LONG-TERM EFFICACY OF FLUOCINOLONE IN EYES WITH IRIS-LENS DIAPHRAGM DISRUPTION AND PCME WITH MEDICATION FIXED IN THE SCLERA (MEFISTO).

PURPOSE: The aim of our prospective off-label, interventional clinical trial was to evaluate the efficacy and safety of the fluocinolone-loop-anchoring technique over two years in eyes with iris-lens diaphragm disruption and pseudophakic cystoid macular edema. METHODS: In 10 eyes, scleral fixation of fluocinolone implant was performed. Main outcome measures were the development of best-corrected visual acuity (BCVA), central retinal thickness over 24 months, and general safety of the procedure. RESULTS: A significant improvement to 0.57 ± 0.38 log MAR (Snellen 20/80) (range 0-1.30) was observed (P = 0.003) at 1 month. Further improvement to 0.45 ± 036 log MAR (Snellen 20/60) was observed until month 18 (P = 0.081). Mean central retinal thickness decreased by 22% from 601.6 ± 235.5 µm to 449.1 ± 128.9 µm at 1 month. In one patient, the implant has to be removed at Month 7 because of elevated intraocular pressure and one patient after globe rupture had a retinal redetachment at Month 4. CONCLUSION: In this study, we showed that the treatment of recalcitrant pseudophakic cystoid macular edema with scleral fixated fluocinolone implant in eyes with disruption of the iris-lens diaphragm provides good anatomical and functional results with a reasonable safety profile over 24 months in eyes where pseudophakic cystoid macular edema is otherwise difficult to treat and often left untreated.

Effect of trabeculectomy on the rate of progression of visual field damage.

OBJECTIVES: This study quantifies the effect of trabeculectomy on the rate of progression (RoP) of visual field (VF) damage utilising pre- and post-operative visual function as the outcome instead of surrogate outcomes of success. METHODS: Clinical and VF data from 199 sequential patients who underwent trabeculectomy between 2015 and 2016 were extracted from the network of sites of Moorfields Eye Hospital NHS Foundation Trust. Of these, we analysed 80 eyes of 74 patients who met our inclusion criteria of at least three reliable VFs before and after surgery (false positive rate <15%). The change in mean RoP (dB/year) was tested using point-wise sensitivity values through a mixed effect model with random effects on both intercepts and slopes. A broken-stick regression of sensitivity over time, with a breakpoint at the day of surgery, modelled the individual change in RoP. RESULTS: We analysed 10 [9,12] VFs per subject (Median [Interquartile Range]). At surgery, the age was 67 [57, 72] years, mean deviation was -10.84 [-14.7, -5.6] dB and the IOP was 18 [15, 20] mmHg. One year after surgery, the IOP was 10 [8,13] mmHg (p = 0.002). Mean RoP before surgery was -0.94 [-1.20, -0.69] dB/year (Mean [95% credible intervals]) and it was slowed down by 0.62 [0.26, 0.97] dB/year (p < 0.001) after surgery. CONCLUSIONS: Trabeculectomy leads to a significant reduction in the RoP of VF loss postoperatively.

Childhood versus early-teenage onset Leber's hereditary optic neuropathy: visual prognosis and capacity for recovery.

OBJECTIVE: In Leber's hereditary optic neuropathy (LHON) in children and teenagers, the influence of age on visual prognosis has not yet been investigated. METHODS: Patients from the mitoNET registry with LHON onset at age 4-16 years with at least 4 years of follow-up without treatment were included. Visual acuity (VA) at baseline, lowest VA ever recorded (nadir) and VA at end of follow-up were compared between childhood onset (ChO, ≤12 years of age) and early-teenage onset (eTO; 13-16 years). RESULTS: Out of 231 patients with LHON, 19 met the inclusion criteria (8.2%). There were 11 patients in the ChO and 8 patients in the eTO group. Mean age at onset was 8.6 (SD 2.1) years (ChO) and 15.4 (SD 0.7) years (eTO) (p<0.00001). Follow-up was mean 184 (SD 129) months (ChO) and 119 (SD 78) months (eTO) (p=0.22). Baseline VA was similar between both groups in better (p=0.96) and worse eyes (p=0.54). In worse eyes, both groups deteriorated similarly (p=0.79) until nadir and showed similar recovery until end of follow-up (p=0.38). In better eyes, both groups deteriorated similarly (p=0.16) until nadir. From nadir until end of follow-up, better eyes in the ChO group showed a significantly better recovery (-0.35 (SD 0.36) vs -0.01 (SD 0.06) logMAR; p=0.02) than eTO eyes. CONCLUSION: Visual prognosis of LHON in children is much more favourable in cases of childhood onset (≤12 years of age) as compared with teenage onset (13-16 years), mostly due to better recovery from nadir in childhood onset.

Inhibition of proliferative vitreoretinopathy by a newly developed methotrexate loaded drug carrier in vitro.

PURPOSE: Repeated intravitreal injections of methotrexate for proliferative vitreoretinopathy, a rare ocular condition that can cause vision loss, have shown beneficial effects in recent clinical studies. The purpose of this study was to develop a slow-release, long-term drug carrier composed of the polymer polylactide-co-glycolide and methotrexate that can be injected intravitreally. METHODS: The required composition of the drug carrier was modeled using pharmacokinetic parameters based on current literature. Release kinetics were determined using an ocular pharmacokinetic model. Epiretinal PVR-membranes were harvested during pars plana vitrectomy and subsequently transferred to cell culture. The effect of the drug carrier on cell migration was investigated using time-lapse microscopy and a scratch-induced migration assay. The colorimetric WST-1-assay and a live-dead-assay were performed to determine viability, and the BrdU-assay was applied for proliferation. RESULTS: The release profile showed an initial and a final burst of methotrexate with an intervening steady state that lasted 9-11 weeks. It showed inhibitory effects on pathobiological processes in human PVR-cells in vitro. Cell velocity in the time-lapse assay, migration in the scratch assay (p = 0.001), and proliferation in the BrdU assay (p = 0.027) were reduced after addition of the drug carrier. These effects occurred without causing a reduction in viability in the WST-1 assay (p > 0.99) and the live-dead assay. CONCLUSION: The methotrexate-loaded drug carrier can maintain a stable concentration for 9-11 weeks and influence the pathobiological process of PVR cells in vitro. Therefore, it represents a potential therapeutic orphan drug for PVR.

Inhibitory activity of ranibizumab, sorafenib, and pazopanib on light-induced overexpression of platelet-derived growth factor and vascular endothelial growth factor A and the vascular endothelial growth factor A receptors 1 and 2 and neuropilin 1 and 2.

BACKGROUND: Cumulative light exposure is significantly associated with progression of age-related macular degeneration. Growth factors and growth factor receptor signaling are known to have a substantial impact on the development of age-related macular degeneration. This study explored the effects of ranibizumab, sorafenib, and pazopanib on vascular endothelial growth factor A (VEGF) receptors 1 and 2 and neuropilin 1 and 2 expression in human retinal pigment epithelial cells. In addition, their effects on light-induced overexpression of VEGF and platelet-derived growth factor were investigated. METHODS: Primary human retinal pigment epithelial cells were exposed to white light and then treated with ranibizumab (0.125 mg/mL), sorafenib (1 µg/mL), or pazopanib (1 µg/mL). Viability of cells, expression of VEGF receptors 1 and 2 and neuropilin 1 and 2 and their mRNA, and secretion of VEGF and platelet-derived growth factor were investigated by reverse transcription-polymerase chain reactions, immunohistochemistry, and enzyme-linked immunosorbent assays. RESULTS: Treatment with sorafenib or pazopanib reduced the expression of VEGF receptors 1 and 2 and neuropilin 1, and sorafenib also reduced neuropilin 2. Light exposure decreased cell viability and increased expression and secretion of VEGF and platelet-derived growth factor. Sorafenib and pazopanib significantly reduced light-induced overexpression and secretion of VEGF and platelet-derived growth factor. Ranibizumab reduced secreted VEGF in cell culture supernatants only. CONCLUSION: Our in vitro results suggest that multikinase inhibitors have promising properties as a potential antiangiogenic treatment for age-related macular degeneration.

Changes of Neuroretinal Rim and Retinal Nerve Fiber Layer Thickness Assessed by Optical Coherence Tomography After Filtration Surgery in Glaucomatous Eyes.

PURPOSE: Lowering the intraocular pressure (IOP) in patients with primary open-angle glaucoma (POAG) with filtration surgery can induce morphological changes to the bulbus and structures of the retina. In this study, we have evaluated changes of Bruch's membrane-based parameters and retinal nerve fiber layer (RNFL) derived by spectral-domain optical coherence tomography (SD-OCT) in eyes that have undergone glaucoma filtration surgery. PATIENTS AND METHODS: SD-OCT imaging of the optic nerve head (ONH) and of the RNFL was performed in 54 eyes of 54 patients with medically uncontrolled POAG before and after IOP-lowering surgery (trabeculectomy or deep sclerectomy). The ONH parameter minimum rim width (MRW) and the size of the Bruch's membrane opening (BMO-Area) were derived from 24 radial B-scans centered on the ONH. RESULTS: The average preoperative IOP was 23.1 ± 7.5 mmHg. One month postoperatively, the average IOP decreased to 12.1 ± 4.6 mmHg (p < 0.01), which caused a significant increase in the thickness of neuroretinal rim. There was no significant change in the automatically detected BMO-Area (p = 0.32). The pressure-related increase in MRW correlated well with the postoperative IOP and cup-to-disc ratio (CDR). In regression analysis, the alteration in thickness of the neuroretinal rim could be well predicted in a model including CDR, change of IOP and mean deviation (MD) (R2 = 0.414, p < 0.001). RNFL showed a significant increase as well. CONCLUSION: IOP-lowering surgery in patients with medically uncontrolled POAG causes an increased thickness of the SD-OCT derived ONH parameters. The changes of the RNFL after surgery showed no significant correlations with IOP changes. In contrast to this, highly significant correlations of MRW values with the IOP could be observed. The BMO-Area remained completely stable A preferred use of RNFL for follow-up should be discussed.

Scleral Fixation of the Fluocinolone Acetonide Implant in Eyes with Severe Iris-Lens Diaphragm Disruption and Recalcitrant CME: The Fluocinolone-Loop-Anchoring Technique (FLAT).

INTRODUCTION: While proven to be an effective treatment for cystoid macular edema (CME) and diabetic macular edema, intravitreal steroid implants (IVSI) may cause undesirable side effects, including steroid-related glaucoma or migration into the anterior chamber in the case of iris-lens diaphragm disruption. Here we present a new surgical technique that allows for the easy implantation and subsequent fixation of the fluocinolone acetonide intravitreal implant without the risk of migration as a feasible and possibly reversible approach in the treatment of persistent CME in severely damaged eyes. METHODS: In this single-center, prospective off-label, proof of principle, scleral fixation of the fluocinolone implant was performed in two eyes with disrupted anterior-posterior segment border and persistent CME. Both eyes were then followed monthly in accordance to a detailed protocol. RESULTS: The procedure was overall well tolerated without severe side effects. There was no migration of the implant in the anterior chamber in either eye. CONCLUSION: Scleral fixation of the fluocinolone implant proved to be a safe and feasible approach in eyes with persistent CME and disrupted anterior-posterior segment border. This new technique also allows for the possible removal of the implant and may therefore be suitable even for eyes at higher risk for side effects, such as glaucoma.

Quantification of epicardial adipose tissue by cardiac CT: Influence of acquisition parameters and contrast enhancement.

PURPOSE: While computed tomography (CT) is frequently used to quantify epicardial adipose tissue (EAT), the effect of different acquisition parameters on EAT volume has not been systematically reported. We assessed the influence of low-voltage acquisition and contrast enhancement on EAT quantification. METHOD: Two independent cohorts (100 and 127 patients) referred for routine coronary CT were included. One cohort received a low-voltage and a standard voltage non-contrast acquisition (120 and 100 kV), the other cohort underwent non-contrast and contrast-enhanced CT. EAT volume was quantified using a semi-automated analysis software. Whereas the lower EAT threshold was consistently set at -190 Hounsfield Units (HU), different upper thresholds for EAT were analyzed. Bland-Altman analysis was used to analyze the agreement of EAT volume between scans with different acquisition parameters. We referred to a non-enhanced 120 kV acquisition with an upper threshold of -30 HU. RESULTS: Mean EAT volume was 159 ±â€¯76 ml as measured in 120 kV non-contrast data sets with an upper threshold of -30 HU. For 100 kV data sets, an upper threshold of -40 HU showed the best correlation (r = 0.961, p < 0.05). Significant overestimation was found for upper thresholds of -20 and -30 HU and significant underestimation for -50 HU. In non-contrast vs. contrast-enhanced acquisitions, there was a significant underestimation of EAT volume for contrast-enhanced scans (mean difference 31 ml, 95% limits of agreement 27 to -89 ml). CONCLUSIONS: CT-based EAT volume quantification in low-voltage and contrast-enhanced images is feasible. However, adjustment of the upper threshold for detection of fat is mandatory.

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.