). Methods In this prospective, interventional pilot study, 46 eyes from 46 consecutive patients with DME were allocated to receive macular laser photocoagulation using navigated laser. Best corrected visual acuity and retreatment rate were evaluated for up to 12 months after treatment. The control group was drawn based on chart review of 119 patients treated by conventional laser at the same institutions during the same time period. Propensity score matching was performed with Stata, based on the nearest-neighbor method. Results Propensity score matching for age, gender, baseline visual acuity, and number of laser spots yielded 28 matched patients for the control group. Visual acuity after navigated macular laser improved from a mean 0.48 ± 0.37 logMAR by a mean +2.9 letters after 3 months, while the control group showed a mean −4.0 letters (P = 0.03). After 6 months, navigated laser maintained a mean visual gain of +3.3 letters, and the conventional laser group showed a slower mean increase to +1.9 letters versus baseline. Using Kaplan-Meier analysis, the laser retreatment rate showed separation of the survival curves after 2 months, with fewer retreatments in the navigated group than in the conventional laser group during the first 8 months (18% versus 31%, respectively, P = 0.02). Conclusion The short-term results of this pilot study suggest that navigated macular photocoagulation is an effective technique and could be considered as a valid alternative to conventional slit-lamp laser for DME when focal laser photocoagulation is indicated. The observed lower retreatment rates with navigated retinal laser therapy in the first 8 months suggest a more durable treatment effect.

Comparative Evaluation of Combined Navigated Laser Photocoagulation and Intravitreal Ranibizumab in the Treatment of Diabetic Macular Edema

Objective To evaluate if a standardized combination therapy regimen, utilizing 3 monthly ranibizumab injections followed by navigated laser photocoagulation, reduces the number of total ranibizumab injections required for treatment of diabetic macular edema (DME). Research Design and Methods A 12-month, prospective comparison of 66 patients with center-involving DME: 34 patients with combination therapy were compared to 32 patients treated with ranibizumab monotherapy. All patients initially received 3 monthly ranibizumab injections (loading phase) and additional injections pro re nata (PRN). Combination therapy patients additionally received navigated laser photocoagulation after the loading phase. Main outcome measures were mean number of injections after the loading phase and change in BCVA from baseline to month 12. Results Navigated laser combination therapy and ranibizumab monotherapy similarly improved mean BCVA letter score (+8.41 vs. +6.31 letters, p = 0.258). In the combination group significantly less injections were required after the 3 injection loading phase (0.88±1.23 vs. 3.88±2.32, p< = 0.001). By month 12, 84% of patients in the monotherapy group had required additional ranibizumab injections as compared to 35% in the combination group (p< = 0.001). Conclusions Navigated laser combination therapy demonstrated significant visual gains in most patients. Retreatment rate and number of injections were significantly lower compared to ranibizumab monotherapy and compared to the results of conventional laser combination therapy previously reported in pivotal anti-VEGF studies.

Indocyanine green increases light-induced oxidative stress, senescence, and matrix metalloproteinases 1 and 3 in human RPE cells.

Purpose:  Indocyanine green (ICG) is a commonly used vital dye for macular surgery. Recent reports implicate that its use might be associated with less favourable results regarding postoperative visual outcome and damage of retinal cells, and atrophic degeneration of the retinal pigment epithelium (RPE) has been described. This study investigates the effects of ICG on light‐induced senescence of RPE cells.

Alkylphosphocholines as a potential pharmacologic prophylaxis for posterior capsule opacification

PURPOSE: To evaluate the effect of alkylphosphocholines (APCs) on human lens epithelial cell (LEC) proliferation, attachment, and migration in a well‐established in vitro model. SETTING: Department of Ophthalmology, Ludwig‐Maximilians‐University, Munich, Germany. METHODS: The immortalized human LEC line HLE‐B3 was incubated for 24 hours with APC in different concentrations in the presence of Eagles modified essential medium supplemented with fetal calf serum under standard cell‐culture conditions. The trypan blue exclusion test and live–dead assay were performed to exclude toxic concentrations. To determine cell proliferation, cells were incubated with APCs at the maximum slope of the growth curve for 24 hours before the tetrazolium dye–reduction assay (MTT test) was performed. After cells were seeded on coated 24‐well plates, incubated with APCs, and rinsed with phosphate‐buffered saline, cell attachment was assessed by the MTT test. Migration was determined by a modified Boyden chamber method after incubation of LECs with APCs. RESULTS: Alkylphosphocholines were effective inhibitors of human LEC proliferation, attachment, and migration at nontoxic concentrations in vitro. The 50% inhibitory concentration was close to 0.1 mM. An APC concentration of 1.0 mM accounted for the following: inhibition of cell proliferation of more than 80%, reduction in cell attachment to 66.5%, and inhibition of cell migration of more than 90%. All effects were dose dependent. No toxic effects were detected compared with controls. CONCLUSIONS: Alkylphosphocholines might have the potential for topical application as a single‐dose agent to prevent posterior capsule opacification formation. However, further studies are needed before a clinical application can be considered.

Temsirolimus Inhibits Proliferation and Migration in Retinal Pigment Epithelial and Endothelial Cells via mTOR Inhibition and Decreases VEGF and PDGF Expression

Due to their high prevalence, retinal vascular diseases including age related macular degeneration (AMD), retinal vein occlusions (RVO), diabetic retinopathy (DR) and diabetic macular edema have been major therapeutic targets over the last years. The pathogenesis of these diseases is complex and yet not fully understood. However, increased proliferation, migration and angiogenesis are characteristic cellular features in almost every retinal vascular disease. The introduction of vascular endothelial growth factor (VEGF) binding intravitreal treatment strategies has led to great advances in the therapy of these diseases. While the predominant part of affected patients benefits from the specific binding of VEGF by administering an anti-VEGF antibody into the vitreous cavity, a small number of non-responders exist and alternative or additional therapeutic strategies should therefore be evaluated. The mammalian target of rapamycin (mTOR) is a central signaling pathway that eventually triggers up-regulation of cellular proliferation, migration and survival and has been identified to play a key role in angiogenesis. In the present study we were able to show that both retinal pigment epithelial (RPE) cells as wells as human umbilical vein endothelial cells (HUVEC) are inhibited in proliferating and migrating after treatment with temsirolimus in non-toxic concentrations. Previous studies suggest that the production of VEGF, platelet derived growth factor (PDGF) and other important cytokines is not only triggered by hypoxia but also by mTOR itself. Our results indicate that temsirolimus decreases VEGF and PDGF expression on RNA and protein levels significantly. We therefore believe that the mTOR inhibitor temsirolimus might be a promising drug in the future and it seems worthwhile to evaluate complementary therapeutic effects with anti-VEGF drugs for patients not profiting from mono anti-VEGF therapy alone.

Axitinib modulates hypoxia-induced blood–retina barrier permeability and expression of growth factors

This study investigates the effects of the multikinase inhibitor axitinib on the expression of vascular endothelial growth factor (VEGF) receptors 1/2 (VEGFR-1/2) and platelet-derived growth factor (PDGF) receptor beta (PDGFR-β), hypoxia-induced increased tissue permeability, occludin, zonula occludens protein 1 (ZO-1), VEGF-A, and PDGF expression of human retinal pigment epithelial (RPE) cells and human umbilical vein endothelial cells (HUVECs). Primary human RPE cells and HUVECs were exposed to hypoxia and axitinib. Viability of cells, tissue permeability, and expression of occludin, ZO-1, VEGF, PDGF, VEGFR-1/2 and PDGFR-β, and their mRNAs, were investigated by reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting, and immunohistochemistry. Treatment with axitinib reduced expression of VEGFR-1/2 and PDGFR-β. Hypoxia decreased cell viability, occludin, and ZO-1 expression and increased tissue permeability, expression, and secretion of VEGF and PDGF. Axitinib significantly reduced hypoxia-induced effects on HUVEC and RPE cells. Our in vitro results suggest that axitinib may have promising properties as a potential treatment for diabetic macular edema.