Real-world experience with brolucizumab in neovascular age-related macular degeneration over 2 years: the REBA extension study.

BACKGROUND: To determine long-term efficacy and safety of intravitreal brolucizumab therapy for neovascular age-related macular degeneration (nAMD) in the real-world setting. METHODS: Retrospective, observational, multicentric study and an extension of the REBA study (Real-world Experience with Brolucizumab in nAMD) to 24 months. The study entailed follow-up of 91 consecutive eyes (67 patients) with nAMD who received brolucizumab therapy and completed 24 months of follow-up. Both treatment-naïve and switch therapy patients were included. All relevant data were collected. The primary outcome measure was changed in best-corrected visual acuity (BCVA) over time. Secondary outcome measures included change in central subfield thickness (CST) and complications. RESULTS: The mean (SD) baseline BCVA was 48.4 (3.5) letters and 36.2 (7.1) letters in treatment-naïve group and switch therapy group, respectively. BCVA gain was + 9.2 (3.7) letters (p = 0.01) and + 7.7 (3.4) letters (p = 0.011), respectively. The change in mean (SD) CST has shown a significant decrease in retinal thickness in treatment-naïve group (from 432.5 (68.4) to 283.0 (51.3) µm; p = 0.018) and in switch therapy group (from 452.5 (40.5) to 271.0 (43.4) µm; p = 0.011) group. One switch patient developed vascular occlusion and another a macular hole after the fifth brolucizumab injection as reported in the primary study. Both patients recovered uneventfully. Three patients demonstrated reversible intraocular inflammation between months 10 and 24. CONCLUSION: Patients showed a significant anatomical and functional response to brolucizumab therapy in the real world, regardless of prior treatment status, until the end of the follow-up period. Overall, 5 significant untoward events were noted.

LASER FLARE PHOTOMETRY IN PRIMARY RHEGMATOGENOUS RETINAL DETACHMENT: An Evaluation of 2,487 Cases.

PURPOSE: Exploratory analysis associated with the prospective, multicenter, randomized PRIVENT trial. To characterize the associations between laser flare photometry and anatomical and epidemiological features of rhegmatogenous retinal detachment (RRD). METHODS: The authors measured laser flare values of all 3,048 prescreened patients excluding those with comorbidities. A mixed regression analysis evaluated the strength of the influencing factors like age, sex, lens status, and presence and extent of RRD on laser flare. RESULTS: Rhegmatogenous retinal detachment was more frequent in men (65.8%) than in women (34.2%, P < 0.001) and in right (52%) than in left eyes (48%, P = 0.045). Phakic RRD affected less quadrants and was less likely to be associated with macula-off status than pseudophakic RRD (48.4% vs. 58.0% macula off, 23% vs. 31% ≥3 quadrants, P < 0.001). Laser flare of affected eyes was significantly higher compared with fellow eyes (12.6 ± 15.2 vs. 8.3 ± 7.4 pc/ms, P < 0.001). The factors age, sex, lens status, presence of RRD, and the number of quadrants affected were independent influencing factors on laser flare. R 2 was 0.145 for phakic and 0.094 for pseudophakic eyes. CONCLUSION: The results indicate that there may be more factors affecting laser flare than previously assumed. This might limit flare as predictive value for PVR and retinal redetachment.

Clinical Landscape of Central Serous Chorioretinopathy in Germany: Retina.net CSC Registry Report Number 1.

INTRODUCTION: The German Registry of central serous chorioretinopathy (CSC) collects data on CSC patients in a nationwide multicenter approach to analyze epidemiology, risk factors, clinical presentations, as well as diagnosis and treatment patterns. METHODS: In this multicenter cohort study, patients with CSC were enrolled in nine tertiary referral centers in Germany between January 2022 and June 2023. After consenting to the study, demographic data, risk factors, reported symptoms, best-corrected visual acuity (BCVA), funduscopic findings, disease severity, and diagnostic and treatment decisions were recorded and analyzed. RESULTS: A total of 539 eyes of 411 CSC patients were enrolled in this study including 308 males (75%) and 103 females (25%). Patients were predominantly of Caucasian origin and had a mean age of 55.5 years (IQR 41.0-70.0). 28% of eyes were classified as acute (<4 months duration) CSC, 28% as chronic (>4 months duration) CSC, 21% as inactive CSC, 11% as chronic atrophic CSC, and 12% as CSC with secondary CNV. 128 patients (31%) demonstrated bilateral CSC. The most common risk factors reported were psychological stress (52%), smoking (38%), arterial hypertension (38%), and a history of or current use of steroids (30%). Most frequently encountered symptoms included decreased visual acuity (76%), metamorphopsia (49%), relative scotoma (47%), blurred vision (19%), and dyschromatopsia (9%). The mean logMAR BCVA on initial examination was 0.2 (≈20/30, IQR 0.2-0.4) but showed significant variation with a tendency of lower BCVA in chronic cases. At the baseline visit, 74% of the overall cohort received no treatment, while 19% underwent local treatment and only 2% underwent systemic treatment. Of the local therapies, anti-VEGF injections were the most frequently performed procedure (33%, mainly for secondary CNV), followed by micropulse laser (28%), focal nonpulsed laser (23%), verteporfin photodynamic therapy (14%), and nonsteroidal anti-inflammatory eye drops (2%). Among intravitreal anti-VEGF agents, aflibercept was used most frequently, followed by bevacizumab and ranibizumab. CONCLUSION: This registry represents one of the largest cohorts of European patients with CSC to date. Patient age and the proportion of women were higher than expected and bilateral active disease was lower than anticipated, highlighting that neither age nor gender should be overemphasized when diagnosing CSC. Therapeutic interventions are heterogeneous and include verteporfin photodynamic therapy, micropulse laser, and anti-VEGF injections in case of secondary CNV.

Intravitreal Injections: Improving Sustainability by Reducing Clinical Waste. / Intravitreale Injektionen: Nachhaltigkeit durch Reduktion von Klinikabfall.

BACKGROUND: Intravitreal injections are one of the most commonly performed ophthalmic procedures. It is estimated that over 1 million intravitreal injections are performed in Germany annually. The aim of this study was to quantify the waste and carbon footprint associated with single-use injection sets, and to establish a waste reduction strategy. MATERIAL AND METHODS: The clinical waste and associated carbon footprint from standard disposable injection sets used by tertiary referral centres in Germany (n = 6) and the United Kingdom (n = 2) were assessed. The safety of performing intravitreal injections with a minimalistic material-sparing approach was evaluated. RESULTS: The average weight of an injection set (and hence the waste generated from each injection) was 165 g. On average, each injection set comprised 145 g (88%) of plastic, 2.1 g (1.3%) of metal, 4.3 g (2.6%) of paper, and 12.9 g (7.8%) of gauze/swabs. The production of such injection sets was extrapolated to a CO2 equivalent of 752.6 tonnes (t), and the incineration of the resulting waste to a CO2 equivalent of 301.7 t. For 1 million injections, this equates to 145.2 t of plastic, 2.1 t of metal, 4.3 t of paper, and 12.9 t of gauze/swabs. A material-sparing approach can reduce injection set-associated waste by 99% without necessarily compromising patient safety. CONCLUSION: A resource-saving approach to intravitreal injections can minimise the generation of clinical waste and its associated carbon footprint, thereby supporting sustainability.

INTRAOCULAR EMULSION OF SILICONE OIL (ITEMS) GRADING SYSTEM: An Evidence-Based Expert-Led Consensus.

PURPOSE: To propose the InTraocular EMulsion of Silicone oil (ITEMS) grading system for the assessment of silicone oil (SiO) emulsion, applicable in a routine clinical setting and validated through an expert-led consensus procedure. METHODS: Seven experts on intraocular liquid tamponades, led by a facilitator, performed a literature review on the detection of SiO emulsion. Based on the proposed ideas, a questionnaire was developed and submitted to the experts on the methods to detect SiO emulsion and the items to grade. After 2 rounds of individual ranking using a 9-point scale and related discussion, the final grading system was developed including items that reached consensus (score ≥7 from ≥75% of members). RESULTS: The agreed ITEMS grading system includes the identification of SiO microbubbles and large SiO bubbles through slit-lamp biomicroscopy, gonioscopy, fundus examination under mydriasis, or ultra-wide-field fundus photography. Moreover, macular and disk optical coherence tomography are used to detect SiO-associated hyperreflective dots. CONCLUSION: An evidence-based expert-led consensus was conducted to develop grading system of SiO emulsion, allowing, for the first time, homogenous collection of data on SiO emulsion. This has the potential to improve the understanding of the role and clinical relevance of SiO emulsion, allowing comparisons between different studies.

Effect of elevated irrigation bottle height during cataract surgery on corneal endothelial cells in porcine eyes.

BACKGROUND: Cataract surgery induces corneal endothelial cell loss (ECL). This study investigates the relationship between bottle height (BH) and ECL induced due to irrigation and aspiration (I/A) in cataract surgery and quantifies protective effects of intraoperatively used ophthalmic viscoelastic substances. METHODS: Intermittent I/A without phacoemulsification was performed in porcine eyes for 10 min with varying BHs of 100 cm (BH100), 125 cm (BH125), 150 cm (BH150) or no treatment (control, no I/A). Additionally, in one group a dispersive ophthalmic viscoelastic substance was injected into the anterior eye chamber before treatment with I/A at a BH of 150 cm (BH150 + V). After exposure of the corneal endothelium to I/A, the corneas were prepared to split corneal buttons on day 0 and cultivated for 15 days. Endothelial cell density (ECD) was analyzed blinded on days 1, 8 and 15. RESULTS: Relative ECL significantly correlated with irrigation BH (control (n = 13): -9.69 ± 6.03% (average ± standard deviation); BH100 (n = 12): -9.69 ± 4.81%-p = 1.000; BH125 (n = 14): -19.44 ± 7.30% - p < 0.001; BH150 (n = 13): -21.99 ± 6.70%-p < 0.001). I/A-induced ECL was significantly decreased by the injection of ophthalmic viscoelastic, as BH150 + V (n = 14; -10.92 ± 4.09%-p = 1.000) showed a cell loss comparable to the control group. CONCLUSIONS: ECL is altered by I/A BH and reduced when viscoelastic substances are used.

Terson Syndrome in Patients with Aneurysmal Subarachnoid Hemorrhage: A 10-Year Single-Center Experience.

BACKGROUND: Terson syndrome (TS), an intraocular hemorrhage associated with aneurysmal subarachnoid hemorrhage (aSAH), occurs in up to 46% of all patients with subarachnoid hemorrhage. Despite its high incidence, TS is underrepresented in the literature, and patients with aSAH are sometimes not systematically evaluated for the presence of TS in clinical practice. This work aims to raise awareness of TS, reevaluate previous scientific findings, describe risk factors associated with the occurrence of TS, and present our local diagnostic and treatment concept. METHODS: All patients with aSAH treated at our institution between October 2010 and May 2020 were included in this retrospective study. The frequency of ophthalmological screening by indirect funduscopy, as well as the results, was investigated. In addition, the collection and statistical analysis of epidemiological and clinical data was performed using χ2, Kruskal-Wallis, and analysis of variance testing; multivariate regression; and receiver operating characteristic analysis. The significance level was set at p < 0.05. RESULTS: A total of 617 patients were treated for aSAH in our institution. Of these, 367 patients (59.5%) were ophthalmologically examined for the presence of TS. The rate of TS in the examined patients was 21.3% (n = 78). Patients with TS had significantly higher Fisher and World Federation of Neurosurgical Societies (WFNS) scores (p < 0.0001). Regression analyses showed WFNS grade (p = 0.003) and the occurrence of seizures (p = 0.002) as independent predictors of TS, as did receiver operating characteristic analyses, which had a significant area under the curve of 0.66 for the combination of WFNS grade and seizures. For 12 (15.4%) patients, the TS had to be surgically treated by pars plana vitrectomy in a total of 14 eyes, which resulted in significant improvement of visual function in all patients: mean preoperative best-corrected visual acuity was 0.03 (± 0.08) versus 0.76 (± 0.21) postoperatively (p < 0.001). CONCLUSIONS: TS is a common complication in patients with aSAH, affecting approximately one in five patients. A higher WFNS grade and the occurrence of seizures are associated with TS; therefore, screening for TS should be performed in these patients.

The Challenge of Treating the Severest Forms of Chronic Noninfectious Posterior and Panuveitis.

BACKGROUND: Noninfectious posterior and panuveitis may exhibit a chronic relapsing clinical course and are challenging to treat. Most affected patients are continuously treated with systemic immunosuppressive therapy, which is potentially associated with significant adverse side effects. METHODS: A cohort of 18 patients presenting with severe noninfectious posterior or panuveitis were evaluated with respect to the clinical course of the disease, with particular focus on best-corrected visual acuity (BCVA), treatment duration, remission rates, reported negative side effects, and the necessity for switching medication. RESULTS: The mean follow-up was 27.8 months. Although BCVA improved significantly, complete or partial remission was observed in only 66.7% of patients. Of the patients, 72.2% underwent a change in medical treatment due to either adverse events or inefficacy of medication. CONCLUSION: Despite new immunosuppressive therapies, effective treatment of severe noninfectious posterior and panuveitis remains a major challenge. We discuss the urgent need for novel treatment strategies in order to prevent systemic adverse effects, and to improve visual outcome and quality of life.

Intravitreal 5-Fluorouracil and Heparin to Prevent Proliferative Vitreoretinopathy: Results from a Randomized Clinical Trial.

PURPOSE: Proliferative vitreoretinopathy (PVR) is the major cause for surgical failure after primary rhegmatogenous retinal detachment (RRD). So far, no therapy has been proven to prevent PVR. Promising results for 5-fluorouracil (5-FU) and low-molecular weight heparin (LMWH) in high-risk eyes have been reported previously. The objective of this trial was to examine the effect of adjuvant intravitreal therapy with 5-FU and LMWH compared with placebo on incidence of PVR in high-risk patients with primary RRD. DESIGN: Randomized, double-blind, controlled, multicenter, interventional trial with 1 interim analysis. PARTICIPANTS: Patients with RRD who were considered to be at high risk for PVR were included. Risk of PVR was assessed by noninvasive aqueous flare measurement using laser flare photometry. METHODS: Patients were randomized 1:1 to verum (200 mg/ml 5-FU and 5 IU/ml dalteparin) and placebo (balanced salt solution) intravitreally applied during routine pars plana vitrectomy. MAIN OUTCOME MEASURES: Primary end point was the development of PVR grade CP (full-thickness retinal folds or subretinal strands in clock hours located posterior to equator) 1 or higher within 12 weeks after surgery. For grading, an end point committee assessed fundus photographs. Secondary end points included best-corrected visual acuity and redetachment rate. A group sequential design with 1 interim analysis was applied using the O'Brien and Fleming boundaries. Proliferative vitreoretinopathy grade CP incidence was compared using a Mantel-Haenszel test stratified by surgeon. RESULTS: A total of 325 patients in 13 German trial sites had been randomized (verum, n = 163; placebo, n = 162). In study eyes, mean laser flare was 31 ± 26 pc/ms. No significant difference was found in PVR rate. Primary analysis in the modified intention-to-treat population results were: verum 28% vs. placebo 23% (including not assessable cases as failures); odds ratio [OR], 1.25; 95% confidence interval [CI], 0.76-2.08; P = 0.77. Those in the per-protocol population were: 12% vs. 12%; OR, 1.05; 95% CI, 0.47-2.34; P = 0.47. None of the secondary end points showed any significant difference between treatment groups. During the study period, no relevant safety risks were identified. CONCLUSIONS: Rate of PVR did not differ between adjuvant therapy with 5-FU and LMWH and placebo treatment in eyes with RRD.

[Optical coherence tomography in the differential diagnostics of important neuro-ophthalmological disease patterns]. / Die optische Kohärenztomographie in der Differenzialdiagnostik wichtiger neuroophthalmologischer Krankheitsbilder.

There are many disease patterns that are treated jointly by neurologists and ophthalmologists, for which optical coherence tomography (OCT) is of important differential diagnostic significance. In this context neurologists are mainly confronted by two patient collectives: patients with an acute ischemic event, who present with an acute but painless monocular visual deterioration (for central retinal artery occlusion) or with a monocular visual field defect (for arterial branch occlusion or anterior ischemic optic neuropathy). The second collective is patients without ophthalmological symptoms but with conspicuous optic nerve findings (papilledema or optic disc drusen). In this overview article both patient collectives are considered separately. In addition, the most important OCT findings for optic neuritis are presented. Before the disease patterns are described in detail, the normal OCT findings and the diagnostic possibilities of OCT are explained.

Diagnosing Central Retinal Artery Occlusion (CRAO) without Fundus Examination. / Diagnose eines Zentralarterienverschlusses (ZAV) ohne Funduskopie.

In the field of ophthalmology, central retinal artery occlusion is still one of the unsolved pathologies, as there is no widely accepted evidence-based therapeutic concept. Meta-analysis suggests that intravenous fibrinolysis might help to improve the outcome if performed within the first 4.5 hours after symptom onset. However, this short window of opportunity is often missed due to delays during diagnostic testing (e.g. time elapsed before performance of an ophthalmological examination) or patient-processing (referring the patient to a specialized medical facility). This article presents a diagnostic tool in the form of a simple questionnaire, comprising a medical history and examinations, which could help to minimize the time required to initiate the appropriate treatment.

Structural and Functional Imaging of the Retina in Central Retinal Artery Occlusion - Current Approaches and Future Directions.

Central retinal artery occlusion (CRAO) is a form of acute ischemic stroke which affects the retina. Intravenous thrombolysis is emerging as a compelling therapeutic approach. However, it is not known which patients may benefit from this therapy because there are no imaging modalities that adequately distinguish viable retina from irreversibly infarcted retina. The inner retina receives arterial supply from the central retinal artery and there is robust collateralization between this circulation and the outer retinal circulation, provided by the posterior ciliary circulation. Fundus photography can show canonical changes associated with CRAO including a cherry-red spot, arteriolar boxcarring and retinal pallor. Fluorescein angiography provides 2-dimensional imaging of the retinal circulation and can distinguish a complete from a partial CRAO as well as central versus peripheral retinal non-perfusion. Transorbital ultrasonography may assay flow through the central retinal artery and is useful in the exclusion of other orbital pathology that can mimic CRAO. Optical coherence tomography provides structural information on the different layers of the retina and exploratory work has described its utility in determining the time since onset of ischemia. Two experimental techniques are discussed. 1) Retinal functional imaging permits generation of capillary perfusion maps and can assay retinal oxygenation and blood flow velocity. 2) Photoacoustic imaging combines the principles of optical excitation and ultrasonic detection and - in animal studies - has been used to determine the retinal oxygen metabolic rate. Future techniques to determine retinal viability in clinical practice will require rapid, easily used, and reproducible methods that can be deployed in the emergency setting.

Intravenous Fibrinolysis for Central Retinal Artery Occlusion: A Cohort Study and Updated Patient-Level Meta-Analysis.

BACKGROUND AND PURPOSE: Central retinal artery occlusion results in sudden, painless, usually permanent loss of vision in the affected eye. There is no proven, effective treatment to salvage visual acuity and a clear, unmet need for an effective therapy. In this work, we evaluated the efficacy of intravenous tissue-type plasminogen activator (IV alteplase) in a prospective cohort study and an updated systematic review and meta-analysis. METHODS: We enrolled consecutive patients with acute central retinal artery occlusion within 48 hours of symptoms onset and with a visual acuity of <20/200 from January 2009 until May 2019. The primary outcomes were safety and functional visual acuity recovery. We compared rates of visual recovery between those treated with alteplase within 4.5 hours of symptom onset to those who did not receive alteplase (including an analysis restricted to untreated patients presenting within the window for treatment). We incorporated these results into an updated systematic review and patient-level meta-analysis. RESULTS: We enrolled 112 patients, of whom 25 (22.3% of the cohort) were treated with IV alteplase. One patient had an asymptomatic intracerebral hemorrhage after IV alteplase treatment. Forty-four percent of alteplase-treated patients had recovery of visual acuity when treated within 4.5 hours versus 13.1% of those not treated with alteplase (P=0.003) and 11.6% of those presenting within 4 hours who did not receive alteplase (P=0.03). Our updated patient-level meta-analysis of 238 patients included 67 patients treated with alteplase within 4.5 hours since time last known well with a recovery rate of 37.3%. This favorably compares with a 17.7% recovery rate in those without treatment. In linear regression, earlier treatment correlated with a higher rate of visual recovery (P=0.01). CONCLUSIONS: This study showed that the administration of intravenous alteplase within 4.5 hours of symptom onset is associated with a higher likelihood of a favorable visual outcome for acute central retinal artery occlusion. Our results strongly support proceeding to a randomized, placebo-controlled clinical trial.

OCT angiography analysis of retinal vessel density in primary open-angle glaucoma with and without Tafluprost therapy.

BACKGROUND: Primary open-angle glaucoma (POAG) is a progressive neurodegenerative disease which leads to irreversible blindness. An elevated intraocular pressure (IOP) is considered to be the main risk factor for the disease progression. It is known that retinal blood flow is altered in POAG eyes. Tafluprost, a prostaglandin analogue which lowers the IOP, has shown to also improve the retinal blood flow in animals. METHODS: The current study therefore evaluated the retinal vessel density in the peripapillary and macular region of POAG patients with normal IOP treated with topical Tafluprost (n = 20) compared to surgically treated patients with normal IOP (n = 22) using optical coherence tomography angiography (OCT-A). The retinal flow density was obtained after binarisation and evaluated in five sectors. RESULTS: There was a significantly higher peripapillary flow density in all sectors in Tafluprost treated eyes when compared to post-surgery eyes. The flow density in the inferior sector of the superficial plexus in the macular region was also significantly higher in the Tafluprost group. CONCLUSIONS: These results indicate that Tafluprost not only lowers IOP, but may also enhance retinal blood flow in POAG patients with a normal IOP.

Self-assembled DNA nanoparticles loaded with travoprost for glaucoma-treatment.

Lipid DNA nanoparticles (NPs) exhibit an intrinsic affinity to the ocular surface and can be loaded by hybridization with fluorophore-DNA conjugates or with the anti-glaucoma drug travoprost by hybridizing an aptamer that binds the medication. In the travoprost-loaded NPs (Trav-NPs), the drug is bound by specific, non-covalent interactions, not requiring any chemical modification of the active pharmaceutical ingredient. Fluorescently labeled Trav-NPs show a long-lasting adherence to the eye, up to sixty minutes after eye drop instillation. Biosafety of the Trav-NPs was proved and in vivo. Ex vivo and in vivo quantification of travoprost via LC-MS revealed that Trav-NPs deliver at least twice the amount of the drug at every time-point investigated compared to the pristine drug. The data successfully show the applicability of a DNA-based drug delivery system in the field of ophthalmology for the treatment of a major retinal eye disease, i.e. glaucoma.

Hypothermia protects retinal ganglion cells against hypoxia-induced cell death in a retina organ culture model.

BACKGROUND: Hypoxia contributes to retinal damage in several retinal diseases, including central retinal artery occlusion, with detrimental consequences like painless, monocular loss of vision. Currently, the treatment options are severely limited due to the short therapy window, as the neuronal cells, especially the retinal ganglion cells (RGCs), are irreversibly damaged within the first few hours. Hypothermia might be a possible treatment option or at least might increase the therapy window. METHODS: To investigate the neuroprotective effect of hypothermia after retinal hypoxia, an easy-to-use ex vivo retinal hypoxia organ culture model developed in our laboratory was used that reliably induced retinal damage on a structural, molecular and functional level. The neuroprotective effect of hypothermia after retinal hypoxia was analysed using optical coherence tomography scans, histological stainings, quantitative real-time polymerase chain reaction, western blotting and microelectrode array recordings. RESULTS: Two different hypothermic temperatures (30°C and 20°C) were evaluated, both exhibited strong neuroprotective effects. Most importantly, hypothermia increased RGC survival after retinal hypoxia. Furthermore, hypothermia counteracted the hypoxia-induced RGC death, reduced macroglia activation, attenuated retinal thinning and protected from loss of spontaneous RGC activity. CONCLUSIONS: These results indicate that already a mild reduction in temperature protects the RGCs against damage and could function as a promising therapeutic option for hypoxic diseases.

Staining of endothelial cells does not change the result of cell density.

To determine the corneal endothelial cell density human donor corneas are usually placed in hypotonic balanced salt solution for unstained cell counting. Experimental studies often stain the corneal endothelium to highlight cells and cell borders and simplify counting. However, staining normally terminates the experiments. Up to date, there is no publication comparing endothelial cell counts before and after staining. This study compared the counting results of unstained (hypotonic balanced salt solution) and stained (trypan blue & alizarin red S) assessment of the corneal endothelial cell density. No evidence for significantly differing cell counts was found between unstained and stained analysis of the corneal endothelial cell density. Therefore, we consider unstained counting non-inferior to stained counting.

Retinal Toxicity of Medical Devices Used during Vitreoretinal Surgery: A Critical Overview.

Retinal toxicity/biocompatibility of medical devices in direct contact with the retina is an important subject for clinicians and scientists. As these effects are not very frequent, there is also a relative lack of information for many clinicians. The past has taught us multiple times that there is a significant safety problem associated with severe loss of vision in affected patients. In this review, we want to classify medical products that are used in the back of the eye, describe recent examples of toxicity, critically reflect on the regulations that exist and suggest improvements that can be done to ensure patient safety without hindering innovation. METHODS: Critical review of the recent papers and personal experience of the authors in this issue. Medical devices used in the back of the eye and recent examples of toxicity are described, regulations that exist are critically reflected and improvements suggested that can ensure patient safety without hindering innovation. RESULTS: There is clear evidence of toxicity after intraocular surgery in any category. Some cytotoxic indirect methods have failed in detecting this toxicity. Some ISO rules do not seem appropriate. Postmarketing safety is missing. There is little data on this issue. CONCLUSIONS: The absence of a clear regulation of the production, purification and evaluation of the toxic effects of the medical devices supposes the possibility that products are not sufficiently safe to obtain the CE mark.

Establishment of a porcine corneal endothelial organ culture model for research purposes.

Human corneas usually are not available for research, as they are used for transplantation only. At the same time, scientific studies on cultured human endothelial cells can produce misleading results due to inevitable dedifferentiation. Therefore, an organ-culture model of porcine corneas-displaying endothelial cell death rates comparable to those of cultured human corneas-would be very desirable. Fresh pig eyes were prepared under sterile conditions to obtain corneoscleral buttons, corneal buttons and so called "split corneal buttons" (new preparation method) and cultivated for 15 days. Morphology of the endothelial cell layer was observed by light microscopy on day 1, 8 and 15. On day 15 staining with trypan blue and alizarin red S was performed. Photographs were evaluated in a randomized, blinded manner. Here, the morphology of the corneal endothelium and the number of endothelial cells per mm2 were analyzed. After 15 days of cultivation the endothelial cell layer was maintained only in corneal buttons and split corneal buttons. Alizarin red S stained areas and the existence of polymorphisms like rosette figures and reformation figures were significantly less frequent in split corneal buttons than in corneal buttons. Loss of endothelial cells was significantly greater in corneal buttons [575 ± 25/250 cells/mm2 (median ± 25%/75%-quantile); 14.8%] than in split corneal buttons [417 ± 138/179 cells/mm2 (median ± 25%/75%-quantile); 10.2%]. The new preparation method of split corneal buttons allows the cultivation of porcine corneas for 2 weeks with cell death rates comparable to those of the corresponding human tissue in cornea banks without the need to add de-swelling additives to the media. This is therefore a simple and highly reliable method model to be applied in intervention studies on corneal endothelial cells in their natural compound.