Detection of SARS-CoV-2-RNA in post-mortem samples of human eyes.

PURPOSE: To detect SARS-CoV-2 RNA in post-mortem human eyes. Ocular symptoms are common in patients with COVID-19. In some cases, they can occur before the onset of respiratory and other symptoms. Accordingly, SARS-CoV-2 RNA has been detected in conjunctival samples and tear film of patients suffering from COVID-19. However, the detection and clinical relevance of intravitreal SARS-CoV-2 RNA still remain unclear due to so far contradictory reports in the literature. METHODS: In our study 20 patients with confirmed diagnosis of COVID-19 were evaluated post-mortem to assess the conjunctival and intraocular presence of SARS-CoV-2 RNA using sterile pulmonary and conjunctival swabs as well as intravitreal biopsies (IVB) via needle puncture. SARS-CoV-2 PCR and whole genome sequencing from the samples of the deceased patients were performed. Medical history and comorbidities of all subjects were recorded and analyzed for correlations with viral data. RESULTS: SARS-CoV-2 RNA was detected in 10 conjunctival (50%) and 6 vitreal (30%) samples. SARS-CoV-2 whole genome sequencing showed the distribution of cases largely reflecting the frequency of circulating lineages in the Munich area at the time of examination with no preponderance of specific variants. Especially there was no association between the presence of SARS-CoV-2 RNA in IVBs and infection with the variant of concern (VOC) alpha. Viral load in bronchial samples correlated positively with load in conjunctiva but not the vitreous. CONCLUSION: SARS-CoV-2 RNA can be detected post mortem in conjunctival tissues and IVBs. This is relevant to the planning of ophthalmologic surgical procedures in COVID-19 patients, such as pars plana vitrectomy or corneal transplantation. Furthermore, not only during surgery but also in an outpatient setting it is important to emphasize the need for personal protection in order to avoid infection and spreading of SARS-CoV-2. Prospective studies are needed, especially to determine the clinical relevance of conjunctival and intravitreal SARS-CoV-2 detection concerning intraocular affection in active COVID-19 state and in post-COVID syndrome.

[Cost Comparison of Licensed Intravitreal Therapies for Insufficiently Anti-VEGF Responding Fovea Involving Diabetic Macular Edema in Germany]. / Kostenvergleich zugelassener intravitrealer Therapien bei nicht ausreichend auf primäre Therapie ansprechendem diabetischem Makulaödem mit fovealer Beteiligung in Deutschland.

BACKGROUND: In the treatment of center-involving diabetic macular edema, despite initial therapy with an anti-VEGF compound, an insufficient response may occur. Further therapy options include a switch of anti-VEGF products or to corticosteroid implants, such as Fluocinolone acetonide or Dexamethasone. OBJECTIVES: Firstly, to investigate systematically which evidence-based study data are available describing the efficacy of in-label treatments after primary anti-VEGF treatment, secondly, to investigate which costs go along for the healthcare provider. METHODS: A systematic literature review (SLR) for randomized controlled trials (RCT) was performed in Medline and Embase. A short-term cost-cost model was built in MS Excel with a 3 year time horizon to compare in-label intravitreal options Ranibizumab (Lucentis®), Aflibercept (Eylea®), Fluocinolone acetonide implant (Iluvien®), and Dexamethasone implant (Ozurdex®). Cost components comprised of drug and injection costs, optical coherence tomography (OCT) procedures, and adverse events such as endophthalmitis, IOP-lowering drugs and surgery and cataract surgery. RESULTS: A total of 42 publications of 20 RCTs were identified. No study had a clearly defined population after first line anti-VEGF treatment, thus no direct efficacy comparison was possible. In the short-term cost-cost model total costs were 17,542 € for Ranibizumab, 15,896 € for Aflibercept, 10,826 € for Fluocinolone acetonide implant and 12,365 € for Dexamethasone implant. For all treatment regimens, drug costs were the predominant cost component, followed by injection costs (with variations dependent on the specific drug) and OCT costs. In the uni- and multivariate sensitivity analyses, the results obtained were robust to changes of model inputs. CONCLUSIONS: In summary, the short-term cost-cost comparison demonstrates that steroid implants can provide significant cost savings versus in-label anti-VEGF treatment for center-involving diabetic macular edema. Single application of the long-lasting Fluocinolone acetonide implant is the most cost-efficient in-label treatment option.

Long-term results and recurrence rates after spironolactone treatment in non-resolving central serous chorio-retinopathy (CSCR).

PURPOSE: To evaluate the long-term results of spironolactone in non-resolving central serous chorio-retinopathy (CSCR) and recurrence rates of CSCR. METHODS: Interventional uncontrolled open-label prospective clinical trial of patients with non-resolving CSCR who were treated with spironolactone 50 mg daily (Spironolacton AL® 50 mg, ALIUD PHARMA) for up to 16 weeks. Follow-up visits were performed at 3, 6, 9, and 12 months. Retreatment criteria for recurrence were: gain in sub-retinal fluid (SRF) of more than 25 % plus/or increase of central retinal thickness (CRT) of more than 50 µm plus visual symptoms compared to last visit. MAIN OUTCOME MEASURES: 12-month efficacy of upload treatment with spironolactone. Secondary outcome measure was the recurrence rate at 6, 9, and 12 months. RESULTS: Of the 21 study eyes treated, 71 % (n = 15) showed significant improvement or complete regression on OCT examination over 12 months. Nineteen percent of the patients (n = 4) showed a stable course from visit 1 to visit 12. The overall reduction of sub-retinal fluid from visit 1 (156 µm ± 131 SD) to visit 12 (53 µm ± 93 SD) was statistically significant (p = 0.003). The change of mean visual acuity (log MAR) from 0.25 (± 0.17 SD) at baseline to 0.17 (± 0.18 SD) at visit 12 was statistically significant, with p = 0.044. CONCLUSION: Our results confirm a positive effect of spironolactone in non-resolving CSCR in 71 % of cases. Evaluation of recurrence rates and retreatments showed good results in patients who responded to spironolactone primarily. A prospective randomized trial may provide better data about this non-invasive treatment.

Microaneurysm formation rate as a predictive marker for progression to clinically significant macular edema in nonproliferative diabetic retinopathy.

PURPOSE: To evaluate the predictive value of microaneurysm (MA) formation rate concerning the development of clinically significant macular edema (CSME) in patients with mild-to-moderate nonproliferative diabetic retinopathy as evaluated by an automated analysis of central field fundus 30° photographs. METHODS: Two hundred and eighty-seven eyes were included in the study. Photographs obtained at Day 0, at 6, and 12 months were analyzed using the RetmarkerDR software (Critical Health SA) in a masked manner, and the MA formation rate was documented. A threshold of a calculated MA formation rate of 2 or more was chosen to consider a patient "positive." The ability to predict CSME development was then calculated for a period of up to 5 years. HbA1c values, blood pressure, or duration of diabetes were also evaluated. RESULTS: The study population consisted of 89 male and 59 female patients with a mean age of 57.6 years, a mean HbA1c of 7.8, and a mean duration of diabetes of 12.3 years. Forty-seven of 287 eyes (16.4%) developed CSME during follow-up. An increased MA formation rate of >2 MA was clearly associated with development of CSME. Using the automated analysis and a threshold of 2 or more new MA, the authors were able to identify 70.2% of the eyes that developed CSME during follow-up ("true positive") and using a threshold of up to 2 new MA, 71.7% of the patients that did not develop CSME ("true negative"). No significant differences concerning baseline and 1-year HbA1c levels within patient eyes that developed CSME compared with patient eyes below or over the calculated threshold of 2 MA (P = 0.554 and P = 0.890, respectively) were seen. The positive and negative predictive value was calculated to be 33% versus 92.5%, sensitivity was 70%, and specificity was 72%. CONCLUSION: Using the RetmarkerDR software, the authors were able to identify patients with higher risk to develop CSME during follow-up using a threshold of 2 or more MA formation rate. Together with the high negative predictive value, the automated analysis may help to determine the individual risk of a patient to develop sight-threatening complications related to diabetic retinopathy and schedule individual screening intervals.

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.

Microaneurysm turnover in diabetic retinopathy assessed by automated RetmarkerDR image analysis--potential role as biomarker of response to ranibizumab treatment.

PURPOSE: To evaluate the influence of a ranibizumab treatment on microaneurysm (MA) turnover in diabetic retinopathy. METHODS: Sixty-nine eyes were included in this retrospective study. We compared a group of 33 eyes with ranibizumab treatment for diabetic macular edema to 36 eyes with nonproliferative diabetic retinopathy only. Nonmydriatic ultra-widefield scanning laser ophthalmoscopy (Optomap) images were obtained at a mean 4.76 ± 1.69 days prior to the first ranibizumab injection (baseline) and again 35.94 ± 2.44 days after the third consecutive injection in a 4-week interval. In untreated controls, images were obtained at baseline and 97.81 ± 3.16 days thereafter. Images were analyzed using the RetmarkerDR software (Critical Health SA, Coimbra, Portugal), and the turnover of MAs was documented and analyzed. Thereafter, MA turnover was correlated with central retinal thickness (CRT) as assessed by OCT. RESULTS: At baseline, patients in the treatment group had 5.64 ± 0.75 MAs. One month after 3 ranibizumab injections, measured MAs decreased to 4.03 ± 0.66. In the untreated control group, the initial number of 3.36 ± 0.6 MAs remained almost unchanged over 3-4 months (2.89 ± 0.57 MAs). Dynamic analysis showed that after ranibizumab treatment 3.06 ± 0.5 new MAs appeared, while 5.09 ± 0.79 disappeared. In the control group, 2.11 ± 0.4 new MAs appeared and 2.61 ± 0.48 disappeared. MA turnover was significantly higher with ranibizumab compared to the control group (8.15 ± 1.14 vs. 4.72 ± 0.81, p < 0.001). Consistently, CRT decreased from 444 to 330 µm in the ranibizumab group, while there was no change in the control group (291 vs. 288 µm). CONCLUSION: The treatment of macular edema using ranibizumab does not only reduce macular thickness, but also has an impact on the turnover of MAs in diabetic retinopathy. RetmarkerDR analysis showed that more pre-existent MAs disappeared than new MAs developed, and the absolute number of MAs also decreased.

Nonmydriatic ultra-wide-field scanning laser ophthalmoscopy (Optomap) versus two-field fundus photography in diabetic retinopathy.

The purpose of this study was to investigate the diagnostic properties of a 2-laser wavelength nonmydriatic 200° ultra-wide-field scanning laser ophthalmoscope (SLO) versus mydriatic 2-field 45° color fundus photography (EURODIAB standard) for assessing diabetic retinopathy (DR). A total of 143 consecutive eyes of patients with different levels of DR were graded regarding DR level and macular edema based on 2-field color photographs or 1 Optomap Panoramic 200 SLO image. All SLO images were nonmydriatic and all photographs mydriatic. Grading was performed masked to patient and clinical data. Based on photography, 20 eyes had no DR, 44 had mild, 18 moderate and 42 severe nonproliferative DR, and 19 eyes had proliferative DR. Overall correlation for grading DR level compared to Optomap SLO was moderate with kappa 0.54 (p < 0.001), fair-to-moderate in macular edema grading with kappa 0.39 (p < 0.001), and substantial for grading clinically significant macular edema (kappa 0.77). The wide-field SLO offers a wider field of view and can potentially better differentiate lesions by applying the 2 laser wavelengths. However, these advantages over 2-field fundus photography need to be confirmed in further studies.

Alterations of vascular pigment epithelium detachments associated with age-related macular degeneration during upload with intravitreal ranibizumab.

PURPOSE: To describe morphologic alterations of pigment epithelial detachments (PEDs) associated with neovascular age-related macular degeneration during anti-vascular endothelial growth factor upload therapy with ranibizumab. METHODS: Prospective, single-arm interventional study. Primary outcome was the reduction of height of PED during monthly treatment using ranibizumab. Secondary outcomes were factors influencing the regression of PED. Inclusion criteria were presence of PED associated with naive neovascular age-related macular degeneration, visual acuity of >20/200, and height of PED >150 µm on optical coherence tomography. All eyes (n = 54) received 3 injections of ranibizumab in monthly intervals ("upload therapy"). Last review examination was performed 14 weeks after the initial treatment. RESULTS: The mean PED height decreased from 515 µm (SD, 268.3) to 294 µm (SD, 201.9) at Week 14 with the highest degree of regression after the first treatment. A complete resolution of PED was noted in 8 eyes (15%). Using conventional regression model, none of the factors investigated, including height of PED, presence of intraretinal or subretinal fluid, intraretinal cysts, macular volume, retinal thickness, presence of foveal depression, presence of hemorrhage, and visual acuity, had a significant impact on the morphologic response. Using a modified binary logistic regression model ("bootstrapping"), presence of foveal depression (P > 0.033), and retinal thickness (P > 0.004) showed statistical significance. CONCLUSION: This study on the responses and potential predictive factors associated with vascularized PED during the uploading phase of intravitreal ranibizumab shows a complete resolution of the PED in 15% of the cases.

[Photo-based examination for diabetic eye pathologies in a German ophthalmological practice without personal doctor-patient contact]. / Fotobasierte Untersuchung auf diabetische Augenveränderungen in einer deutschen Augenarztpraxis ohne direkten Arzt-Patienten-Kontakt.

BACKGROUND: An increasing number of patients suffering from diabetes require regular ophthalmological check-ups to diagnose and/or treat potential diabetic retinal disease. Some countries have already implemented systematic fundus assessments including artificial intelligence-based programs in order to detect sight-threatening retinopathy. The aim of this study was to improve the detection of diabetic fundus changes in Germany without examination by a doctor and to create an easy access to ophthalmological examinations. MATERIAL AND METHODS: In this prospective monocentric study 93 patients in need for a routine check-up for diabetic retinopathy were included. The study participants took up an offer of an examination (visual examination, non-mydriatic camera-based fundus examination) without doctor-patient contact. Patient satisfaction with the organization and examinations was assessed using a questionnaire. RESULTS: The mean age was 53.5 years (SD 13.6 years, 49.5% female) and 17 eyes (18.3%) showed a diabetic retinopathy which was detected using a camera-based examination. Within the small sample, no patient had to repeat the examination due to poor image quality. All categories of the questionnaire showed a good to very good satisfaction, indicating a high acceptance of the other examination form that took place at the ophthalmologist's premises. CONCLUSION: In our study in an ophthalmological practice a high level of acceptance among the patients interested in the screening for diabetic retinopathy without any direct patient-doctor contact was achieved. Our study shows a very good acceptance and feasibility. Future use of artificial intelligence in clinical practice may help to be able to screen many more patients as in this study imaging quality was very good.

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-ß), 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-ß, 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-ß. 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.

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.

Comparison of intravitreal bevacizumab upload followed by a dexamethasone implant versus dexamethasone implant monotherapy for retinal vein occlusion with macular edema.

PURPOSE: To compare the efficacy and safety of three intravitreal bevacizumab upload injections followed by a dexamethasone implant versus dexamethasone implant monotherapy in eyes with macular edema due to retinal vein occlusion. METHODS: Sixty-four eyes of 64 patients were included in this prospective, consecutive, nonrandomized case series: group 1 consisted of 38 patients (22 with central retinal vein occlusion, CRVO, 16 with branch retinal vein occlusion, BRVO) treated using a dexamethasone implant (Ozurdex) alone; group 2 consisted of 26 patients (14 CRVO, 12 BRVO) treated with three consecutive intravitreal bevacizumab injections at monthly intervals followed by a dexamethasone implant. In case of recurrence, both cohorts received further dexamethasone implants. Preoperatively and monthly best corrected visual acuity (BCVA, ETDRS), central retinal thickness (Spectralis-OCT), intraocular pressure, and wide-angle fundus photodocumentation (Optomap) were performed. The primary clinical endpoint was BCVA at 6 months after initiation of therapy. Secondary endpoints were central retinal thickness and safety of the therapy applied. RESULTS: In group 1, an increase in BCVA of 2.5 (±1.6) letters in the CRVO and of 13.0 (±3.2) letters in BRVO patients was seen after 6 months, in group 2 of 5.9 (±0.4) letters (CRVO) and 3.8 (±2.4) letters (BRVO), which was not statistically significant. When comparing the two treatment groups with respect to the type of vein occlusion, there was a significant advantage for BRVO patients for the dexamethasone implant monotherapy (BRVO patients in group 1, p = 0.005). Central retinal thickness showed a significant reduction after 6 months only in patients of group 1, both for CRVO (p = 0.01) and BRVO (p = 0.003). First recurrence after the first dexamethasone implant injection occurred after 3.8 months (mean) in CRVO and 3.5 months in BRVO patients (group 1), versus 3.2 and 3.7 months, respectively, in group 2. In group 1, 63.6% with CRVO and 50% with BRVO showed an increased intraocular pressure after treatment; in group 2, 57.1% with CRVO and 50.0% with BRVO, respectively. CONCLUSION: In CRVO, there was no difference between the two treatment strategies investigated. However, in BRVO, dexamethasone implant monotherapy was associated with better functional outcome.

Filtering blue light reduces light-induced oxidative stress, senescence and accumulation of extracellular matrix proteins in human retinal pigment epithelium cells.

BACKGROUND: Cumulative light exposure is significantly associated with ageing and the progression of age-related macular degeneration. To prevent the retina from blue-light damage in pseudophakia, blue light-absorbing intraocular lenses have been developed. This study compares the possible protective effects of a blue light-absorbing intraocular lens to an untinted ultraviolet-absorbing intraocular lens with regard to light-induced oxidative stress and senescence of human retinal pigment epithelium. METHODS: As primary human retinal pigment epithelium cells were exposed to white light, either an ultraviolet- and blue light-absorbing intraocular lens or ultraviolet-absorbing intraocular lens was placed in the light beam. After 60 min of irradiation, cells were investigated by electron microscopy for viability, induction of intracellular reactive oxygen species, and senescence-associated ß-galactosidase activity. Expression and secretion of matrix metalloproteinases 1 and 3 and their mRNA were determined by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay. RESULTS: Light exposure induced structural damage, decreased retinal pigment epithelium cell viability, and increased reactive oxygen species, senescence-associated ß-galactosidase activity and matrix metalloproteinases 1 and 3 expression and secretion. Although both types of intraocular lens significantly reduced these effects, the protective effects of the ultraviolet- and blue light-absorbing intraocular lens were significantly stronger than those of the ultraviolet-absorbing intraocular lens. CONCLUSIONS: The ultraviolet- and blue light-absorbing intraocular lens demonstrated significantly better protection against light-induced oxidative stress, senescence and structural damage than the ultraviolet-absorbing intraocular lens. These in vitro findings support the hypothesis that the ultraviolet- and blue light-absorbing intraocular lens may prevent retinal damage in clinical use.

Intracameral injection of bevacizumab for the treatment of neovascular glaucoma.

PURPOSE: To assess the duration of the effect of intracameral bevacizumab in patients presenting with rubeosis iridis and neovascular glaucoma (NVG). METHODS: Retrospective analysis of 24 consecutive eyes of 24 patients with decompensated NVG (> 21 mm Hg) treated with a single intracameral injection of bevacizumab over a minimum follow-up of 6 months. The endpoint of the study was the need for retreatment due to recurrence of raised intraocular pressure (IOP). Secondary outcome was the course of visual acuity (VA) and IOP over 6 months. RESULTS: A Kaplan-Meier calculation revealed a mean duration of the treatment effect of 23 ± 4.4 days. Compared to mean IOP before treatment (26.3 mm Hg), decreases to 17.5 mm Hg at 1 week after treatment (p < 0.002) and to 17.1 mm Hg (p < 0.005) at 6 months following a single injection were seen. At 6 months, additional treatment was performed in 87.5% (n = 21) of eyes. VA remained stable or improved in 75% (n = 18) of all cases. CONCLUSION: The IOP-lowering effect of intracameral bevacizumab can be seen 1 week after the injection, but is limited to a period of approximately 3 weeks. However, the fast and effective response to intracameral bevacizumab injection opens a time window for additional treatments, which are often necessary.

Alpha-lipoic acid for the prevention of diabetic macular edema.

INTRODUCTION: To evaluate the effect of α-lipoic acid (ALA) on the occurrence of diabetic macular edema. METHODS: Randomized, double-blind, placebo-controlled, multicenter, multinational study. Patients were randomized to the treatment group with 600 mg ALA per day or the placebo group. Every 6 months stereo fundus photographs, HbA1c levels, and an ophthalmological examination were documented. The primary endpoint was the occurrence of clinically significant macular edema (CSME) within a follow-up period of 2 years. RESULTS: We randomized 235 patients with type II diabetes mellitus into the treatment group (mean age 58.0 years) and 232 into the placebo group (mean age 57.9 years). Mean HbA1c level was 8.1, with no significant differences between the treatment (mean 8.2, SD ± 1.35) and placebo groups (mean 8.1, SD ± 1.29). HbA1c values remained constant over time. In the treatment and placebo groups, 84 and 86 patients (35.7 and 37.1%) had insulin-dependent diabetes mellitus (IDDM) with a median duration of diabetes of 9.3 versus 9.0 years in the placebo group. Visual acuity remained unchanged during the entire trial. Concerning the primary endpoint, the study provided a negative result, i.e. 26/235 patients in the treatment group and 30/232 patients in the placebo group developed CSME. Confirmatory intention-to-treat analysis of the primary endpoint revealed no statistically significant difference between groups (log-rank test, p = 0.7108, HR = 0.9057 with CI = 0.5355-1.5317). Median follow-up was identical (2.00 years). CONCLUSIONS: A daily dosage of 600 mg ALA does not prevent the occurrence of CSME in IDDM patients.

[The Eye in Internal Medicine: Diabetic retinopathy]. / Das Auge in der Inneren Medizin: Die diabetische Retinopathie.

Diabetic retinopathy has seen tremendous progress in diagnostic tools and treatment in recent 15 years. Sight threatening stages like proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME) can be treated much more effectively now. The recognition of vascular endothelial growth factor (VEGF) as a driver of proliferation and macular edema has led to the development of VEGF inhibiting drugs such as antibodies (Bevacizumab), fragments of an antibody (Ranibizumab), or a so called VEGF trap (Aflibercept). Laser treatment is no longer a gold standard. Today laser therapy is part of a combined treatment strategy. DME can be monitored quantitatively by ocular coherence tomography (OCT) measurements. For non-responders to VEGF inhibiting drugs, we have secondline corticosteroidal implants. However, screening examinations and early diagnosis of DME and PDR remain crucial. The same accounts for the collaboration of opthalmologists, general practioners, and diabetologists. Good control of diabetes and blood pressure is still important.

Effect of calcium dobesilate on occurrence of diabetic macular oedema (CALDIRET study): randomised, double-blind, placebo-controlled, multicentre trial.

BACKGROUND: Medical treatment for diabetic retinopathy could have an important role in prevention of complications such as visual loss. We aimed to assess the effect of calcium dobesilate on occurrence of diabetic macular oedema. METHODS: We undertook a randomised, double-blind, placebo-controlled, multicentre study in 40 centres in 11 countries. We enrolled outpatients with adult-onset type 2 diabetes and mild-to-moderate non-proliferative diabetic retinopathy, and randomly allocated them via sealed envelopes either calcium dobesilate (1500 mg per day) or placebo. The primary endpoint was development of clinically significant macular oedema (CSME) within a follow-up period of 5 years. Patients who dropped out of the study early were censored. Analysis was by intention to treat. FINDINGS: We enrolled 635 patients. 324 were randomly allocated calcium dobesilate and 311 were assigned placebo. In the calcium dobesilate group, 86 patients developed CSME compared with 69 in the placebo group. Accounting for censored cases, estimated cumulative 5-year CSME probability was 35% and 28%, respectively (hazard ratio 1.32, 95% CI 0.96-1.81; p=0.0844). Adverse events did not differ between treatment groups (78 [24%] on calcium dobesilate and 90 [29%] with placebo). No relevant drug-related complications were noted. Nine patients (3%) died in the calcium dobesilate group and eight (3%) deaths were recorded on placebo. INTERPRETATION: Calcium dobesilate did not reduce the risk of development of CSME.

Comparison of intravitreal bevacizumab versus triamcinolone for the treatment of diffuse diabetic macular edema.

BACKGROUND: Our purpose was to compare the effect of triamcinolone and bevacizumab (Avastin) on the retinal thickness and functional outcome in patients with diabetic macular edema. METHODS AND MATERIALS: A collective of 32 patients, who had been treated by a single 4.0-mg intravitreal triamcinolone injection (group 1), was matched to 32 patients ('matched pairs'), who had received 3 injections of 1.25 mg of bevacizumab within 3 months in 4-week intervals (group 2). The outcome variables were changes in best corrected visual acuity (VA) and central retinal thickness 3 months after therapy. RESULTS: Both groups did not differ regarding preoperative VA and central retinal thickness measured by optical coherence tomography. The baseline mean VA was 0.72 +/- 0.39 logMAR in group 1 and 0.73 +/- 0.39 logMAR in group 2 (p = 0.709). The mean central retinal thickness measured by optical coherence tomography was 548 +/- 185 mum in group 1 and 507 +/- 192 mum in group 2. While the patients in group 1 experienced a slight increase in VA of on average 0.7 lines following a single triamcinolone injection to a mean of 0.64 +/- 0.40 logMAR (p = 0.066) after 3 months, the patients in group 2 showed almost no effect on VA with an average increase of 0.2 lines to a mean VA of 0.72 +/- 0.30 logMAR (p = 0.948) following 3 intravitreal injections of bevacizumab. Comparing the effect on VA between both groups no statistically significant difference (p = 0.115) was noted. Concerning decrease in central retinal thickness both therapies were highly effective (p < 0.001 each), again, without statistically significant difference between the groups (p < 0.128). CONCLUSION: Our data suggest that a single triamcinolone injection may be as effective as a 3 times repeated intravitreal administration of bevacizumab for the treatment of diabetic macular edema. Further prospective trials should be performed.

Amadeus II microkeratome: optimizing microkeratome settings for high flap accuracy using optical low coherence reflectometry.

PURPOSE: To investigate the impact of various experimental microkeratome settings and blade reuse on the accuracy of the flap thickness created with the new Amadeus II microkeratome (SIS, Ziemer Ophthalmic, Port, Switzerland). METHODS: In this prospective study, 120 porcine eyes were used to create corneal flaps with the Amadeus II using 2 different cutting heads (140 microm, 160 microm) with the Surepass blade. Using each blade twice, a head advance speed of 1.5 mm/s and 3.5 mm/s and oscillation rates of 8000 rpm, 10,000 rpm, and 13,000 rpm were used. Flap thickness was measured by optical low coherence reflectometry (OLCR). Descriptive statistical analysis was based on means, medians, and quartiles, with graphical representation on box plot. Pearson correlation test and Mann-Whitney U-test for unpaired samples were employed to identify the impact of different settings. RESULTS: Using the 140 microm cutting head, highest precision of the flap thickness was achieved with a head advance rate of 1.5 mm/s and an oscillation rate of 10,000 rpm (mean 132.1+/-10.0 microm; range 120.2-147.2 microm). Reusing the blade, highest accuracy (mean 130+/-6.9 microm; range 118.5-135 microm) was achieved with 8000 rpm. Using the 160 microm cutting head, an optimum flap thickness was reached with a head advance rate of 3.5 mm/s and an oscillation rate of 13,000 rpm (mean 162.4+/-7.7 microm; range 151.9-169.8 microm). Reusing the blade with the 160 microm cutting head, an adjustment to 3.5 mm/s and 10,000 rpm was necessary (mean 157.4+/-7.7 microm; range 153.7-161.8 microm). CONCLUSIONS: Optimized microkeratome settings lead to minimized deviation from the intended flap thickness and are mandatory to improve flap accuracy. OLCR is an ideal method to proof individualized settings.

Customizing the Amadeus II microkeratome: evaluation of cut quality with various settings using electron microscopy.

PURPOSE: To evaluate the cut quality of keratectomy specimens created with the new Amadeus II microkeratome (SIS, Ziemer Ophthalmic, Port, Switzerland) using scanning electron microscopy (SEM). Methods. Corneal cuts were performed in 24 freshly enucleated porcine eyes using the Amadeus II microkeratome with combinations of cutting-head depth, oscillation rate, head-advance speed, and reuse of the blade. For the cutting trials, a 140-microm and 160-microm cutting head with three oscillation rates of 8,000, 10,000, and 13,000 rpm and two head-advance speed rates of 1.5 and 3.5 mm/s were chosen. In each setting, the blade was reused for a second time. All eyes were included, resulting in 4 groups with 6 eyes for each configuration. The surface and edge of the corneal cut was examined using SEM. RESULTS: At fixed oscillation rates, an increase in head-advance speed led to lower quality cuts, higher surface roughness, and irregular cut edges for both cutting heads (140 microm/160 microm), especially when using the blade for a second time. At fixed head-advance speeds an increase in oscillation rates improved the cut quality for both cutting heads (140 microm/160 microm). This results in smoother surface characteristics and more regular cut edges, especially when using the blade for the first time. CONCLUSIONS: Using the Amadeus II microkeratome for laser in situ keratomileusis procedures, the optimum oscillation rate, the optimum head-advance speed, and a single use of the blade will produce a very smooth and regular surface and cut edge for safe, comfortable, and improved customized refractive surgery.