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To reduce treatment burden and optimise patient outcomes in diabetic macular oedema, we present 1-year results from two phase 3 trials of faricimab, a novel angiopoietin-2 and vascular endothelial growth factor-A bispecific antibody.YOSEMITE and RHINE were randomised, double-masked, non-inferiority trials across 353 sites worldwide. Adults with vision loss due to centre-involving diabetic macular oedema were randomly assigned (1:1:1) to intravitreal faricimab 6·0 mg every 8 weeks, faricimab 6·0 mg per personalised treatment interval (PTI), or aflibercept 2·0 mg every 8 weeks up to week 100. PTI dosing intervals were extended, maintained, or reduced (every 4 weeks up to every 16 weeks) based on disease activity at active dosing visits. The primary endpoint was mean change in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Efficacy analyses included the intention-to-treat population (non-inferiority margin 4 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); safety analyses included patients with at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (YOSEMITE NCT03622580 and RHINE NCT03622593).3247 patients were screened for eligibility in YOSEMITE (n=1532) and RHINE (n=1715). After exclusions, 940 patients were enrolled into YOSEMITE between Sept 5, 2018, and Sept 19, 2019, and 951 patients were enrolled into RHINE between Oct 9, 2018, and Sept 20, 2019. These 1891 patients were randomly assigned to faricimab every 8 weeks (YOSEMITE n=315, RHINE n=317), faricimab PTI (n=313, n=319), or aflibercept every 8 weeks (n=312, n=315). Non-inferiority for the primary endpoint was achieved with faricimab every 8 weeks (adjusted mean vs aflibercept every 8 weeks in YOSEMITE 10·7 ETDRS letters [97·52% CI 9·4 to 12·0] vs 10·9 ETDRS letters [9·6 to 12·2], difference -0·2 ETDRS letters [-2·0 to 1·6]; RHINE 11·8 ETDRS letters [10·6 to 13·0] vs 10·3 ETDRS letters [9·1 to 11·4] letters, difference 1·5 ETDRS letters [-0·1 to 3·2]) and faricimab PTI (YOSEMITE 11·6 ETDRS letters [10·3 to 12·9], difference 0·7 ETDRS letters [-1·1 to 2·5]; RHINE 10·8 ETDRS letters [9·6 to 11·9], difference 0·5 ETDRS letters [-1·1 to 2·1]). Incidence of ocular adverse events was comparable between faricimab every 8 weeks (YOSEMITE n=98 [31%], RHINE n=137 [43%]), faricimab PTI (n=106 [34%], n=119 [37%]), and aflibercept every 8 weeks (n=102 [33%], n=113 [36%]).Robust vision gains and anatomical improvements with faricimab were achieved with adjustable dosing up to every 16 weeks, demonstrating the potential for faricimab to extend the durability of treatment for patients with diabetic macular oedema.F Hoffmann-La Roche.

This article is intended to clearly present the basic principles for the use of intraocular tamponades in vitreous/retinal surgery in the event of retinal detachment and other pathologies using additional video footage. It examines the various gases, silicone oils and perfluorocarbon liquids with their indications, administration and in particular intraoperative handling including pitfalls and complications. Characteristic animations show the principles of use in surgery in a comprehensible way. The two lead authors dedicate this article to their teacher Prof. Dr. V.-P. Gabel, who in the early 1990s successfully established the first vitrectomy courses for ophthalmologists at Regensburg University Eye Clinic each year. Many colleagues who still work in retinal surgery today first started learning about this segment on these courses. The other coauthors participated under his supervision in annual vitrectomy wet labs run by the German Academy of Ophthalmology.In diesem Artikel sollen die Grundlagen zur Verwendung intraokularer Tamponaden in der Glaskörper-/Netzhautchirurgie bei Ablatio retinae und anderen Pathologien anhand zusätzlichen Videomaterials anschaulich dargestellt werden. Behandelt werden die verschiedenen Gase, Silikonöle und flüssigen Perfluorocarbone mit ihren Indikationen, ihrer Anwendung und insbesondere der intraoperativen Handhabung mit Fallstricken und Komplikationen. Charakteristische Animationen zeigen dabei nachvollziehbar die Prinzipien in der chirurgischen Handhabung. Seitens der beiden Erstautoren ist dieser Artikel ihrem Lehrer Herrn Prof. Dr. V.-P. Gabel gewidmet, der in den frühen 90er-Jahren die ersten Vitrektomiekurse für Augenärzte an der Universitäts-Augenklinik Regensburg erfolgreich im jährlichen Rhythmus etabliert hat und in denen viele heute noch netzhautchirurgisch tätige Kolleginnen und Kollegen ihre ersten Schritte in diesem Segment erlernt haben. Die weiteren Co-Autoren partizipierten unter seiner Leitung an jährlichen Vitrektomie-Wetlabs im Rahmen der Augenärztlichen Akademie Deutschlands.

Purpose Central serous chorioretinopathy (CSC) is a disease presenting with detachment of the neurosensory retina and characteristic focal leakage on fluorescein angiography. The spontaneous remission rate is 84% within 6 months. In this study, the efficacy of selective retina therapy (SRT) was examined in patients with therapy refractory persistent acute CSC defined by symptoms for at least 6 months and persistent subretinal fluid (SRF) despite eplerenone therapy. Material and methods This is a prospective, monocentric observational study in 17 eyes (16 patients, mean age 42 years, 2 female). SRT was performed with the approved R:GEN laser (Lutronic, South Korea), a micropulsed 527-nm Nd:YLF laser device, with a train of 30 pulses of 1.7 μs at 100-Hz repetition rate at the point of focal leakage determined by fluorescein angiography (FA) at baseline (BSL). Visits on BSL, week 4 (wk4), and week 12 (wk12) included best corrected visual acuity (BCVA, logMar), central retinal thickness (CRT) on spectral domain optical coherence tomography (SD-OCT), and FA. Statistical analysis was performed by pair-by-pair comparisons of multiple observations in each case with Bonferroni correction for multiple testing. (IBM SPSS Statistics 25®). Results Mean CRT at BSL was 387.69 ± 110.4 μm. CRT significantly decreased by 106.31 μm in wk4 (95%-KI: 21.42–191.2; p = 0.01), by 133.63 μm in wk12 (95%-KI: 50.22–217.03; p = 0.001) and by 133.81 μm (95%-KI: 48.88–218.75; p = 0.001) compared to BSL. Treatment success defined as complete resolution of SRF occurred at wk4 in 7/17 eyes (35.3%) and at wk12 in 10/17 eyes (58.8%). Re-SRT was performed in 7/17 eyes (41.2%) after an average of 107.14 ± 96.59 days. Treatment success after Re-SRT was observed in 4/6 eyes (66.6%, 12 weeks after Re-SRT). Mean BCVA did not change significantly from BSL to any later timepoint after adjusting for multiple testing. Notably, eyes with treatment success showed better BCVA at all timepoints and gained more letters compared to failures. Conclusion Single or repetitive SRT may be an effective and safe treatment in 2 of 3 patients suffering from acute persistent CSC after 6 months of symptoms or more. We observed complete resolution of SRF in around 60% of eyes 12 weeks after first SRT treatment and also 12 weeks after Re-SRT treatment in eyes with persistent or recurrent SRF. Results on the long-term course after SRT are still pending.

Purpose To investigate the influence of treatment regularity with intravitreal aflibercept injections (IVT-AFL injections) on visual acuity (VA) outcomes in patients with neovascular age-related macular degeneration (nAMD) enrolled in the PERSEUS trial who received at least 7 IVT-AFL injections during the first year. Methods This was a post hoc analysis of the PERSEUS trial, a prospective, non-interventional, multicenter cohort study, and included 370 patients with nAMD who had received ≥ 7 IVT-AFL injections during year 1. In addition to the prespecified subgroups of treatment-naïve and previously treated patients, results were compared between patients with regular (n = 209) and irregular (n = 161) treatment. Regular treatment was defined as initial dosing with monthly IVT-AFL injections for 3 months, then bimonthly IVT-AFL injections until month 12. Irregular treatment was defined as any deviation from regular treatment (provided ≥ 7 injections were received). The outcome of primary interest was the mean change in VA from baseline after 12 months. Further outcomes of interest included VA gain or loss, proportion of patients achieving reading vision, and percentage of patients with fluid. Results At month 12, the mean (± standard deviation, SD) VA improvement from baseline was 6.1 ± 15.6 Early Treatment Diabetic Retinopathy Study letters in the regular cohort and 2.5 ± 16.7 letters in the irregular cohort with ≥ 7 IVT-AFL injections (P = 0.0514). Best results were obtained in the treatment-naïve regular sub-cohort with a mean ± SD VA improvement of 8.0 ± 17.7 letters, whereas treatment-naïve patients with irregular treatment experienced a considerably lower VA gain (2.8 ± 20.0 letters). Irregular treatment consistently correlated with inferior results in treatment-naïve patients. At month 12, the proportion of treatment-naïve patients who had experienced a worsening of ≥ 5 letters was 29.6% in the irregular sub-cohort versus 13.6% in the regular sub-cohort (P = 0.0049). However, among the treatment-naïve patients, the mean number of injections was significantly higher in the irregular than in the regular sub-cohort (8.0 ± 1.2 vs. 7.4 ± 0.6; P = 0.0001). Furthermore, compared with the treatment-naïve, regular sub-cohort, patients in the irregular sub-cohort had more visits (19.1 ± 8.6 vs. 16.1 ± 5.7), VA tests (14.2 ± 6.9 vs. 12.0 ± 4.6), and optical coherence tomography examinations (5.1 ± 3.7 vs. 3.4.0 ± 3.0). Conclusions Although irregularly treated patients received more injections and more monitoring visits during the first year of IVT-AFL treatment, they experienced worse VA outcomes than regularly treated patients.

Intravitreal injection (IVI) of drugs for treatment of various macular diseases is now one of the most frequently performed surgical procedures worldwide. As mostly chronic diseases are treated, the indications for treatment often mean a continuous treatment over years with a corresponding effort regarding spatial, personnel and financial resources. The diagnosis and indications for treatment are nowadays mainly made by spectral domain optical coherence tomography (SD-OCT). The ability to clinically assess and evaluate a fluorescence angiography is less practiced, although these are still a component of the indications for intravitreal injections. Therefore, it can happen that despite all diligence patients may receive anti-vascular endothelial growth factor (VEGF) treatment, sometimes permanently, based on a misinterpretation of the macular diagnosis or disease activity and these indications, once made, are rarely questioned or retracted. Therefore, the aim of this manuscript is to point out possible and typical misinterpretations in the indications or continuation of IVI treatment with anti-VEGF by means of case studies and to sensitize for differential diagnoses.Die intravitreale operative Medikamenteneingabe (IVOM) bei verschiedenen Makulaerkrankungen ist heute eine der am häufigsten durchgeführten operativen Behandlungen weltweit. Da zumeist chronische Erkrankungen behandelt werden, bedeutet die Indikation zur Behandlung oft eine kontinuierliche Therapie über Jahre mit einem entsprechenden Aufwand bezüglich räumlicher, personeller und finanzieller Ressourcen. Dabei werden die Diagnose und Indikation zur Behandlung heute maßgeblich über die Spectral-Domain-optische Kohärenztomographie (SD-OCT) gestellt. Die Fähigkeit zur klinischen Beurteilung und Bewertung einer Fluoreszenzangiographie wird weniger geübt, obwohl diese immer noch Bestandteil der Indikationsstellung ist. So kann es passieren, dass Patienten zum Teil dauerhaft eine Anti-VEGF(„vascular endothelial growth factor“)-Therapie auf Basis einer Fehleinschätzung der makulären Diagnose oder der Aktivität der Erkrankung erhalten und diese Indikation – sobald einmal gestellt – selten hinterfragt oder zurückgenommen wird. Ziel dieses Manuskriptes ist es daher, anhand von Fallbeispielen auf mögliche und typische Fehlinterpretationen bei der Indikation oder Fortsetzung einer IVOM-Therapie mittels Anti-VEGF hinzuweisen und für Differenzialdiagnosen zu sensibilisieren.

Purpose Transforming growth factor-beta (TGFB)-mediated epithelial-mesenchymal transition (EMT) plays a crucial role in the pathogenesis of retinal fibrosis, which is one of the leading causes of impaired vision. Current approaches to treating retinal fibrosis focus, among other things, on inhibiting the TGFB signaling pathway. Transient expression of microRNAs (miRNAs) is one way to inhibit the TGFB pathway post-transcriptionally. Our previous study identified the miRNA miR-302d as a regulator of multiple TGFB-related genes in ARPE-19 cells. To further explore its effect on primary cells, the effect of miR-302d on TGFB-induced EMT in primary human retinal pigment epithelium (hRPE) was investigated in vitro. Methods hRPE cells were extracted from patients receiving enucleation. Transfection of hRPE cells with miR-302d was performed before or after TGFB1 stimulation. Live-cell imaging, immunocytochemistry staining, Western blot, and ELISA assays were utilized to identify the alterations of cellular morphology and EMT-related factors expressions in hRPE cells. Results hRPE cells underwent EMT by TGFB1 exposure. The transfection of miR-302d inhibited the transition with decreased production of mesenchymal markers and increased epithelial factors. Meanwhile, the phosphorylation of SMAD2 activated by TGFB1 was suppressed. Moreover, miR-302d expression promoted TGFB1-induced fibroblast-like hRPE cells to revert towards an epithelial stage. As confirmed by ELISA, miR-302d reduced TGFB receptor 2 (TGFBR2) and vascular endothelial growth factor A (VEGFA) levels 48 hours after transfection. Conclusions The protective effect of miR-302d might be a promising approach for ameliorating retinal fibrosis and neovascularization. MiR-302d suppresses TGFB-induced EMT in hRPE cells via downregulation of TGFBR2, even reversing the process. Furthermore, miR-302d reduces the constitutive secretion of VEGFA from hRPE cells.

Purpose To evaluate the effect of corneal density and thickness on the accuracy of tonometry readings obtained via three most used techniques. Method Intraocular pressures of 45 patients’ right eyes were measured using Goldmann Applanation, iCare, and non-contact tonometry methods. Corneal parameters were obtained using the Pentacam Camera System. Data obtained were analyzed using Paired t Test, Pearson’s correlation coefficient, multiple linear regression analysis, and Bland–Altman plots. Results The mean corneal thickness was 545.4 ± 3.93 μm. The mean corneal density of total, stromal, 0–2 mm, and 2–6 mm zones were 27.85 ± 6.23 GSU, 24.61 ± 6.05 GSU, 20.76 ± 2.96 GSU, and 20.81 ± 3.51 GSU respectively. IOP readings had a statistically significant correlation with corneal stromal thickness, as well as with total and stromal density. The stromal density, however, showed higher correlation with the three tonometry methods than did the total density (iCare: − .482 (0.001) stromal density versus− .464 (0.001) total density, NCT: − .376 (0.011) versus − .353 (0.017), GAT: − .306 (0.041) versus − .296 (0.048)). Statistical differences were found in comparing the iCare readings with GAT (P P P > 0.05). Conclusion This study shows that both central corneal thickness and stromal density are significant influential factors of reliable IOP readings. It is necessary to consider more corneal biomechanical properties, as well as exercise a high degree of caution in any new attempts towards adjusting an IOP-correction equation.

The treatment of macular edema with intravitreal injections has revolutionized the treatment of associated diseases in ophthalmology. However, with a few exceptions, this is a chronic treatment where patients require many injections and usually need to stay in treatment for years. Patient adherence and control of patient flow are critical to treatment success. In this manuscript, we describe the development of a patient-oriented organization management for intravitreal injections in a university hospital.In 2015, the intravitreal treatment in our clinic was switched to the treat-and-extend regime. At the same time, the optimization of the previous organizational processes in perioperative management was evaluated. For the period 2015 to 2018, we analyzed and gradually optimized the procedures of our intravitreal injection therapy in a survey with a specialized service provider.Through the analysis of the original processes, the patient appointment was optimized, work processes were summarized, spatially reorganized and there was only a slight increase in the number of staff involved compared with the significant increase in the number of injections. Through these measures, the total in-hospital-time of the patients could be drastically reduced and at the same time the number of patients on one operation day could be multiplied.In the context of chronic treatment with intravitreal injections, the care of an increased number of patients is a logistical challenge. By optimizing processes, existing resources can be better used to meet the increased demands. An optimized system offers the patient greater adherence and a better visual outcome largely independent of the medication used.Die Behandlung eines Makulaödems mittels intravitrealer Injektionen hat die Behandlung der assoziierten Krankheitsbilder in der Augenheilkunde revolutioniert. Abgesehen von einigen wenigen Ausnahmen handelt es sich jedoch um eine chronische Behandlung, bei der die Patienten viele Injektionen benötigen und i. d. R. über Jahre in Behandlung bleiben müssen. Die Adhärenz der Patienten und die Steuerung des Patientenflusses ist mit entscheidend für den Behandlungserfolg. In diesem Manuskript beschreiben wir die Entwicklung eines patientennahen Organisationsmanagements für intravitreale Injektionen in einer Universitätsklinik.Im Jahr 2015 wurde in unserer Klinik die intravitreale Behandlung auf das Treat-and-Extend-Regime umgestellt. Zugleich erfolgte die Evaluation der Optimierung der bisherigen Organisationsabläufe im perioperativen Management. Für den Zeitraum 2015 bis 2018 haben wir im Rahmen einer Erhebung mit einem spezialisierten Dienstleister die Abläufe unserer intravitrealen Injektionstherapie analysiert und schrittweise optimiert.Durch die Analyse der ursprünglichen Abläufe wurde die Patienteneinbestellung optimiert, Arbeitsabläufe wurden zusammengefasst sowie räumlich neu geordnet und es fand eine verglichen mit der deutlichen Erhöhung der Injektionszahlen nur geringfügige Erhöhung der beteiligten Mitarbeiterzahl statt. Durch diese Maßnahmen konnte sowohl die Gesamtaufenthaltszeit der Patienten deutlich reduziert werden als auch zugleich die Patientenzahl bei guter Adhärenz und guten Visusergebnissen an einem Operationstag vervielfacht werden.Im Rahmen der chronischen Behandlung mittels intravitrealer Injektionen ist die Versorgung einer gestiegenen Anzahl an Patienten eine logistische Herausforderung. Durch Optimierung von Abläufen können vorhandene Ressourcen besser genutzt werden, um den gestiegenen Anforderungen gerecht zu werden. Ein optimiertes System bietet für den Patienten eine höhere Adhärenz und ein besseres Visusergebnis weitgehend unabhängig von dem verwendeten Medikament.

Purpose To evaluate the real-world effectiveness of intravitreal aflibercept injections in Germany in patients with neovascular age-related macular degeneration over 24 months. Methods PERSEUS was a prospective, non-interventional cohort study. The primary endpoint was the mean change in visual acuity (VA) from baseline. Secondary endpoints included the proportion of patients with a VA gain or loss of ≥ 15 letters and the frequency of injections and examinations. Patients with regular (bimonthly after 3 monthly injections during year 1 and ≥ 4 injections in year 2) and irregular (any other) treatment were analyzed. The last observation carried forward (LOCF) and the observed cases (OC) approach was applied for primary endpoint analysis to account for missing data. Results 803 patients were considered for effectivity analysis. At month 24, only 38% of the patients were still under observation. The LOCF population included 727, the OC population 279 patients. Treatment-naïve patients improved by 6.3 (LOCF)/8.1 (OC) letters with regular treatment over 24 months but only by 3.3 (LOCF)/3.1 (OC) letters with irregular treatment. The proportion of treatment-naïve patients achieving a VA improvement of ≥ 15 letters was similar between regularly and irregularly treated cohorts. However, considerably more patients in the irregular cohorts experienced a VA worsening of ≥ 15 letters than in the regular cohorts (LOCF: 18.7% vs. 7.4%). Conclusions Regular IVT-AFL treatment resulted in better VA outcomes than irregular treatment at month 24. However, only a minority of patients received regular treatment over a 2-year period.

Even in the era of intravitreal injection therapy (intravitreal operative injection of medication, IVOM) for the treatment of macular and retinal diseases, such as age-related macular degeneration (AMD), proliferative diabetic retinopathy (DR) and diabetic macular edema (DME) as well as proliferative stages and/or macular edema due to retinal vein occlusion (RVO), conventional retinal laser treatment is still of importance. It can be focally performed on an on-label basis for DME and macular edema due to branch RVO (BRVO) and its use as panretinal treatment for proliferative stages in retinal diseases as well as for the treatment of retinal holes is undisputed. The spectrum is extended by the treatment of less common diseases, such as retinal hemangioblastoma, macroaneurysms and subhyaloid macular hemorrhage. There is cause for concern that knowledge about the correct performance of retinal laser application might be shifted into the background due to an increase of IVOM treatment, which could lead to an increase in unnecessary errors. The aim of this manuscript is to increase awareness for the correct indications and execution of retinal laser treatment based on case examples of flawed or insufficient treatment.

Introduction: The evaluation of retinal vessels and the retinal blood flow is important for ocular diseases. We introduce a spectral domain optical coherence tomography (SD-OCT) based method for facilitating a retinal blood vessel analysis using the scattering properties of retinal vessels. The intensity of the distal shadow of vessels caused by the scattered signal is measured, correlated with the pulsatile ocular blood flow (POBF), and its repeatability is analyzed.Methods: About 20 eyes of 20 healthy, young participants (mean age 23.15 years, standard deviation 2.3 years) were included in the analysis. Participants underwent ophthalmic diagnostics including three repeated SD-OCT examinations and measurement of POBF. The vessel shadow intensity analysis is based on peripapillary SD-OCT scans and automatically analyses the intensity of the distal vessel shadow compared to its surroundings.Results: The distal shadow of arteries in SD-OCT scans correlated with the POBF (r = 0.647, p = 0.002). Furth...

We aimed to evaluate the neuroprotective efficacy of rasagiline in pseudophakic patients who had surgery for macula-off rhegmatogenous retinal detachment (RRD). This was a 6-month, prospective, randomized, double-blind, placebo-controlled pilot study. Patients presenting with acute macula-off RRD were recruited and randomized 1:1 to receive rasagiline 1 mg/day or placebo for 7 days. Best-corrected visual acuity (BCVA) and optical coherence tomography were acquired 1 day before as well as 2 days, 3 weeks, 3 months and 6 months after surgery. We screened 26 patients with RRD whereof 23 were eventually included and randomized. The primary outcome was final BCVA. Secondary outcomes included central retinal thickness (CRT) and adverse events (AE). We evaluated photoreceptor cells (prc) recovery through morphological measurements. The baseline characteristics were comparable between groups. BCVA significantly improved in both groups (letters gained: rasagiline 61.5 ± 18.1 vs placebo 55.3 ± 29.2, p = 0.56), but no significant inter-group difference was found at any visit. CRT was stable 3 weeks after surgery onwards, with no inter-group difference. No treatment-emergent AE occurred. Significant prc restoration was observed from 3 weeks to 6 months after surgery, without inter-group difference at either visit. Ellipsoid zone integrity (β = 0.517, p = 0.008) and foveal bulge (β = 0.387, p = 0.038) were significant predictors of good final BCVA. In conclusion, perioperative oral treatment with rasagiline 1 mg/day for 7 days did not show significant benefits on visual or anatomical outcomes in macula-off RRD patients.

Human amniotic membrane (hAM) has been employed as scaffolding material in a wide range of tissue engineering applications, especially as a skin dressing and as a graft for corneal treatment, due to the structure of the extracellular matrix and excellent biological properties that enhance both wound healing and tissue regeneration. This review highlights recent work and current knowledge on the application of native hAM, and/or production of hAM-based tissue-engineered products to create scaffolds mimicking the structure of the native membrane to enhance the hAM performance. Moreover, an overview is presented on the available (cryo) preservation techniques for storage of native hAM and tissue-engineered products that are necessary to maintain biological functions such as angiogenesis, anti-inflammation, antifibrotic and antibacterial activity.

Background The subconjunctival anesthesia with local anesthetics is considered as a low-risk procedure allowing ocular surgery without serious complications typical for retro- or parabulbar anesthesia, especially in patients with preexisting Optic Nerve damage. We report development of ipsilateral transient amaurosis accompanied with mydriasis and both, direct and consensual light response absence. Case presentation Three patients with advanced refractory glaucoma undergoing laser cyclophotocoagulation (CPC) for intraocular pressure lowering experienced these adverse effects just few minutes after subconjunctival injection of mepivacaine 2% solution (Scandicaine® 2%, without vasoconstrictor supplementation). The vision was completely recovered to usual values in up to 20 h after mepivacaine application. Extensive ophthalmological examination, including cranial magnetic resonance imaging (MRI), revealed no further ocular abnormalities, especially no vascular constriction or thrombotic signs as well as no retinal detachment. The oculomotor function remained intact. The blockade of ipsilateral ciliary ganglion parasympathetic fibers by mepivacaine may be the responsible mechanism. Systemic pathways as drug-drug interactions seem to be unlikely involved. Importantly, all three patients tolerated the same procedure previously or at a later date without any complication. Overall, our thoroughly elaborated risk management could not determine the causative factor explaining the observed ocular complications just in the current occasion and not at other time points. Conclusions Doctors should be aware and patients should be informed about such rare complications after subconjunctival local anesthetics administration. Adequate risk management should insure patients’ safety.

Background Intravitreal injections are a mandatory treatment for macular edema due to nAMD, DME and RVO. These chronic diseases usually need chronic treatment using intravitreal injections with anti-VEGF agents. Thus, many trials were performed to define the best treatment interval using pro re nata regimes (PRN), fixed regimes or treat-and-extend regimes (TE). However, real-world studies reveal a high rate of losing patients within a 2-year interval of treatment observation causing worse results. In this study we analyzed retrospectively 2 years of real-world experience with an individualized treat-and-extend injection scheme. Methods Since 2015 our treatment scheme for intravitreal injections has been switched from PRN to TE. Out of 102 patients 59 completed a follow up time of 2 years. Every patient received visual acuity testing, SD-OCT and slit lamp examination prior to every injection. At each visit an injection was performed and the treatment interval was adjusted mainly on SD-OCT based morphologic changes by increasing or reducing in 2-week steps. Individual changes of the treatment protocol by face-to-face communication between physician and patient were possible. Results After 1 year of treatment visual acuity gain in nAMD was 7.4 ± 2.2 ETDRS letters (n = 34; injection frequency: 7.4 ± 0.4) respectively 6.1 ± 4.7 in DME (n = 9; injection frequency: 8.4 ± 1.1) and 9.7 ± 4.5 in RVO (n = 16; injection frequency: 7.6 ± 0.5). After 2 years of treatment results were as following: nAMD: visual acuity gain 6.9 ± 2.1 (injection frequency: 12.6 ± 0.7); DME: 11.1 ± 5.1 (injection frequency: 14.0 ± 1.0); RVO: 7.5 ± 5.0 (injection frequency: 11.2 ± 0.9). Planned treatment exit after 2 year was achieved in 29.4% of patients in nAMD (0% after 1 year); 0% in DME (0% after 1 year); and 31.3% in RVO (0% after 1 year). Patients’ persistence was 94.1% during the follow-up. Conclusion Using a consequent and individualized TE regime in daily practice may lead to a high patients’ persistence and visual acuity gains nearly comparable to those of large prospective clinical trials. Crucial factors are face-to-face communication with the patient as well as a stringent management regime. At this time TE may be the only instrument for proactive therapy which should therefore be regarded as a first-line tool in daily practice.

The transforming growth factor-beta (TGFB) plays an essential role in the pathogenesis of some ophthalmologic diseases, including neovascular age-related macular degeneration (nAMD) and proliferative vitreoretinopathy (PVR). TGFB activates the transcription factors SMAD2 and SMAD3 via the TGFB receptor, which together activate several genes, including VEGFA. TGFB treated ARPE-19 cells show an increased proliferation rate and undergo epithelial to mesenchymal transition (EMT). Since microRNAs (miRNAs) are capable of inhibiting the translation of multiple genes, we screened for miRNAs that regulate the TGFB signalling pathways at multiple levels. In this study, we focused on two miRNAs, miR-302d and miR-93, which inhibit TGFB signalling pathway and therefore TGFB-induced EMT transition as well as VEGFA secretion from ARPE-19 cells. Furthermore, we could show that both miRNAs can retransform TGFB-stimulated mesenchymal ARPE-19 cells towards the morphological epithelial-like state. Taken together, transient overexpression of these miRNAs in RPE cells might be a promising approach for further translational strategies.

Selective retina therapy (SRT) targets the retinal pigment epithelium (RPE) with pulsed laser irradiation by inducing microbubble formation (MBF) at the intracellular melanin granula, which leads to selective cell disruption. The following wound healing process rejuvenates the chorio-retinal junction. Pulse energy thresholds for selective RPE effects vary intra- and interindividually. We present the evaluation of an algorithm that processes backscattered treatment light to detect MBF as an indicator of RPE cell damage since these RPE lesions are invisible during treatment. Eleven patients with central serous chorioretinopathy and four with diabetic macula edema were treated with a SRT system, which uses a wavelength of 527 nm, a repetition rate of 100 Hz, and a pulse duration of 1.7 μs. Fifteen laser pulses with stepwise increasing pulse energy were applied per treatment spot. Overall, 4626 pulses were used for algorithm parameter optimization and testing. Sensitivity and specificity were the metrics maximized through an automatic optimization process. Data were verified by fluorescein angiography. A sensitivity of 1 and a specificity of 0.93 were achieved. The method introduced in this paper can be used for guidance or automatization of microbubble-related treatments like SRT or selective laser trabeculoplasty.

Purpose Selective retina therapy (SRT) has shown great promise compared to conventional retinal laser photocoagulation as it avoids collateral damage and selectively targets the retinal pigment epithelium (RPE). Its use however is challenging in terms of therapy monitoring and dosage because an immediate tissue reaction is not biomicroscopically discernibel. To overcome these limitations real time optical coherence tomography (OCT) might be useful to monitor retinal tissue during laser application. We have thus evaluated a proprietary OCT system for its capability of mapping optical changes introduced by SRT in retinal tissue. Methods Freshly enucleated porcine eyes covered in DMEM upon collection were utilized and a total of 175 scans from ex vivo porcine eyes were analyzed. The porcine eyes were used as an ex vivo model and results compared to two time resolved OCT scans recorded from a patient undergoing SRT treatment (SRT Vario Medical Laser Center Lübeck). In addition to OCT fluorescin angiography and fundus photography were performed on the patient and OCT scans were subsequently investigated for optical tissue changes linked to laser application. Results Biomicroscopically invisible SRT lesions were detectable in OCT by changes in the RPE / Bruch's complex both in vivo and the porcine ex vivo model. Laser application produced clearly visible optical effects such as hyper reflectivity and tissue distortion in the treated retina. Tissue effects were even discernible in time resolved OCT imaging when no hyper reflectivity persisted after treatment. Data from ex vivo porcine eyes showed similar to identical optical changes while effects visible in OCT appeared to correlate with applied pulse energy leading to an additional reflective layer when lesions became visible in indirect ophthalmoscopy. Conclusions Our results support the hypothesis that real time high resolution OCT may be a promising modality to obtain additional information about the extent of tissue damage caused by SRT treatment. Data shows that our ex vivo porcine model adequately reproduces the effects occurring in vivo and thus can be used to further investigate this promising imaging technique.

PURPOSE Modifications in ocular blood flow may play a significant role in glaucoma development. Optical coherence tomography angiography (OCT-A) is based on the detection and analysis of the reflection behaviour of motion in a static environment and therefore is able to quantify the retinal flow density. We used this new technology to examine the density of the active flow vasculature in the macular area in glaucoma patients compared to healthy patients. METHODS Thirty patients with primary open-angle glaucoma (mean age: 72.6 ± 7.1 years) and 21 healthy patients (mean age: 70.3 ± 8.6 years) were recruited. Patients received perimetry and OCT measurements of the peripapillary retinal nerve fibre layer thickness (RNFLT) and macular retinal thickness and OCT-A of the macular area in the superficial and deep retinal (DR) plexus. Flow density of the OCT-A scan was calculated by binarisation and quantification of the pixel density. RESULTS Macular flow density was globally and nasally reduced in glaucoma patients in the superficial (globally: p = 0.0203; nasally: p = 0.0003) and DR plexus (globally: p = 0.0113, nasally: p

High resolution optical coherence tomography (OCT) enables better visualization of ophthalmic microstructures than conventional imaging. When using an ophthalmic microscope, integrated optical coherence tomography (iOCT) high resolution real time visualization is possible.We report on the first 110 patients operated on using a microscope integrated OCT (iOCT) during surgical procedures for the treatment of various posterior segment pathologies.Microstructural changes that appeared during surgery were depicted precisely by iOCT, and the morphology visualized before and after each surgical step was used to help deciding how to adapt the surgical flow. The iOCT data and real-time imaging of retinal anatomy gives the surgeon the possibility of deploying patient- and operation-specific interventional procedures.To date, iOCT is only available in standing microscopes with no measurement or tracking features. Moreover, metal instruments currently obscure the scanned images. In the future, non-metal, transparent instruments (OCT-friendly surgical tools), tracking features, an autofocus and higher resolution could enable full and immediate intraoperative SD-OCT diagnostics in real time.Die hochauflösende optische Kohärenztomografie (OCT) ermöglicht eine kontrastreiche Bildgebung von Mikrostrukturen, die mit konventioneller Bildgebung nicht so detailliert darstellbar waren. Wir berichten über unsere Erfahrungen beim Einsatz der intraoperativen OCT (iOCT) in der vitreoretinalen Chirurgie.110 Patienten mit vitreoretinalen Erkrankungen (Makulaforamen, epiretinale Membranen, vitreomakulärem Traktionssyndrom, Ablatio und Glaskörperblutung) wurden unter Visualisierung mit dem im Mikroskop integrierten iOCT-Gerät operiert.Das iOCT liefert durch die Integration von Mikroskop und SD-OCT eine sofortige Visualisierung der „Region of Interest“ (ROI). Der Operateur erhält neben dem Mikroskopbild die intraoperative Darstellung aller Netzhautschichten, des Glaskörpers sowie der Instrument-Gewebe-Interaktion in Echtzeit und kann diese intraoperativ sofort verfügbare Information für die chirurgische Strategie nutzen.Bisher ist das iOCT nur als Standmikroskop erhältlich, es besitzt keine Messfunktion, keine Tracking-Funktion, und die Metallinstrumente verdecken den Scan. Künftig könnten transparente Instrumente, Tracking-Funktionen, ein Autofokus sowie eine noch bessere Auflösung eine optimierte, lückenlose, hochauflösende intraoperative OCT-Diagnostik in Echtzeit erlauben.

With about 50-60 million cases in the US alone, dry eye disease represents a severe health care problem. Cyclosporin A (CsA) would be a potent candidate for a causal therapy. However, CsA is not sufficiently water soluble to be administrated via simple eye drops. We developed an in situ nanosuspension (INS) as a novel approach towards the administration of CsA to the cornea. It precipitates upon contact with the tear fluid and creates CsA nanoparticles that enter the cornea and release the drug by dissolution. We selected two liquid poly(ethylene glycols) (PEG) that dissolve CsA and create nanoparticles by precipitation of CsA upon water contact. Aqueous solutions of PEG and Solutol, a non-ionic surfactant, were well tolerated by primary human epithelial cells in vitro. To determine the critical water content needed for a precipitation, the solubility of CsA was investigated in quaternary systems of drug, solvent, surfactant and water. The best INS formulation showed a particle size of 505 ± 5 nm, a polydispersity index (PdI) of 0.23 ± 0.03 and a neutral zeta potential of -0.07 ± 0.05 mV. After single administration to porcine eyes in vitro, 3165 ± 597 ng(CsA)/g(cornea) were detected in corneal tissue, while the levels of Restasis a commercial formulation were, with 545 ± 137 ng(CsA)/g(cornea), significantly lower (P0.01). These results demonstrate that an INS is a promising, novel approach towards the causal treatment of inflammatory diseases at the anterior eye.

To evaluate the changes in the size of choroidal neovascularization (CNV) lesion using spectral domain-optical coherence tomography (SD-OCT) in patients with treatment-resistant neovascular age-related macular degeneration (AMD) who were switched from ranibizumab to aflibercept.In this prospective case-series, 33 eyes of 30 patients with treatment-resistant neovascular AMD were included. Treatment-resistant neovascular AMD was defined as choriodal neovascularization secondary to AMD determined by subretinal fluid and/or intraretinal fluid/cysts after more than 6 months of monthly ranibizumab therapy. Enrolled eyes were received intravitreal aflibercept injections at weeks 0, 4, and 8. Maximum area of CNV lesion in the cross-sectional area in the B-scan was measured using Heidelberg Eye Explorer software. The same cross-sectional sections containing maximum area of CNV lesion were used during the follow-up. CNV subtypes were determined based on fluorescein angiography images prior to ranibizumab therapy. Main outcome measures were changes in best-corrected visual acuity (BCVA), central subfield thickness (CST), and area of CNV lesion.There were five classic (15%), seven minimally classic (21%), and 21 occult subtypes of CNV (64%). Four weeks after the third injection, BCVA improvement and reduction of the retinal thickness in nine standard ETDRS subfields were significant (both P 0.001). Regarding and regardless of CNV subtypes, mean area of CNV lesion decreased significantly at final visit. Overall, a dry macula was achieved in 21 eyes (64%) and 12 eyes (36%) showed decreased or unchanged edema.Switching to aflibercept seems to result in reduction of CNV lesion area in short-term follow-up of patients with treatment-resistant neovascular AMD. Lasers Surg. Med. 48:668-677, 2016. © 2016 Wiley Periodicals, Inc.

PURPOSE To evaluate 3-year follow-up treatment outcomes with ranibizumab (Lucentis(®)) 0.5 mg administered either monthly or quarterly on a pro re nata (PRN) basis according to a disease activity-guided monitoring and treatment algorithm. METHODS A total of 316 treatment-naive eyes of 316 patients with exudative age-related macular degeneration met the criteria for inclusion in this retrospective, interventional case series. Patients were treated with ranibizumab 0.5 mg according to a disease activity-guided algorithm with monthly monitoring. Optical coherence tomography and fluorescein angiography were routinely used to assess disease activity: active lesions were treated with a series of three monthly injections, whereas inactive lesions were treated with quarterly injections. RESULTS Mean Early Treatment Diabetic Retinopathy Study best-corrected visual acuity improved from 52 letters at baseline to 59 letters at 12 months, achieved with a mean of 7.1 injections, 61 letters at 24 months with a mean of 5.0 injections administered in the second year and 60 letters at 36 months with a mean number of 5.2 injections. CONCLUSIONS Monthly visits and a morphology-driven PRN regimen with 3 injections in case of recurrence plus quarterly injections in case of inactive CNV resulted in an average VA gain of 7-9 letters that could be maintained over 3 years.

To observe the excursions of short-term intraocular pressure (IOP) after 20-G pars-plana vitrectomy (ppV).In a prospective study, 851 patients (age: mean 63 ± 15 years) underwent unilateral ppV for various vitreoretinal diseases using different endotamponades [Balanced Salt Solution (BSS) 33.1%, Air 7.2%, SF(6) 33.6%, silicon oil 5000 cst 26.1%]. Intraocular pressure was measured in all patients before and at 3, 6, 24 and 48 hr after surgery. Survival analysis was performed to determine the cumulative hazard of IOP changes depending on endotamponade and time point after ppV (Log-Rang - Mantel Cox; p0.0001). At baseline, IOP ranged from 0 to 50 mmHg (mean IOP: 15.3 ± 5.3 mmHg). Mean IOP after surgery revealed a slight elevation (3 hr: 16.5 ± 11.0 mmHg; 6 hr 16.9 ± 9.8 mmHg; 24 hr 19.7 ± 8.0 mmHg; 48 hr 17.3 ± 6.2 mmHg; range: 0-64 mmHg). Silicon oil filling revealed highest mean values at already 3 hr after surgery (21.8 mmHg). Also, BSS filling showed a peak after 3 hr; however, mean values were lower. Equivalent high IOP values as for silicon oil tamponade were found for gas filling; however, maximal peak was reached after 24 hr but not after 3 hr post-treatment. The cumulative hazard in all patients to reach IOP ≥ 30 mmHg after 24 hr was 23.9%; (IOP ≥ 40 mmHg = 8.2%). Herein, oil filling revealed highest risk at all time points after surgery. The risk of suffering from IOP5 mmHg lasting longer than 6 hr was only 1.2% after 20 G vitrectomy.Intraocular pressure measurements after ppV are important to prevent unintentional high IOP, especially within the early phase (3 hr post-treatment) in eyes with silicon oil filling. Gas filling leads to prolonged IOP increase (24 hr post-treatment). Long-lasting hypotony (≥ 6 hr) is very rare after 20G vitrectomy.

Purpose: To assess the interobserver variability (IOV) in indicating retreatment for neovascular Age-related macular degeneration 4 weeks after three Ranibizumab loading doses using spectral domain OCT (SD-OCT) as the primary objective diagnostic tool. Material and methods: Four observers decided for or against 4th Ranibizumab injection in 108 patients by six different rating rounds (RR) based on the SD-OCT findings after the loading doses. Postoperative OCT images were supplemented consecutively with information from a chart review as the ‘patients subjective estimation of vision (SE)’, the course of best-corrected visual acuity (BCVA) and the preoperative OCT as well as all information collectively. Agreement rates (AR) and Kappa statistics were calculated. Results: Based on post-treatment OCT findings only (RR1), mean reinjection rate of all observers was 37.5%. Adding supplementary information, mean reinjection rate decreased to 20% when all information was available reflecting the ‘real’ situation (RR 6). Interobserver agreement rates varied from 66.7% to 90.7% depending on rating rounds and interobserver pairs. Mean AR and Kappa values (KV) were as following: AR 81.6%, KV 0.61 (RR1: ‘only post-OP OCT’); AR 76.7%, KV 0.33 (RR2: post-OP OCT + SE); AR 80.3%, KV 0.45 (RR3: post-OP OCT + BCVA); AR 80.7%, KV 0.46 (RR4: pre- and post-OP OCT); AR 82.2%, KV 0.49 (RR5: post-OP OCT + SE + BCVA); and finally AR 83.6%, KV 0.47 (RR6: pre- and post-OP OCT + SE + BCVA). The overall mean agreement rate was 80.9% with a Kappa of 0.47. Conclusion: IOV for indicating retreatment after three Ranibizumab loading doses reveals only moderate agreement in Kappa statistics, which seems to be too low considering the high costs for retreatments. More concise guidelines based on the post-treatment OCT scans as the presumably most sensitive and noninvasive objective tool to follow choroidal neovascularization activity by judging the course of sub- and intraretinal fluid are necessary.

BACKGROUND: Heavier than water tamponades offer the possibility to support the inferior part of the fundus after retinal detachment. The aim of this study was to evaluate the anatomic and functional outcome of complicated retinal detachment treated with vitreous surgery and heavy silicone oil (HSO) tamponade. Surgery was performed in eyes with rhegmatogenous retinal detachment (RD) predominantly in the lower hemisphere or with penetrating injury (either as primary intervention or after development of proliferative vitreoretinopathy [PVR]). MATERIALS AND METHODS: Sixty-one eyes of 61 patients with RD - mostly complicated by PVR - and a minimum follow-up of 12 months were included in this study. Vitreoretinal surgery with HSO (Oxane HD) tamponade was performed in all patients. In 52 patients, heavy silicone oil was used in the management of complicated RD. 9 patients had surgery for complicated RD after penetrating eye injury.The mean follow-up period was 30.3 +/- 10.2 months. RESULTS: The overall final anatomic success rate was 79 %. In 39 % of the cases the retina remained attached during the entire follow-up period. CONCLUSIONS: The anatomic success rate after surgery with HSO (Oxane HD) was relatively low; however, only complex cases bearing a higher risk of retinal re-detachment received HSO in this study. Oxane HD does not appear to have major advantages compared to conventional silicone oil or other new-generation heavy silicone oils in these cases.

Spectral domain optical coherence tomography (SD-OCT) in patients can deliver retinal cross-sectional images with high resolution. This may allow the evaluation of the extent of damage to the retinal pigment epithelium (RPE) and the neurosensory retina after laser treatment. This article aims to investigate the value of SD-OCT in comparing laser lesions produced by conventional laser photocoagulation and selective retina treatment (SRT).In a retrospective study, conventional retinal laser (CRL) lesions and SRT laser lesions were evaluated with SD-OCT. One hundred seventy-five CRL lesions were investigated in 10 patients with diabetic maculopathy at timepoints between 1 hr and 4 years after treatment. Ninety-one SRT lesions were examined in 9 patients with central serous retinopathy, geographic atrophy, and diabetic maculopathy at timepoints between 1 hr and 2 years. CRL lesions were applied with an ophthalmoscopically slightly grayish-white appearance (Nd:YAG laser at 532-nm wavelength; power 100-200 mW; retinal spot diameter 100 microm; pulse duration 100 ms). SRT lesions were applied with a Nd:YLF (527 nm; pulse duration 200 ns [30 pulses at 100 Hz]; energy 100-200 microJ/pulse; retinal spot diameter 200 microm) and were visible only angiographically.All CRL lesions were characterized by high reflectivity in OCT images throughout the full thickness of the neurosensory tissue 1 hr after irradiation, suggesting complete neurosensory coagulation. Strong contraction through the full thickness of the neurosensory layers was observed within 7 days after treatment. In contrast, the neural retina appeared unaffected after SRT. For both lesion types, the RPE layer appeared to be regular or thinner immediately after treatment, whereas within a period of 4 weeks, a RPE thickening indicating RPE proliferation was observable. One year and later after treatment, CRL lesions were characterized by RPE atrophy combined with significant damage of the neurosensory tissue. SRT lesions aged one year and older revealed unaffected neurosensory structures and an intact RPE layer.Spectral domain OCT can be used clinically to follow the development of laser-induced lesions over time. Postoperative RPE proliferation was observed in both CRL and SRT laser lesions. RPE atrophy appeared subsequently only in CRL lesions, whereas the neurosensory retina appeared unaffected following SRT. These results suggest the selective effect of SRT in humans without causing adverse effects to the neurosensory retina.

Background Selective retina therapy (SRT) solely affecting the RPE while sparing of the photoreceptors is usually performed with a train of repetitive laser pulses of 1.7 microseconds in duration. It was our purpose to evaluate the principle feasibility of SRT with shorter 200 nanoseconds laser pulses in patients. Methods Nineteen patients with macular disorders [diabetic maculopathy (DMP), geographic atrophy (GA), drusen maculopathy and central serous chorioretinopathy (CSR)] were treated with a prototype of a SRT laser (Nd:YLF laser; 527 nm; 1.7 microseconds and 200 nanoseconds pulse duration; 30 pulses at 100 Hz; spot size: 200 µm). Test lesions (n = 175) with increasing energy were applied at the lower arcade to determine the individual angiographic and ophthalmoscopic threshold radiant exposures (therapeutic window) before applying the central treatment lesions within these ranges additionally guided by online optoacoustic measurements. Postoperatively RPE damage was visualized and confirmed by fluorescein angiographic leakage and correlated with optoacoustic results. Additionally ED50 damage thresholds were calculated by probit analysis. Results None of the short repetitive 200 nanoseconds laser pulses led to retinal hemorrhages or retinal ruptures. Nearly all of the test- and treatment lesions could be visualized by angiography indicating desired RPE damage but were ophthalmoscopically invisible suggesting intact neurosensory retinal structures. ED50 cell damage threshold energies were significantly lower using 200 nanoseconds (99.6 µJ; n = 122) instead of 1.7 microseconds (196.3 µJ; n = 53) laser pulses. Optoacoustic and angiographic visibility correlated in 83.7% (200 nanoseconds) and 87.5% (1.7 microseconds). Conclusions Selective RPE effects can safely be achieved using shorter 200 nanoseconds laser pulses in patients without adverse effects to the neurosensory retina. The required pulse energy compared to the standard 1.7 microseconds regime was reduced by about a factor of 2 suggesting a reduced heat generation and flow into adjacent tissues during the shorter laser impact and thus possibly enhancing selectivity. Optoacoustics also seem to be a viable alternative in 200 nanoseconds treatment for a non-invasive online dosimetry control system. Lesers Surg. Med. 40:616–624, 2008. © 2008 Wiley-Liss, Inc.

Background Post-translational protein modification by lipid peroxidationproducts orglycation is a feature of aging as well as pathologic processes in postmitotic cells at the ocular fundus exposed to an oxidative environment. The accumulationofmodifiedproteinssuchasthose found inlipofuscinand advanced glycation end products (AGEs) contribute greatly to the fundus auto-fluorescence. The distinct fluorescence spectra of lipofuscin and AGE enable their differentiation in multispectral fundus fluorescence imaging. Method A dual-centre consecutive case series of 78 pseudophacic patients is reported. Digital colour fundus photographs as well as auto-fluorescence images were taken from 33 patients with age related macular degeneration (AMD), 13 patients with diabetic retinopathy (RD), or from 32 cases without pathologic findings (controls). Fluorescence was excited at 475–515 nm or 476–604 nm and recorded in the emission bands 530–675 nm or 675–715 nm, respectively. Fluorescence images excited at 475–515 nm were taken by a colour CCD-camera (colour-fluorescence imaging) enabling the separaterecording of green and red fluorescence. The ratio of green versus red fluorescence was calculated within a representative region of each image. Results The 530–675 nm auto-fluorescence in AMD patients was dominated by the red emission (green vs. red ratio, g/r=0.861). In comparison, the fluorescence of the diabetics was green-shifted (g/r=0.946; controls: g/r= 0.869). Atrophic areas (geographic atrophy, laser scars) showed massive hypo-fluorescence in both emission bands. Hyper-fluorescent drusen and exudates, unobtrusive in the colour fundus images as well as in the fluorescence images with emission >667 nm, showed an impressive green-shift in the colour-fluorescence image. Conclusions Lipofuscin is the dominant fluorophore at long wavelengths (>675 nm or red channel of the colour fluorescence image). In the green spectral region, we found an additional emission of collagen and elastin (optic disc, sclera) as well as deposits in drusen and exudates. The green shift of the auto-fluorescence in RD may be a hint of increased AGE concentrations.

PURPOSE A review of treat-and-extend regimens (TERs) with intravitreal anti-vascular endothelial growth factor agents in retinal diseases. METHODS There is a lack of consensus on the definition and optimal application of TER in clinical practice. This article describes the supporting evidence and subsequent development of a generic algorithm for TER dosing with anti-vascular endothelial growth factor agents, considering factors such as criteria for extension. RESULTS A TER algorithm was developed; TER is defined as an individualized proactive dosing regimen usually initiated by monthly injections until a maximal clinical response is observed (frequently determined by optical coherence tomography), followed by increasing intervals between injections (and evaluations) depending on disease activity. The TER regimen has emerged as an effective approach to tailoring the dosing regimen and for reducing treatment burden (visits and injections) compared with fixed monthly dosing or monthly visits with optical coherence tomography-guided regimens (as-needed or pro re nata). It is also considered a suitable approach in many retinal diseases managed with intravitreal anti-vascular endothelial growth factor therapy, given that all eyes differ in the need for repeat injections. CONCLUSION It is hoped that this practical review and TER algorithm will be of benefit to health care professionals interested in the management of retinal diseases.

To carry out a prospective investigation of the functional and morphological outcome of idiopathic epiretinal membrane (IEM) surgery with or without the assistance of indocyanine green (ICG) in a randomised controlled clinical trial. Sixty patients who underwent vitrectomy with removal of IEM combined with cataract surgery were randomly allocated to two groups: 27 patients were operated on with ICG 0.1% in glucose 5%, 33 patients without ICG. Functional outcome was assessed 3-4 months postoperatively with improvement of best-corrected visual acuity (BCVA), Amsler grid test, and automated and kinetic perimetry. Postoperative residual or recurrent IEM was assessed with bio-microscopy, and macular oedema with optical coherence tomography (OCT). Improvement in BCVA was the main outcome measure. BCVA improved in 49 patients, remained unchanged in five and decreased in five. Improvement in BCVA and reduction of macular oedema were statistically significant within both groups (P

* BACKGROUND AND OBJECTIVE: To determine whether fundus autofluorescence imaging is able to show changes in retinal pigment epithelium (RPE) fluorescence after thermal laser photocoagulation. * PATIENTS AND METHODS: In vivo imaging of fundus autofluorescence was performed with a scanning laser ophthalmoscope. A laser with a wavelength of 488 nm was used for excitation of the tissue and autofluorescence was detected above 500 nm using a barrier filter. One hundred eight eyes of 87 patients who had had previous laser treatment were monitored. The appearance and size of the laser lesions were documented and correlated to the time of treatment. Immediate changes were observed prospectively in 13 eyes; long-term follow-up was studied retrospectively in 95 eyes. * RESULTS: In all patients but one, autofluorescence was decreased in the area of laser lesions 1 hour after laser treatment. After 1 month, previously decreased autofluorescence in all lesions changed to significantly increased autofluorescence, which was stable up to 6 months after treatment. Mixed forms were present approximately 6 to 12 months after treatment, showing a central island of increased autofluorescence surrounded by a ring of decreased autofluorescence. After 1 to 2 years, lesions again changed to complete dark spots, enlarging later on. * CONCLUSION: RPE destruction and subsequent proliferation after continuous wave laser photocoagulation can be visualized noninvasively by autofluorescence imaging. Immediate decreased autofluorescence may indicate acute damage of the RPE, subsequent increased autofluorescence seems to indicate proliferative behavior of the RPE, and final dark spots can indicate RPE atrophy secondary to a denaturation of neurosensory retinal tissue. Thus, autofluorescence can be used in the long-term monitoring of RPE changes after laser treatment. The enlargement of the laser atrophy zone demonstrates the potential risk of visual loss after central laser photocoagulation even years after treatment. [Ophthalmic Surg Lasers Imaging 2004;35:131-138.]

A2-E is the dominant fluorophore of lipofuscin in the retinal pigment epithelium. In an in-vitro setup, we determined the temperature-dependent changes of the A2-E fluorescence with the aim of also assessing the potential value of such measurements for determining retinal temperature by autofluorescence measurements during laser treatment.A2-E was biosynthesized and diluted in Dimethyl Sulfoxide (DMSO) to 1 microM. Fluorescence measurements were performed with a photospectrometer under various temperatures ranging from 20 degrees C to 75 degrees C. Autofluorescence was excited at 467 nm, and emission was detected around 632 nm.A2-E fluorescence intensity showed a linear decrease concomitant with temperature increment. At 75 degrees C, the fluorescence intensity decreased by 43% compared to at 20 degrees C. Fluorescence intensity was completely reversible dependent on the temperature, which cannot be explained by thermal A2-E alteration.If the A2-E temperature-dependent fluorescence in-vitro is transferable to human fundus auto-fluorescence, then it may be possible to apply an autofluorescence-based online detection device for noninvasive determination of fundus temperature during in vivo laser treatment. This is of clinical relevance, especially for the application of photodynamic therapy (PDT) and transpupillary thermotherpy (TTT).

Purpose: Selective retina therapy (SRT), the confined laser heating and destruction of retinal pigment epithelial cells, has been shown to treat acute types of central serous chorioretinopathy (CSC) successfully without damaging the photoreceptors and thus avoiding laser-induced scotoma. However, a benefit of laser treatment for chronic forms of CSC is questionable. In this study, the efficacy of SRT by means of the previously used 1.7-µs and shorter 300-ns pulse duration was evaluated for both types of CSC, also considering re-treatment for nonresponders. Material and Methods: In a two-center trial, 26 patients were treated with SRT for acute (n = 10) and chronic-recurrent CSC (n = 16). All patients presented with subretinal fluid (SRF) in OCT and leakage in fluorescein angiography (FA). SRT was performed using a prototype SRT laser system (frequency-doubled Q-switched Nd:YLF-laser, wavelength 527 nm) with adjustable pulse duration. The following irradiation settings were used: a train of 30 laser pulses with a repetition rate of 100 Hz and pulse durations of 300 ns and 1.7 µs, pulse energy 120-200 µJ, retinal spot size 200 µm. Because SRT lesions are invisible, FA was always performed 1 h after treatment to demonstrate laser outcome (5-8 single spots in the area of leakage). In cases where energy was too low, as indicated by missing FA leakage, energy was adjusted and the patient re-treated immediately. Observation intervals were after 4 weeks and 3 months. In case of nonimprovement of the disease after 3 months, re-treatment was considered. Results: Of 10 patients with active CSC that presents focal leakage in FA, 5 had completely resolved fluid after 4 weeks and all 10 after 3 months. Mean visual acuity increased from 76.6 ETDRS letters to 85.0 ETDRS letters 3 months after SRT. Chronic-recurrent CSC was characterized by less severe SRF at baseline in OCT and weaker leakage in FA than in acute types. Visual acuity changed from baseline 71.6 to 72.8 ETDRS letters after 3 months. At this time, SRF was absent in 3 out of 16 patients (19%), FA leakage had come to a complete stop in 6 out of 16 patients (38%). In 6 of the remaining chronic CSC patients, repeated SRT with higher pulse energy was considered because of persistent leakage activity. After the re-treatment, SRF resolved completely in 5 patients (83.3%) after only 25 days. Conclusion: SRT showed promising results in treating acute CSC, but was less effective in chronic cases. Interestingly, re-treatment resulted in enhanced fluid resolution and dry conditions after a considerably shorter time in most patients. Therefore, SRT including re-treatment if necessary might be a valuable CSC treatment alternative even in chronic-recurrent cases.

PURPOSE Optical coherence tomography (OCT) was used to analyze the thickness of various retinal layers of patients following successful macula-off retinal detachment (RD) repair. METHODS Optical coherence tomography scans of patients after successful macula-off RD repair were reanalyzed with a subsegmentation algorithm to measure various retinal layers. Regression analysis was performed to correlate time after surgery with changes in layer thickness. In addition, patients were divided in two groups. Group 1 had a follow-up period after surgery of up to 7 weeks (range, 21-49 days). In group 2, the follow-up period was >8 weeks (range, 60-438 days). Findings were compared to a group of age-matched healthy controls. RESULTS Correlation analysis showed a significant positive correlation between inner nuclear-outer plexiform layer (INL-OPL) thickness and time after surgery (P=0.0212; r2=0.1551). Similar results were found for the ellipsoid zone-retinal pigment epithelium complex (EZ-RPE) thickness (P=0.005; r2=0.2215). Ganglion cell-inner plexiform layer thickness (GCL-IPL) was negatively correlated with time after surgery (P=0.0064; r2=0.2101). For group comparison, the retinal nerve fiber layer in both groups was thicker compared to controls. The GCL-IPL showed significant thinning in group 2. The outer nuclear layer was significantly thinner in groups 1 and 2 compared to controls. The EZ-RPE complex was significantly thinner in groups 1 and 2 compared to controls. In addition, values in group 1 were significantly thinner than in group 2. CONCLUSIONS Optical coherence tomography retinal layer thickness measurements after successful macular-off RD repair revealed time-dependent thickness changes. Inner nuclear-outer plexiform layer thickness and EZ-RPE thickness was positively correlated with time after surgery. Ganglion cell-inner plexiform layer thickness was negatively correlated with time after surgery.

BACKGROUND AND OBJECTIVE To describe fundus autofluorescence patterns in choroidal neovascularization secondary to age-related macular degeneration before and after photodynamic therapy (PDT). PATIENTS AND METHODS Sixty-eight consecutive eyes were indicated for PDT after standard fluorescein angiography, which showed completely classic choroidal neovascularization (CNV) (n = 52), occult with no classic CNV (n = 7), and predominantly classic CNV (n = 9). Standardized PDT was performed and patients were examined 2 to 3 months later. Angiography and autofluorescence measurements were performed again and compared with preoperative values. RESULTS At baseline, autofluorescence was mainly decreased in areas of completely classic CNV (79%), but showed a regular or mottled pattern in occult CNV. A slightly increased (50%) or normal (50%) autofluorescence was seen at the rim of the classic lesions within the junctional zone. Membrane demarcation was improved (90%) in classic membranes 2 to 3 months after PDT. After PDT for occult membranes, a transformation into classic membranes with residual leakage and need for further PDT was observed (6 of 7 eyes), showing the described autofluorescence patterns. For the mixed type of CNV, both described patterns of autofluorescence distribution were found. CONCLUSION Especially classic CNVs reveal distinct characteristics of significantly decreased autofluorescence, presumably due to their localization above the retinal pigment epithelium level, leading to blockage of autofluorescence. Autofluorescence patterns after PDT included enhanced demarcation of the membrane, suggesting reactive retinal pigment epithelial changes. Autofluorescence might be an interesting tool to distinguish noninvasively between classic and occult CNV in age-related macular degeneration and to monitor changes after PDT. [Ophthalmic Surg Lasers Imaging 2006;37:406-414.] AUTHORS From the University Eye Hospital Regensburg (CF, RS, TT, AW, HGS, V-PG), Regensburg; and the University Eye Hospital Kiel (AB), Kiel, Germany. Accepted for publication March 9, 2005. Address reprint requests to Carsten Framme, MD, University Eye Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg, Germany.

Purpose To investigate microrobots as an assistive tool for minimally invasive intraocular surgery and to demonstrate mobility and controllability inside the living rabbit eye. Methods A system for wireless magnetic control of untethered microrobots was developed. Mobility and controllability of a microrobot are examined in different media, specifically vitreous, balanced salt solution (BSS), and silicone oil. This is demonstrated through ex vivo and in vivo animal experiments. Results The developed electromagnetic system enables precise control of magnetic microrobots over a workspace that covers the posterior eye segment. The system allows for rotation and translation of the microrobot in different media (vitreous, BSS, silicone oil) inside the eye. Conclusions Intravitreal introduction of untethered mobile microrobots can enable sutureless and precise ophthalmic procedures. Ex vivo and in vivo experiments demonstrate that microrobots can be manipulated inside the eye. Potential applications are targeted drug delivery for maculopathies such as AMD, intravenous deployment of anticoagulation agents for retinal vein occlusion (RVO), and mechanical applications, such as manipulation of epiretinal membrane peeling (ERM). The technology has the potential to reduce the invasiveness of ophthalmic surgery and assist in the treatment of a variety of ophthalmic diseases.

Background/Aims: To investigate the long-term effects of multiple intravitreal injections (IVTs) of ranibizumab (Lucentis) on intraocular pressure (IOP) in patients with neovascular age-related macular degeneration. Methods: In 320 eyes, IOP measurements were performed at baseline prior to injection and compared with IOP measurements of the last visit. Correlations between mean IOP change and total number of IVTs, visual acuity or patient age were tested. Results: The mean IOP increase was 0.8 ± 3.1 mm Hg (p < 0.0001). Seven eyes showed final IOP values between 22 and 25 mm Hg. The mean follow-up was 22.7 ± 14.1 months. No further correlations between IOP change and number of IVTs, visual acuity or patient age have been found. Conclusions: This study demonstrated a statistically significant IOP increase in patients treated with repeated injections of ranibizumab. However, IOP increase required no glaucoma treatment during the study. Therefore, repeated injections with ranibizumab can be considered safe with regard to long-term IOP changes in patients without ocular hypertension or glaucoma.

Blue-light fundus autofluorescence (FAF) imaging is currently widely used for assessing dry age-related macular degeneration (ARMD). However, at this wavelength, the fovea appears as circular zone of marked hypofluorescence, due to the absorption of macular pigment (MP). This dark spot could be misinterpreted as an atrophic area and could lead to difficulties in identifying small, central changes. The purpose of the study was to analyze differences in image quality, FAF patterns, and lesion size, when using conventional blue-light (Λ(1) = 488 nm) and green-light (Λ(2) = 514 nm) FAF.Patients older than 50 years with central areas of geographic atrophy (GA) secondary to ARMD were enrolled. Images were recorded with a modified confocal scanning laser ophthalmoscope (cSLO). Image quality and patterns were analyzed. The quantification of the GA was performed with customized image-analysis software.In total, 95 eyes were included. The borders of the central atrophic patches and the boundaries of the preserved foveal island were better identified in 514-nm images. In both excitation wavelengths the signal-to-noise ratio was sufficient for the identification of the FAF pattern. Significant differences were observed in the size of the GA areas detected in the 488- and 514-nm wavelength images (4.29 ± 3.76 mm(2) vs. 3.80 ± 3.68 mm(2); P0.001).The green-light FAF images (514 nm) are superior for the accurate analysis of small, central, pathologic changes, and for the determination of the central GA lesion size. Using only blue-light FAF could lead to an overinterpretation of the size of atrophic patches and the center involvement, because it suggests the presence of atrophy in the fovea.

The progress of wet age-related macular degeneration can now be controlled by intravitreal drug injection. This approach requires repeated injections, which could be avoided by delivering the drug to the retina. Intraocular implants are a promising solution for drug delivery near the retina. Currently, their accurate placement is challenging, and they can only be removed after a vitrectomy. In this paper, we introduce an approach for minimally invasive retinal drug delivery using magnetic intraocular inserts. We briefly discuss the electromagnetic-control system for magnetic implants and then focus on evaluating their ability to move in the vitreous humor. The mobility of magnetic intraocular implants is estimated in vitro with synthesized vitreous humors, and ex vivo with experiments on cadaver porcine eyes. Preliminary results show that with such magnetic implants a vitrectomy can be avoided.

This article gives an overview of the vitreal anatomy and its changes in ageing, which have a significant impact on the two main retinal complications after damage of the vitreolenticular barrier, namely retinal detachment and cystoid macular edema. The possible reasons and pathomechanisms for this entity of retinal diseases in the context of anterior segment interaction are highlighted, and a summary of references is provided showing the epidemiology and consequences of such interventions.

To identify differences in extracellular matrix contents between idiopathic epiretinal membranes (IEM) of cellophane macular reflex (CMRM) or preretinal macular fibrosis (PMFM) type.Idiopathic epiretinal membranes were analysed by light and quantitative transmission electron microscopy, immunohistochemistry and Western blotting. Substantial differences between CMRM and PMFM were observed regarding the nature of extracellular fibrils. In CMRM the fibrils were thin, with diameters between 6 and 15 nm. Between the fibrils, aggregates of long-spacing collagen were observed. In PMFM the diameters of fibrils measured either 18-26 or 36-56 nm. Using immunogold electron microscopy, 6-15 nm fibrils in CMRM were labelled for collagen type VI, while the fibrils in PMFM remained unstained. Using Western blotting and immunohistochemistry, a strong signal for collagen type VI was observed in all CMRM, while immunoreactivity was weak or absent in PMFM. In contrast, PMFM showed immunoreactivity for collagen types I and II, which was weak or absent in CMRM. Both types of membranes showed immunoreactivity for collagen types III and IV, laminin and fibronectin with similar intensity.The presence of high amounts of collagen type VI in CMRM and the relative absence of collagen types I and II is the major structural difference to PMFM.

An unintentional embolization of retinal arteries is rare and has been documented as a complication after embolization of arteries supplying head and neck tumors. However, occlusion of the central retinal artery with severe loss of vision has never been reported to be a complication from embolization of tumor-supplying ethmoidal branches of the ophthalmic artery. A 40 year-old male patient with a history of right nephrectomy for renal cell carcinoma underwent preoperative radiological embolization of an ethmoidal metastasis after having experienced a life-threatening sinus bleeding. Repeated probing of the ophthalmic artery with an endovascular microcatheter for particle embolization of the tumor-supplying arteries was performed under anticoagulation with heparin. Postoperatively, a standard ophthalmological examination including extended vascular evaluation by angiography was performed. After extended probing of the ophthalmic artery a marked reduction in its blood flow occurred. Despite post-interventional imaging showing persisting perfusion of the central retinal and ciliary arteries, the patient developed complete loss of vision on this side four days later. At this time fundoscopy and fluorescein angiography revealed a recanalized central artery occlusion, while indocyanin angiography showed infarctions of the choroid. Radiological intervention via the ophthalmic artery can result in complete loss of vision, even after limited and transient obstruction of the vessel.

For geographic atrophy (GA) due to age-related macular degeneration (AMD) there is so far no approved treatment option. Usually, increased autofluorescence (AF) levels of different patterns adjacent to the atrophic area indicate lipofuscin-laden retinal pigment epithelium (RPE) cells at a high risk for apoptosis. Herein, SRT was used to selectively treat these cells to stimulate RPE proliferation, in order to reduce or ideally stop further growth of the atrophic area.Six eyes of six patients with bilateral equally pronounced GA were treated by SRT, while the fellow eye served as control. Irradiation was performed using a prototype SRT laser (Medical Laser Center Lübeck, Nd:YLF laser; 527 nm; 200 ns/1.7 micros pulse duration; 30 repetitive pulses at 100 Hz). Test lesions with increasing energies were applied at the lower vessel arcade to determine the individual angiographic and ophthalmoscopic threshold radiant exposures. Treatment was then performed in the area of increased AF adjacent to the GA using energies between both thresholds. The GA progression rates of treated and fellow eyes were evaluated.After a 1-year follow-up, a progression of the atrophic area was observed in the treated eyes (0.7-8.0 mm(2)/yr, mean 3.0 mm(2)/yr; 46%/yr) whereas the progression rates of the fellow eyes were insignificantly lower (0.46-4.04 mm(2)/yr, mean 1.9 mm(2)/yr; 30%/yr; p = 0.134). The progression rate in the treated eyes of two patients increased significantly, while in the other four patients, the progression rates were nearly the same between both eyes. Moreover, one of these two eyes showed an unexpected RPE reaction after treatment, since all laser lesions led to RPE atrophy and thus an accelerated enlargement of the GA occurred.SRT in the hyperautofluorescent areas of GA was not able to stop or slow down the progression of GA. However, modified treatment strategies might be more promising, e.g. placing the spots outside the hyperautofluorescent areas where RPE apoptosis is postulated. Moreover, SRT studies on GA might be more successfully performed on specific subgroups of GA, based on autofluorescence and other findings.

To compare the efficacy of pars plana vitrectomy (ppV) with intravitreal injection of recombinant tissue plasminogen activator (rtPA) and gas versus ppV with subretinal injection of rtPA and intravitreal injection of gas.Nonrandomized, retrospective, interventional, comparative consecutive series including 47 patients with submacular hemorrhage. Eighteen patients were treated with ppV, intravitreal injection of rtPA and 20% SF6 gas [group A: mean age 78 years, mean duration of symptoms 6.6 days, 15 age-related macular degeneration (AMD), three retinal arterial macroaneurysm (RAMA)]. Twenty-nine patients were treated with ppV, subretinal injection of rtPA and intravitreal injection of SF6 gas (group B: mean age 75 years, mean duration of symptoms 5.9 days, 26 AMD, two RAMA, one blunt ocular trauma). The main outcome measure was complete displacement of submacular hemorrhage from the fovea.Complete displacement of submacular hemorrhage was achieved in less patients in group A (22%) than in group B (55%) (p = 0.025). In group A, mean best-corrected visual acuity (BCVA) change was logMAR -0.14, standard deviation (SD) = 0.64, and in group B logMAR -0.32, SD = 0.68 without statistically significant difference between the two groups (p = 0.2, Mann-Whitney test). Complications (retinal detachment, vitreous hemorrhage, and recurrence of submacular hemorrhage) were more frequent in group B than in group A.ppV with subretinal injection of rtPA and intravitreal injection of gas was more effective than ppV with intravitreal injection of rtPA and gas in terms of complete displacement of submacular hemorrhage; however, it may be associated with a higher rate of postoperative complications. Functional improvement in the majority of patients suggests the absence of direct retinal toxicity of subretinally applied rtPA.

To evaluate the significance of multislice CT for the diagnosis of uncertain penetrating globe injuries.Based on a retrospective chart review between 2002 and 2007, we identified 59 patients presenting with severe ocular trauma with uncertain rupture of the globe due to massive subconjunctival and/or anterior chamber hemorrhage. The IOP (intraocular pressure) was within normal range in all patients. High resolution multidetector CT (MD-CT) scans (16 slice scans) with axial and coronar reconstructions were performed in all patients. The affected eye was examined for signs of penetrating injury such as abnormal eye shape, scleral irregularities, lens dislocation or intravitreal hemorrhages. Four experienced radiologists read the CT scans independently. Beside the diagnosis, the relevant morphological criteria and the optimal plane orientation (axial or coronar) were specified. The sensitivity, specificity, and negative and positive predictive value were calculated. Additionally the interobserver variability was determined by applying the Cohen's kappa test. Surgical sclera inspections were performed in all cases as a standard of reference. The evaluations of the CT examination were compared with the surgery reports.59 patients were evaluated (42 men, 17 women). The mean age was 29 years (range 7 - 91). In 17 patients a rupture of the globe was diagnosed during surgery. 12 of these 17 penetrating injuries (70.6 %) were classified correctly by MDCT, 5 of the 17 (29.4 %) were not detectable. 42 patients did not have an open globe injury. 41 of these patients were diagnosed correctly negative by MDCT, and one patient was classified false positive. This results in a sensitivity of 70 % with a specificity of 98 %. There was high inter-rater agreement with kappa values between 0.89 - 0.96. Most discrepancies were caused by wrong negative findings. The most frequent morphologic criteria for open globe injury were the deformation (n = 10) and the volume reduction (n = 7) of the globe. These changes were most certain and visible in the axial orientation.In about one third of all unclear cases with rupture of the globe due to severe trauma, CT evaluation failed to correctly diagnose the open globe injury, which might lead to a delay in necessary surgical intervention. Thus, surgical sclera inspection is always mandatory in such unclear trauma cases regardless of the MD-CT results.