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Zusammenfassung Hintergrund Das Retina.net ROP-Register erhebt Daten von Kindern, die eine seltene behandlungsbedürftige Frühgeborenenretinopathie (Retinopathy of Prematurity, ROP) entwickeln. Ziel dieser Auswertung ist die Untersuchung der Daten zur behandlungsbedürftigen ROP, Epidemiologie, Therapie und deren Änderungen über einen Zeitraum von 15 Jahren an der Medizinischen Hochschule Hannover. Methoden Analyse der Daten der therapiebedürftigen Fälle der ROP eines Zentrums für die Geburtsjahre 2001 bis 2016 (Therapie in 2002 bis 2017) als Gesamtzeitraum und in 5 Abschnitten. Ergebnisse Es wurden 65 Kinder behandelt (23 weiblich), davon wurden 11 (16,9 %) extern auf ROP gescreent und zur ROP-Behandlung zugewiesen. Für den Zeitraum 2006 bis 2016 lag die Inzidenz der behandlungsbedürftigen ROP unter den gescreenten Kindern bei 4,1 %. Das mittlere Gestationsalter betrug 25,7 Schwangerschaftswochen (SSW) (Standardabweichung [SA] = 1,8), das Geburtsgewicht 763 g (SA = 235), das postmenstruelle Alter bei Behandlung 38,2 Wochen (SA = 3,2), das postnatale Alter 12,4 Wochen (SA = 3,2). Über die Zeit zeigte sich kein signifikanter Unterschied der demografischen Parameter. Am häufigsten (57 Augen bei 31 Kindern) wurde eine Zone II, 3+-Erkrankung behandelt; 58 Kinder erhielten eine Laserkoagulation (N = 114 Augen), 7 Kinder bilateral eine Anti-VEGF-Therapie (Bevacizumab) (N = 14 Augen), welche ab 2014 eingesetzt wurde. Eine Wiederbehandlung bei Wiederaufflammen der behandlungsbedürftigen ROP war in einem Fall nach initialer Laserbehandlung notwendig. Kinder mit behandlungsbedürftiger ROP zeigten häufig neonatologische Komorbiditäten, in mehr als 90 % Beatmung, bronchopulmonale Dysplasie und erhielten Transfusionen. Schlussfolgerung Dies ist die erste monozentrische Auswertung über 15 Jahre im Rahmen des Retina.net ROP-Registers. Ab 2014 sehen wir einen Wechsel von der Laserkoagulation zur Anti-VEGF-Therapie (Bevacizumab), während im betrachteten Kollektiv die demografischen Daten und Behandlungsparameter weitgehend konstant waren.

Background: Patients with Sjögren’s syndrome and polyneuropathy more frequently develop cranial nerve affection when compared to patients with chronic inflammatory demyelinating polyneuropathy (CIDP). We therefore aimed to analyze trigeminal corneal nerve fibre characteristics in both patient groups. Methods: A total of 26 patients with Sjögren’s syndrome associated neuropathy and 29 patients with CIDP were recruited at our university hospital and compared to 6 healthy controls. Dry eye symptoms and signs were assessed via clinical examination and the Ocular Disease Surface Index questionnaire. Trigeminal corneal nerve fibres were analyzed via corneal confocal microscopy (CCM) as a non-invasive in vivo microscopy. Results: CCM revealed significantly reduced corneal nerve fibre density and corneal nerve fibre main branch density in the Neuro-Sjögren group when compared with healthy controls. There were no significant group differences between the Neuro-Sjögren and the CIDP group for any of the microscopic parameters. Dry eye assessment showed similarly reduced scores for both patient groups, while healthy controls showed better results for objective dry eye signs. There was no correlation between microscopic parameters of the corneal confocal microscopy and parameters of dry eye assessment. Conclusions: Our data revealed trigeminal corneal nerve affection in patients with neuropathy associated with Sjögren’s syndrome and patients with CIDP detected by CCM. No difference was found between both neuropathy groups indicating that CCM is not able to distinguish between both entities.

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 Optic disc pits (ODPs) are rare congenital anomalies. Several patients develop optic disc pit maculopathy (ODP-M): visual impairment caused by intra- and/or subretinal fluid. Treatment mode remains controversial. This study was designed to investigate the effectiveness of pars plana vitrectomy (PPV) and gas tamponade with or without internal limiting membrane (ILM)-peeling in improving visual acuity and reducing subretinal fluid in ODP-M patients. Methods We retrospectively reviewed the charts of 16 patients who underwent surgery for ODP-M from 2002–2015. Six patients underwent PPV with gas tamponade (group 1); ten patients additionally received ILM-peeling (group 2). Pre- and postoperative visual acuity and central retinal thickness (CRT) were compared between groups, as well as retinal morphology and the number of secondary vitrectomies and complications. Results Median visual acuity improved by 2 ETDRS lines in both groups (p = 0.713, Mann–Whitney U test). Median CRT decreased by 426.5 µm and 460 µm (p = 0.931). One patient in group 1 underwent repeat vitrectomy for persistent retinoschisis. Three patients in group 2 required repeat vitrectomy: two to treat a macular hole, one for peripheral retinal holes with retinal detachment. Conclusion In our cohort, PPV with gas tamponade proved to be an effective first-line treatment for ODP-M. Additional ILM-peeling did not give a significant benefit in this study.

Purpose To evaluate the relationship between macular pigment optical density (MPOD) and glaucoma. Methods Forty-three patients with an established glaucoma diagnosis (25 females, 18 males, mean age 70 (range 34-84)) and 43 healthy controls (28 females, 15 males, mean age 62 (range 30-87)) were included in this prospective diagnostic case-control study. All subjects underwent detailed eye examination including ophthalmoscopy, best-corrected visual acuity, biomicroscopy, measurement of the axial length of the eye, objective refraction, lens status, central foveal thickness on spectral-domain optical coherence tomography (SD-OCT). In all glaucoma patients, a visual field assessment and a measurement of the retinal nerve fibre layer (RNFL) on SD-OCT were done. MPOD was determined using the macula pigment module of the Spectralis HRA+OCT (Heidelberg Engineering GmbH, Heidelberg, Germany) at 0.51°, 1.02° and 1.99° retinal eccentricity using two-wavelength autofluorescence imaging. Results In the glaucoma group, the median of the visual field mean defect was 5.1 db (quartiles 3.0 and 13.5) and the mean RNFL-thickness global was 65.9 µm (SD ± 16.1). Median MPOD measured at 0.51°, 1.02° and 1.99° retinal eccentricity in the glaucoma group was 0.42 DU, 0.34 DU and 0.13 DU, in the control group 0.40 DU, 0.35 DU and 0.12 DU respectively. There was no statistically significant difference of median MPOD between glaucomatous and control eyes (p=0.510, 0.735, 0.481). No significant relation between MPOD at 1.02 retinal eccentricity and the presence of glare symptoms was found (p=0.948). However, age seems to correlate with median MPOD measured at 1.02 retinal eccentricity (p=0.017). Conclusion There was no evidence for lower MPOD levels in our glaucoma patients; lower MPOD was not related to the presence of glare symptoms. However there seems to be a positive correlation between age and MPOD at 1.02° retinal eccentricity. To further investigate the relation between glare reported by glaucoma patients and glare disability linked to lower MPOD levels, additional studies are necessary that include both detailed inquiry of the quality of glare and a glare quantification and precise analysis of MPOD levels in glaucoma patients.

Purpose: To compare ischemia-related clinical outcomes in patients treated with either ranibizumab pro re nata (PRN) or single dexamethasone implant in the Branch Retinal Vein Occlusion (COMRADE-B)...

Patients suffering from type 2 diabetes are at an increased risk of developing classical microvascular complications such as retinopathy, neuropathy, and nephropathy, which represent a significant health burden. Tight control of blood glucose, blood pressure, and serum cholesterol reduce the risk of microvascular complications but effective pharmacologically targeted treatment options for the treatment and prevention of diabetic microangiopathy are still lacking. Pharmacological inhibition of sodium glucose cotransporter 2 (SGLT2) might have the potential to directly protect against microvascular complications and could represent a potential treatment option. Randomized controlled clinical proof of concept trials are needed to investigate a potential central role of SGLT2 inhibitors in the prevention of diabetic microangiopathy and its classical clinical complications of retinopathy, neuropathy, and nephropathy.

Background It is unclear whether or not an additional encircling band improves outcome in vitrectomy for pseudophakic retinal detachment (PRD). Also unclear is whether small gauge transconjunctival trocar-guided vitrectomy is as successful as conventional 20 gauge (G) vitrectomy. Methods 257 adult patients with uncomplicated PRD were enrolled in 14 vitreoretinal centres across Germany. Contingent on availability of qualified surgeons, eligible patients were randomly assigned either (i) with ratio 1:1 to 20 G vitrectomy plus encircling band (group E1) or 20 G vitrectomy without any buckle (group C) or (ii) with ratios 1:1:1 to group E1, C or 23/25 G vitrectomy without any buckle (group E2). Treatment success was defined as no indication for any retina reattaching procedure during the follow-up of 6 months. Results Success was reached in 79.0% (=79/100, group E1) versus 73.5% (=72/98, group C) (p=0.558, OR 1.32, 95% CI 0.65 to 2.65. In group E2 87.7% (=50/57) of patients reached success compared with 78.7% (=48/61) in group C, demonstrating non-inferiority of E2 to C regarding the prespecified margin of 0.8 (OR scale; p=0.05, OR 2.17, 95% CI 0.80 to 5.89). Best corrected visual acuity significantly increased after surgery independent of technique, that is, on average −0.7 (from 1.0 to 0.3) logMAR. Patients suffered from a shift in spherical refraction of −1.0 D in group E1 compared with −0.1 D in group C. Similarly, intraoperative complications (15.2% vs 8.8% of patients) and serious adverse events (30.3% vs 22.5% of patients) were more frequent in group E1. Conclusions Vitrectomy with gas is an efficient and safe treatment for uncomplicated PRD. An additional encircling band does not significantly reduce the risk for any second procedure necessary to reattach the retina in 20 G vitrectomy. Small gauge transconjunctival vitrectomy is not inferior to the conventional 20 G technique. Trial registration number DKRS 00003158, Results.

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.

Bernd Junker,1 Jens F Jordan,2 Carsten Framme,1 Amelie Pielen1 1University Eye Hospital, Medical School Hannover, Hannover, 2Eye Center, Medical Center, University of Freiburg, Freiburg, Germany Importance: This study is the first description of the use of the intraoperative optical coherence tomography (iOCT) for trabecular meshwork surgery with the Trabectome in a regular clinical setting.Background: The aim of this study is to evaluate intraoperatively the immediate success of ab interno trabeculotomy with the Trabectome defined as a removal of the trabecular meshwork.Design: This is a retrospective clinical study performed in the University Eye Hospital, Medical School Hannover.Participants: A total of nine consecutive Caucasian patients suffering from primary open angle glaucoma, pigment dispersion glaucoma, or pseudoexfoliation glaucoma took part in the study.Methods: All patients underwent ab interno trabeculotomy surgery with the Trabectome using a commercially available iOCT to visualize the anterior chamber angle (ACA) before and after the procedure. The visualization was done using a modified Swan-Jacobs lens (all nine patients) or without lens (view from above, five patients).Main outcome measures: The main outcome of this study is the success of visualization of the ACA on iOCT, especially the postprocedural visualization of the wound gap after removal of the trabecular meshwork.Results: Using the view from above, the ACA could be visualized before and after the procedure in only two of the five cases. Using the modified Swan-Jacobs lens, the ACA could be visualized before the procedure and the trabecular meshwork opening after the procedure in all nine patients.Conclusion: The iOCT can be used to objectify the immediate success of the surgical procedure, ie, the removal of the trabecular meshwork, of ab interno trabeculotomy with the Trabectome. The procedure itself cannot be captured sufficiently via iOCT. Keywords: glaucoma, imaging, iOCT, trabecular meshwork surgery

Amelie Pielen,1,2 W Lloyd Clark,3 David S Boyer,4 Yuichiro Ogura,5 Frank G Holz,6 Jean-Francois Korobelnik,7,8 Brigitte Stemper,9,10 Friedrich Asmus,9 Kay D Rittenhouse,11 Christiane Ahlers,9 Robert Vitti,12 Namrata Saroj,12 Oliver Zeitz,9,13,14 Julia A Haller15 On behalf of the COPERNICUS and GALILEO study group 1Eye Center, University Hospital Freiburg, Eye Hospital, Freiburg, 2Hannover Medical School, University Eye Hospital, Hannover, Germany; 3Palmetto Retina Center, Columbia, SC, USA; 4Retina-Vitreous Associates Medical Group, Beverly Hills, CA, USA; 5Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; 6Department of Ophthalmology, University of Bonn, Bonn, Germany; 7Service d’ophtalmologie, CHU de Bordeaux, 8Service d’ophtalmologie, University of Bordeaux, Inserm, Bordeaux Population Health Research Center, Team LEHA, UMR 1219, Bordeaux, France; 9Bayer AG, Berlin, 10Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany; 11Bayer US LLC, Whippany, NJ, 12Regeneron Pharmaceuticals, Tarrytown, NY, USA; 13AKH Eye Clinic, Braunschweig, 14Universitätsklinikum Hamburg-Eppendorf, Klinik und Poliklinik für Augenheilkunde, Hamburg, Germany; 15Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA, USA Objectives: To report on the efficacy and safety of intravitreal aflibercept in patients with macular edema secondary to central retinal vein occlusion (CRVO) in an integrated analysis of COPERNICUS and GALILEO. Patients and methods: Patients were randomized to receive intravitreal aflibercept 2mg every 4weeks or sham injections until week 24. From week 24 to week 52, all intravitreal aflibercept-treated patients in both studies and sham-treated patients in COPERNICUS were eligible to receive intravitreal aflibercept based on prespecified criteria. In GALILEO, sham-treated patients continued to receive sham treatment through week 52. Results: At week 24, mean gain in best-corrected visual acuity and mean reduction in central retinal thickness were greater for intravitreal aflibercept-treated patients compared with sham, consistent with individual trial results. At week 52, after 6months of intravitreal aflibercept as-needed treatment in COPERNICUS, patients originally randomized to sham group experienced visual and anatomic improvements but did not improve to the extent of those initially treated with intravitreal aflibercept, while the sham group in GALILEO did not improve over week 24 mean best-corrected visual acuity scores. Ocular serious adverse events occurred in&nbsp

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

Purpose The COMRADE studies are the first randomized controlled head-to-head trials comparing the efficacy and safety of intravitreal ranibizumab versus dexamethasone (DEX) in patients with macular oedema secondary to retinal vein occlusion (RVO). The COMRADE extension trial was designed to provide additional 6-month data of patients who completed the core studies. Methods In this open-label, phase IV study patients who completed the COMRADE core studies were prospectively enrolled. Overall, 92 branch RVO (BRVO) patients (ranibizumab 52, DEX 40) and 83 central RVO (CRVO) patients (ranibizumab 61, DEX 22) were treated, and 94.6% of BRVO patients and 97.6% of CRVO patients completed the extension study. Patients were assigned to the same treatment group as in the core studies. Patients were monitored monthly and received either 0.5 mg ranibizumab or a 0.7 mg DEX implant as needed. Results Over the course of the extension, treatment-emergent adverse events (TEAEs) of the study eye occurred in 55.8% of BRVO patients on ranibizumab and in 62.5% of those on DEX. Among CRVO patients, 65.5% in the ranibizumab group and 59.1% in the DEX group developed TEAEs. Overall, elevated intraocular pressure (IOP) was more frequent with DEX than ranibizumab treatment. Mean average change in best-corrected visual acuity (BCVA) in BRVO patients was significantly better for ranibizumab than DEX (p = 0.0249). The CRVO results were consistent with BRVO's, although not significant (p = 0.1119). Conclusion When used according to the European labels, ranibizumab revealed a better ocular safety profile and produced greater average BCVA gains than DEX. By the end of the additional 6-month study period, this difference in BCVA was more pronounced in BRVO as in CRVO patients. The main limitation of the COMRADE studies was that DEX patients received only a single intravitreal treatment during the first 6 months, which is presumably not adequate. However, frequent DEX implants could lead to more steroid-related side effects, especially to an increased intraocular pressure.

Purpose: This is a prospective, randomized, multicenter, investigator-initiated trial to evaluate the 12-month effectiveness of isovolemic hemodilution (IH) with prompt versus deferred intravitreal injections (IVI) of ranibizumab 0.5 mg for the treatment of macular edema secondary to early central retinal vein occlusion (CRVO). Methods: Eyes with macular edema due to CRVO having occurred not more than 8 weeks previously received either monthly ranibizumab IVI in combination with IH (group I, n = 28) or IH alone (group II, n = 30). From month 2 to 12, the patients in both groups could be treated with monthly intravitreal ranibizumab. The main outcome variables were gain of visual acuity and the course of central retinal thickness as measured with optical coherence tomography. Results: At 12 months, eyes in group I on average gained +28.1 (±19.3) letters compared to +25.2 (±20.9) letters in group II (p = 0.326). This result was achieved with significantly fewer injections in group II. Additionally, 30% of the eyes in group II did not need ranibizumab IVI during the 12 months of the trial. Conclusion: Ranibizumab IVI in addition to IH proved to be highly effective in increasing visual acuity and reducing macular edema secondary to CRVO. Initial IH in early CRVO may be a first treatment option in patients anxious about IVI.

Purpose To compare standard-of-care grid laser photocoagulation versus intravitreal ranibizumab (IVR) versus a combination of both in the treatment of chronic (>3 months) macular oedema secondary to branch retinal vein occlusion. Methods Prospective, randomized, multicentre clinical trial. Thirty patients with a best-corrected visual acuity (BCVA) between 20/320 and 20/40 were randomized 1:1:1 to receive grid laser or three monthly injections of 0.5 mg IVR or both followed by 3 months of observation. Results Mean change from baseline BCVA at month 6 was +2 letters [laser; 0.04 logMAR, 95% confidence interval (−0.17; 0.25)], +17 letters [IVR; 0.34 (0.19; 0.5)] and +6 letters [combination; 0.12 (0.01; 0.24)] (IVR versus laser p = 0.02 and IVR versus combination p = 0.02). At month 3, mean improvement in central retinal thickness (CRT) was 90.6 μm (laser) (−18.65; 199.8), 379.5 μm (IVR) (204.2; −554.8), and 248 μm (167.2; −328.8) (combination) (IVR versus laser p = 0.005, laser versus combination p = 0.02). During the observation period, CRT improved in laser [37.6 μm (−66.82; 142.0)], but deteriorated in IVR [−142.4 μm (−247.6; −37.16)] and combination [−171.7 μm (−250.4; −92.96)] (laser versus IVR p = 0.01, laser versus combination p = 0.002) indicating recurrent oedema. Less laser retreatments (at 8 weeks) were required in combination group (2/10) than grid group (7/10). Conclusion Six-month results suggest that ranibizumab may be superior to grid laser in improving visual acuity. Grid combined with IVR neither enhanced functional and morphological improvement of IVR nor did it prevent or prolong recurrence of oedema. In IVR groups, CRT increased slowly after stopping injections, whereas improvement in visual acuity was sustained, indicating that morphological changes occur prior to functional impairment.

Fingolimod 0.5-mg once-daily is an approved therapy for patients with relapsing–remitting multiple sclerosis (MS). Several pivotal and real-world studies have demonstrated that fingolimod is associated with the development of macular edema (ME). Herein, we present a case of a diabetic MS patient who developed severe bilateral ME during fingolimod treatment. By means of this case study we provide a detailed review about fingolimod associated macular edema (FAME), its current incidence with or without diabetes mellitus, and previous therapy attempts and outcomes in MS patients. Intravitreal administration of antibodies raised against vascular endothelial growth factor A (VEGF-A) has not yet been used in the management of FAME, however, the excellent therapeutic response in our patient may justify the use of anti-VEGF-A agents in combination with cessation of fingolimod to achieve fast resolution of FAME and to prevent visual deficits, particularly in bilateral FAME. OA gold

Purpose: To compare the efficacy and safety of ranibizumab 0.5 mg versus dexamethasone 0.7 mg according to their European labels in macular oedema secondary to branch retinal vein occlusion (BRVO) in a 6-month, phase IIIb, randomized trial. Methods: Patients received eithermonthly ranibizumabfor 3 months followed byPro re nata (PRN) treatment (n = 126) or a sustained-release dexamethasone implant followedbyPRNshaminjections (n = 118).Mainoutcomesweremeanaveragechange in best-corrected visual acuity(BCVA)frombaseline tomonth1throughmonth6,mean changes inBCVAand foveal centre point thickness (FCPT), and adverse events (AEs). Results: There was no difference in BCVA gains between the treatments prior to month 3. Best-corrected visual acuity (BCVA) gain with dexamethasone declined thereafter. From month 3 to month 6, mean BCVA change from baseline was significantly higher with ranibizumab than with dexamethasone [raw means (standard deviation):+16.2 ( 11) letters versus+9.3 ( 10.1) letters].Atmonth 6, the difference in BCVA gains from baseline was +17.3 letters in the ranibizumab versus +9.2 letters in the dexamethasone group. Patients in the ranibizumab group received a mean of 2.94 loading injections and 1.74 PRN retreatment injections, while those in the dexamethasone group received a single loading injection. Elevated intraocular pressure (IOP) and AEs were more frequent with dexamethasone than ranibizumab treatment. Conclusion: Ranibizumab PRN resulted in greater visual acuity (VA) gains in macular oedema following BRVO compared with single-dose dexamethasone over a 6-month study period, observed from month 3, when administered according to their European label. In clinical practice, retreatment with dexamethasone may be required prior to this point.

Background To identify predictive factors for improvement of visual acuity and central retinal thickness by intravitreal bevacizumab for the treatment of macular edema (ME) due to branch retinal vein occlusion (BRVO). Methods Two hundred and five eyes from 204 patients with ME secondary to BRVO were retrospectively included at six sites. All eyes received intravitreal bevacizumab therapy (1.25 mg/0.05 ml). The mean follow-up was 36.8 ± 12.7 weeks (range, 18 to 54 weeks). Measurement of ETDRS best-corrected visual acuity (BCVA, in all eyes) and optical coherence tomography (OCT, in 87% of eyes) were performed at baseline and at follow-up examinations every 12 weeks. Using fluorescein angiography, the perfusion status of the macula at baseline could be assessed in 84% of the eyes. The main outcome measures were changes in BCVA and central retinal thickness (CRT). For analysis of predictive factors, the results at 24 weeks were used. Results The median BCVA was 0.6 LogMAR at baseline and improved to 0.4 LogMAR at 24 and 48 weeks. This visual improvement was associated by a significant reduction in CRT, decreasing from a baseline of 454 μm to 267 μm and 248 μm after 24 and 48 weeks respectively. Eyes with ME and intact (perfused) or interrupted (ischemic) foveal capillary ring showed a 2-line increase of median BCVA [45 eyes (22%) and 128 eyes (62%) respectively]. However, the final median BCVA was significantly worse in eyes with ischemic ME (0.6 versus 0.3 logMAR in perfused ME). Other factors for visual improvement were absence of previous treatments of the ME, age younger than 60 years and low baseline BCVA (≥0.6 logMAR) (2, 3, and 2 median BCVA lines increase respectively). Furthermore, eyes with duration of the ME of less than 12 months responded with a 3-line increase of the median BCVA. Final CRT only showed minor differences between the subgroups. During the entire follow-up, retreatments were performed in 85% of the eyes, with a median number of injections of three (mean 3.2; range, 1 to 10) and a median time-interval between injections of 11.6 weeks (mean 14.6 weeks). Conclusions Intravitreal injection of bevacizumab resulted in a significant improvement of BCVA and reduction of ME in BRVO. Baseline BCVA, patient’s age, and duration of BRVO were found to be of prognostic relevance for visual improvement. A less favorable outcome of the bevacizumab therapy in eyes with longstanding BRVO would advocate initiation of treatment within 12 months after onset.

INTRODUCTION: Optic neuritis leads to degeneration of retinal ganglion cells whose axons form the optic nerve. The standard treatment is a methylprednisolone pulse therapy. This treatment slightly shortens the time of recovery but does not prevent neurodegeneration and persistent visual impairment. In a phase II trial performed in preparation of this study, we have shown that erythropoietin protects global retinal nerve fibre layer thickness (RNFLT-G) in acute optic neuritis; however, the preparatory trial was not powered to show effects on visual function. METHODS AND ANALYSIS: Treatment of Optic Neuritis with Erythropoietin (TONE) is a national, randomised, double-blind, placebo-controlled, multicentre trial with two parallel arms. The primary objective is to determine the efficacy of erythropoietin compared to placebo given add-on to methylprednisolone as assessed by measurements of RNFLT-G and low-contrast visual acuity in the affected eye 6 months after randomisation. Inclusion criteria are a first episode of optic neuritis with decreased visual acuity to ≤0.5 (decimal system) and an onset of symptoms within 10 days prior to inclusion. The most important exclusion criteria are history of optic neuritis or multiple sclerosis or any ocular disease (affected or non-affected eye), significant hyperopia, myopia or astigmatism, elevated blood pressure, thrombotic events or malignancy. After randomisation, patients either receive 33 000 international units human recombinant erythropoietin intravenously for 3 consecutive days or placebo (0.9% saline) administered intravenously. With an estimated power of 80%, the calculated sample size is 100 patients. The trial started in September 2014 with a planned recruitment period of 30 months. ETHICS AND DISSEMINATION: TONE has been approved by the Central Ethics Commission in Freiburg (194/14) and the German Federal Institute for Drugs and Medical Devices (61-3910-4039831). It complies with the Declaration of Helsinki, local laws and ICH-GCP. TRIAL REGISTRATION NUMBER: NCT01962571. peerReviewed

Purpose The German retinopathy of prematurity (ROP) Registry collects data on treated ROP in a multicentre approach to analyse epidemiology and treatment patterns of severe ROP. Methods Nine centres entered data from 90 treated ROP infants (born between January 2011 and December 2013) into a central database. Analysis included incidence rate of severe ROP, demographic data, stage of ROP, treatment patterns, recurrence rates, relevant comorbidities and ophthalmological or systemic complications associated with treatment. Results Treatment rate for ROP was 3.2% of the screened population. The most frequent ROP stage at time of treatment was zone II, stage 3 + (137 eyes). Treatment was bilateral in 97% of infants. Treatment patterns changed over time from 7% anti-vascular endothelial growth factor (VEGF) monotherapy in 2011 to 32% in 2014. Overall, laser treatment was the predominant treatment. However, all infants with zone I disease received anti-VEGF treatment. About 19% of infants required retreatment (16% of laser-treated and 21% of anti-VEGF treated infants). Mean time between first and second treatment was 3.8 weeks (± 11 days) for laser-treated and 10.4 weeks (± 60 days) for anti-VEGF-treated infants. Conclusion This study is the first multicentre analysis of severe ROP in Germany. The identified treatment patterns find laser as the most prevalent form of therapy, with an increasing use of anti-VEGF therapy over recent years. Recurrence rates were relatively high overall with slightly higher recurrence rates and later recurrence times in the anti-VEGF group. Anti-VEGF was predominantly used for high-risk stages like AP-ROP and zone I disease.

BACKGROUND: Central retinal vein occlusion (CRVO) is a common disease characterized by a disrupted retinal blood supply and a high risk of subsequent vision loss due to retinal edema and neovascular disease. This study was designed to assess the concentrations of selected signaling proteins in the vitreous and blood of patients with ischemic CRVO. METHODS: Vitreous and blood samples were collected from patients undergoing surgery for ischemic CRVO (radial optic neurotomy (RON), n = 13), epiretinal gliosis or macular hole (control group, n = 13). Concentrations of 40 different proteins were determined by an ELISA-type antibody microarray. RESULTS: Expression of proteins enriched in the vitreous (CCL2, IGFBP2, MMP10, HGF, TNFRSF11B (OPG)) was localized by immunohistochemistry in eyes of patients with severe ischemic CRVO followed by secondary glaucoma. Vitreal expression levels were higher in CRVO patients than in the control group (CRVO / control; p < 0.05) for ADIPOQ (13.6), ANGPT2 (20.5), CCL2 (MCP1) (3.2), HGF (4.7), IFNG (13.9), IGFBP1 (14.7), IGFBP2 (1.8), IGFBP3 (4.1), IGFBP4 (1.7), IL6 (10.8), LEP (3.4), MMP3 (4.3), MMP9 (3.6), MMP10 (5.4), PPBP (CXCL7 or NAP2) (11.8), TIMP4 (3.8), and VEGFA (85.3). In CRVO patients, vitreal levels of CCL2 (4.2), HGF (23.3), IGFBP2 (1.23), MMP10 (2.47), TNFRSF11B (2.96), and VEGFA (29.2) were higher than the blood levels (vitreous / blood, p < 0.05). Expression of CCL2, IGFBP2, MMP10, HGF, and TNFRSF11B was preferentially localized to the retina and the retinal pigment epithelium (RPE). CONCLUSION: Proteins related to hypoxia, angiogenesis, and inflammation were significantly elevated in the vitreous of CRVO patients. Moreover, some markers known to indicate atherosclerosis may be related to a basic vascular disease underlying RVO. This would imply that local therapeutic targeting might not be sufficient for a long term therapy in a systemic disease but hypothetically reduce local changes as an initial therapeutic approach. peerReviewed

Purpose To assess the impact of baseline perfusion status on best-corrected visual acuity (BCVA) in patients with macular edema due to central retinal vein occlusion treated with intravitreal aflibercept (IVT-AFL) injection. Methods Patients received IVT-AFL 2 mg (IVT-AFL 2q4) or sham monthly up to Week 24 (W24). From W24-W52, all IVT-AFL–treated patients in both studies and sham-treated patients in COPERNICUS were eligible to receive IVT-AFL based on visual and anatomical outcomes (IVT-AFL 2q4+PRN, sham+IVT-AFL PRN). Sham-treated patients in GALILEO were eligible to receive IVT-AFL after W52. Retinal perfusion (

Although anti-VEGF therapy of exudative AMD with bevacizumab and ranibizumab proved efficacious in the majority of patients, CNV activity does not respond to continued treatment after repeated injections in a considerable amount of patients. These are referred to as nonresponders. A change of the drug to bevacizumab or ranibizumab could possibly offer an alternative option for the treatment of nonresponding exudative AMD. A total of 138 nonresponders who switched therapy from bevacizumab to ranibizumab (n=114) or vice versa (n=24) were included in a retrospective study. Visual acuity (VA) and foveal thickness before and after the switch of therapy were compared. By means of linear regression analysis, we analyzed possible prognostic factors associated with a favorable outcome for visual acuity. Linear regression analysis revealed a statistically significant benefit for nonresponders when treatment was changed to a different anti-VEGF drug (bevacizumab or ranibizumab). VA at the time of the switch was positively correlated with a beneficial development of VA after changing the drug. There was no significant correlation with age, macular thickness, number of injections before the switch, or the development of VA under treatment before the switch. Both patients switching to Avastin and Lucentis benefitted without statistically significant differences. An exchange of bevacizumab with ranibizumab or vice versa should be considered in nonresponders in the treatment of exudative AMD. Further prognostic factors may help to identify patients who might benefit from a switch. These factors should be investigated in further studies.

Semaphorins are known modulators of axonal sprouting and angiogenesis. In the retina, we identified a distinct and almost exclusive expression of Semaphorin 3F in the outer layers. Interestingly, these outer retinal layers are physiologically avascular. Using functional in vitro models, we report potent anti-angiogenic effects of Semaphorin 3F on both retinal and choroidal vessels. In addition, human retinal pigment epithelium isolates from patients with pathologic neovascularization of the outer retina displayed reduced Semaphorin 3F expression in 10 out of 15 patients. Combined, these results elucidate a functional role for Semaphorin 3F in the outer retina where it acts as a vasorepulsive cue to maintain physiologic avascularity.

BACKGROUND: Intravitreal agents have replaced observation in macular edema in central (CRVO) and grid laser photocoagulation in branch retinal vein occlusion (BRVO). We conducted a systematic review to evaluate efficacy and safety outcomes of intravitreal therapies for macular edema in CRVO and BRVO. METHODS AND FINDINGS: MEDLINE, Embase, and the Cochrane Library were systematically searched for RCTs with no limitations of language and year of publication. 11 RCTs investigating anti-VEGF agents (ranibizumab, bevacizumab, aflibercept) and steroids (triamcinolone, dexamethasone implant) with a minimum follow-up of 1 year were evaluated. EFFICACY CRVO: Greatest gain in visual acuity after 12 months was observed both under aflibercept 2 mg: +16.2 letters (8.5 injections), and under bevacizumab 1.25 mg: +16.1 letters (8 injections). Ranibizumab 0.5 mg improved vision by +13.9 letters (8.8 injections). Triamcinolone 1 mg and 4 mg stabilized visual acuity at a lower injection frequency (-1.2 letters, 2 injections). BRVO: Ranibizumab 0.5 mg resulted in a visual acuity gain of +18.3 letters (8.4 injections). The effect of dexamethasone implant was transient after 1.9 implants in both indications. SAFETY: Serious ocular adverse events were rare, e.g., endophthalmitis occurred in 0.0-0.9%. Major differences were found in an indirect comparison between steroids and anti-VEGF agents for cataract progression (19.8-35.0% vs. 0.9-7.0%) and in required treatment of increased intraocular pressure (7.0-41.0% vs. none). No major differences were identified in systemic adverse events. CONCLUSIONS: Anti-VEGF agents result in a promising gain of visual acuity, but require a high injection frequency. Dexamethasone implant might be an alternative, but comparison is impaired as the effect is temporary and it has not yet been tested in PRN regimen. The ocular risk profile seems to be favorable for anti-VEGF agents in comparison to steroids. Because comparative data from head-to-head trials are missing currently, clinicians and patients should carefully weigh the benefit-harm ratio. peerReviewed

PURPOSE To assess the correlation between hyperreflective foci (HF) and visual and anatomical outcomes in treatment-resistant neovascular age-related macular degeneration (AMD) using spectral-domain optical coherence tomography (SD-OCT). METHODS This was a prospective interventional case series. Thirty-three eyes of 30 consecutive patients with treatment-resistant neovascular AMD were enrolled. Intravitreal aflibercept injections were performed at week 0 (baseline), week 4, and week 8. Spectral-domain OCT images were obtained before each injection and 4 weeks after the third injection. The main focus was on the measurement of choroidal neovascularization (CNV) size in the cross-sectional area in the B-scan through the fovea, and HF number along line segments of 1- and 3-mm length passing through the fovea. RESULTS Mean number of HF in the radius of 500 μm decreased from 8.36 ± 7.58 to 4.15 ± 3.39 (P = 0.02). Mean number of HF in the radius of 1500 μm was reduced from 21.30 ± 12.47 to 10.45 ± 6.34 (P < 0.001). Mean CNV area decreased from 0.35 ± 0.22 to 0.22 ± 0.16 mm2 (P < 0.001). There was a significant positive correlation between HF reduction in the radius of 500 μm and decrease in central subfield thickness (CST) (r = 0.43, P = 0.01), but no statistically significant correlation was found between HF decline in the radius of 1500 μm and other parameters. CONCLUSIONS Switching from ranibizumab to aflibercept caused significant decrease in the number of HF 1 month after aflibercept upload, and HF decrease in the radius of 500 μm was correlated positively with the reduction in CST.

PURPOSE. Recent studies demonstrated that short peptides derived from activity-dependent neurotrophic factor (ADNF) and activity-dependent neuroprotective protein (ADNP) are neuroprotective at femtomolar concentrations. We evaluated these findings in cultures of purified rat retinal ganglion cells (RGCs) using two such peptides: ADNF-9 and NAP. In a second step, the influence of these peptides on neurite outgrowth in retinal explants was investigated. METHODS. Retinal ganglion cells (RGCs) were purified from newborn (postnatal day [P]0‐P2) rat retina by immunopanning with antibodies against Thy1.1 and were cultured in serum-free N2 medium for 2 days. RGCs were treated with ADNF-9 and NAP at concentrations ranging from 10 18 to 10 10 M. Survival was quantified by counting viable cells by phase-contrast microscopy. Retinal explants from postnatal (P9‐P11) rats were cultured in three-dimensional fibrin clots in serum-free medium for 3 days. Explants were treated with 1 M NAP or 1 M ADNF-9. Neurite outgrowth was visualized by staining with Sudan black and quantified by measuring axonal length. RESULTS. Both peptides enhanced survival of RGCs in a dosedependent manner. ADNF-9 showed a maximum effect at 0.1 pM with an increase in survival to 177% (95% confidence interval: 149‐204) of the control level. The EC50 was 10.9 fM. NAP showed a maximum effect at 5 pM with an increase in survival to 167% (146‐189) and an EC50 of 6.1 fM. In the explants, 1 M ADNF-9 enhanced axonal outgrowth to 126% (118‐133) and 1 M NAP to 117% (98‐137) compared with the control. CONCLUSIONS. Both peptides, ADNF-9 and NAP, not only increase RGC survival in vitro but also support neurite outgrowth in retinal explants. These peptides deserve further attention as potential neuroprotective compounds in retinal and optic nerve diseases. (Invest Ophthalmol Vis Sci. 2005;46:933‐938)