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Despite the success of antiangiogenic therapy in controlling exudation in neovascular age-related macular degeneration (nAMD), the involvement of the outer retina in fibrosis results in gradual vision loss over time. The development of drugs that prevent or ameliorate fibrosis in nAMD requires that it is accurately detected and quantified with reliable endpoints and identification of robust biomarkers. Achievement of such an aim is currently challenging due to the lack of a consensus definition of fibrosis in nAMD. As a first step towards the establishment of a clear definition of fibrosis, we provide an extensive overview of the imaging modalities and criteria used to characterize fibrosis in nAMD. We observed variety in the selection of individual and combinations of imaging modalities, and criteria for detection. We also observed heterogeneity in classification systems and severity scales for fibrosis. The most commonly used imaging modalities were color fundus photography (CFP), fluorescence angiography (FA) and optical coherence tomography (OCT). A multimodal approach was frequently utilized. Our review suggests that OCT offers a more detailed, objective and sensitive characterization than CFP/FA. Thus, we recommend it as a primary modality for fibrosis evaluation. This review provides a basis for future discussions to reach a consensus definition using standardized terms based on a detailed characterization of fibrosis, its presence and evolution, and taking into consideration impact on visual function. Achieving this goal is of paramount importance for the development of antifibrotic therapies.

In this work we evaluated a postprocessing, customized automatic retinal OCT B-scan enhancement software for noise reduction, contrast enhancement and improved depth quality applicable to Heidelberg Engineering Spectralis OCT devices. A trained deep neural network was used to process images from an OCT dataset with ground truth biomarker gradings. Performance was assessed by the evaluation of two expert graders who evaluated image quality for B-scan with a clear preference for enhanced over original images. Objective measures such as SNR and noise estimation showed a significant improvement in quality. Presence grading of seven biomarkers IRF, SRF, ERM, Drusen, RPD, GA and iRORA resulted in similar intergrader agreement. Intergrader agreement was also compared with improvement in IRF and RPD, and disagreement in high variance biomarkers such as GA and iRORA.

Background To investigate anterior scleral thickness in a cohort of healthy subjects using enhanced depth imaging anterior segment optical coherence tomography. Methods Observational case series. The mean scleral thickness in the inferonasal, inferotemporal, superotemporal, and superonasal quadrant was measured 2 mm from the scleral spur on optical coherence tomography in healthy volunteers. Results Fifty-three eyes of 53 Caucasian patients (25 male and 28 female) with an average age of 48.6 years (range: 18 to 92 years) were analysed. The mean scleral thickness was 571 μm (SD 84 μm) in the inferonasal quadrant, 511 μm (SD 80 μm) in the inferotemporal quadrant, 475 (SD 81 μm) in the superotemporal, and 463 (SD 64 μm) in the superonasal quadrant. The mean scleral thickness was significantly different between quadrants (p

Fifty-five degree wide-field spectral domain optical coherence tomography provides an alternative to standard 30° optical coherence tomography lens with comparable thickness values with a greater field of view., Purpose: To assess whether retinal thickness measurements with a standard 30° spectral domain optical coherence tomography (SD-OCT) are comparable with wide-field 55° SD-OCT. Methods: Thirty-three healthy individuals were scanned using 55° as well as 30° SD-OCT according to a standardized protocol. Automated retinal layer segmentation of standard and wide-field SD-OCTs was assessed using customized software. Results: Both lenses showed a high correlation when analyzing total retinal thickness within the central, the inner, and the outer retinal ring (r = > 0.9). Automated thickness measurements with the 55° system were marginally higher compared with the 30° lens. The thickness of each separate retinal layer using automated segmentation showed excellent correlations within the inner and outer rings (range: r = 0.6—r = 0.9 for the inner ring and range: r = 0.9—r = 1.0 for the outer ring). Conclusion: Fifty-five degree wide-field SD-OCT provides a good overview of the posterior pole and presents similar quantitative values as a standard 30° OCT lens. Therefore, thickness values are comparable when switching between these two lenses.

This study confirms that fluorescence lifetime imaging ophthalmoscopy is able to identify and quantify macular alterations after surgical reattachment of macula-off rhegmatogenous retinal detachment that relate to visual acuity. Fluorescence lifetime imaging ophthalmoscopy could be a useful noninvasive diagnostic tool to assess eyes after rhegmatogenous retinal detachment repair., Purpose: The purpose of this study was to investigate fluorescence lifetime imaging ophthalmoscopy lifetimes after macula-off rhegmatogenous retinal detachment (RRD) repair. Methods: Fifty-eight patients with successful macula-off RRD reattachment surgery were included. Retinal autofluorescence was excited with 470 nm, and amplitude-weighted mean fluorescence lifetimes (Tm) were measured in a short spectral channel (SSC, 498–560 nm) and a long spectral channel (LSC, 560–720 nm). Tm were obtained within a standardized Early Treatment Diabetic Retinopathy Study grid and correlated with Tm. The unaffected fellow eye served as control. Results: Fifty-eight patients (age: 65 ± 1.6 years, 11 women) were imaged at median 1.5 months postoperatively. Tm were significantly prolongxxxed within areas of previously detached retina in the long spectral channel and particularly in the central subfield in the short spectral channel. Short lifetimes in the center of the Early Treatment Diabetic Retinopathy Study grid correlated with better visual acuity (short spectral channel; r2 = 0.18, P = 0.001, long spectral channel; r2 = 0.08, P = 0.03). Areas of residual subretinal fluid pockets in four RRD eyes displayed short fluorescence lifetimes. Conclusion: Areas of previously detached retina exhibit significant fluorescence lifetime changes. We found a significant correlation of fluorescence lifetimes within the fovea with visual acuity after successful RRD repair. Our data suggests that the prolongation of fluorescence lifetimes in the fovea is mainly driven by loss of macular pigment. Therefore, fluorescence lifetime imaging ophthalmoscopy may be useful in the prediction of long-term functional outcomes after macula-off RRD surgery.

Purpose:Intraretinal cystoid spaces are commonly found after surgical peeling of epiretinal membranes. In this study, we explored whether these cysts were associated with ganglion cell loss and thus might be a manifestation of retrograde maculopathy. The latter is a nonvascular edema with a characte

AimTo report long-term outcomes on best-corrected visual acuity (BCVA) and treatment intervals with a treat-and-extend (T&E) regimen in patients with neovascular age-related macular degeneration (nAMD).MethodsThis observational study included treatment-naïve patients with nAMD, treated with aflibercept. A specific T&E protocol without a loading phase and predefined exit criteria was administered. After reaching predefined ‘exit-criteria’, the treatment period was complete, and patients were observed three monthly.ResultsEighty-two patients with a follow-up period of ≥2 years were included. BCVA (mean±SD, ETDRS letters) increased from 51.9±25.2 at baseline to 63.7±17.7 (pConclusionsAfter 4 years of treatment, initial vision gains were maintained with a reasonable treatment burden, even without an initial loading phase. Our results on functional outcomes are comparable with large controlled studies.

Purpose: To evaluate real-life outcomes in treatment-naive patients with diabetic macular edema (DME) treated with anti-vascular endothelial growth factor (VEGF) agents using a treat-and-extend regimen without a fixed loading phase. Methods: Best-corrected visual acuity (BCVA) and central retinal thickness (CRT) measured using optical coherence tomography at baseline and after 1 year of treatment, intervals and number of injections were analyzed. Subgroup analysis was performed to compare anatomical and functional outcomes between patients receiving ranibizumab or aflibercept. Results: Seventy-five eyes of 61 patients met the inclusion criteria and had follow-up for 1 year. Baseline BCVA and CRT were 68.1 ± 13.2 letters and 424 ± 135 µm, retrospectively. After 1 year, there was a significant mean gain in BCVA of +5.8 ± 7.4 letters (paired t test: p < 0.0001) and a significant decrease in mean CRT of –117 ± 134 µm (paired t test: p < 0.0001). The mean number of anti-VEGF injections was 10.0 ± 1.6 (range 6–12). The mean maximum interval between injections was 8.5 ± 2.9 weeks (range 4–14) and the mean interval 6.0 ± 1.2 weeks (range 4.1–8.9). 96% of eyes could be extended after a mean of 5.3 injections and 17% of patients could be extended before reaching a formal loading dose of 3 injections. Subgroup analysis did not reveal any differences in outcomes between patients treated with ranibizumab or aflibercept. Subretinal fluid at baseline was associated with better BCVA gain after 1 year (stepwise forward regression analysis, p = 0.003). Conclusion: Our results suggest that not all patients with DME require a fixed loading phase when initiating anti-VEGF treatment. Finding anatomical predictors to identify this subgroup of patients would help to reduce treatment burden and optimize clinical outcomes.

Purpose: To evaluate longitudinal changes in retinal layer thickness and clinical outcome in patients with MEWDS.Methods: In 20 patients with MEWDS, SD-OCT images and BCVA were assessed at baseline, and at months 1, 3, and 12. SD-OCTs were segmented and measurements were performed within the fovea and a MEWDS lesion. Baseline and follow-up values in the affected eye were compared to measurements performed at the corresponding location in the fellow eye.Results: ONL thickness was 4.7% thicker in MEWDS-eyes compared with the baseline, with a significant decrease of 9% at 3 months. Within the lesion, INL thickness was 7.9% increased at baseline and decreased significantly over the follow-up of 12 months. BCVA was decreased at baseline (0.2 ± 0.18logMAR) and at the 3 months but after 12 months had increased to 0.01 ± 0.04 logMAR.Conclusion: MEWDS shows the involvement of different retinal layers and characteristic changes over the disease course.

More than 15 years ago, the results of the pivotal trials supporting the intravitreal use of ranibizumab were published [...]

Purpose To evaluate the impact of the vitreomacular interface (VMI) in a treat-and-extend (TREX) regimen with exit strategy in patients with neovascular age-related macular degeneration (nAMD). Design Retrospective cohort study. Participants Five hundred ninety-three eyes of 498 patients with nAMD. Methods Eyes were treated according to a TREX regimen with an exit criterion, which was defined as no signs of disease activity during 3 consecutive 16-week injection visits. The impact of the VMI and the presence of an epiretinal membrane (ERM) assessed by spectral-domain OCT were evaluated based on the parameters mentioned below. Main Outcome Measures Effect of vitreomacular adhesion (VMA) and ERM on mean treatment interval, number of injections, likelihood of fulfilling the exit criterion, choroidal neovascularization recurrences, CRT decrease, and BCVA improvement. Results During the TREX period, posterior vitreous detachment (PVD) eyes needed significantly fewer injections (mean, 10.6 ± 5.9) than VMA eyes (mean, 12.6 ± 6.7; P = 0.0008), and the mean injection interval was shorter in VMA eyes (8.3 ± 3.1 weeks) than in PVD eyes (9.5 ± 3.5 weeks; P = 0.0008). Eyes with PVD at baseline and without an ERM were 9.2 and 11.4 times more likely to fulfill the exit criterion than eyes with VMA and ERM, respectively ( P = 0.006 and P = 0.004, respectively, corrected). Although CRT decrease ( P = 0.16) and BCVA improvement ( P = 0.32) did not differ with respect to the VMI configuration, ERM had a significant impact on CRT decrease (ERM present, +11 ± 198 μm vs. ERM absent, −92 ± 136 μm; P = 0.041). Vitreomacular adhesion at treatment cessation was associated significantly with disease recurrence (likelihood ratio, 7.8; P = 0.013, corrected), whereas the presence of an ERM was not associated with choroidal neovascularization recurrence ( P = 0.18). Conclusions The configuration of the VMI and the presence of an ERM have a significant impact on the treatment frequency, the chance to meet the exit criterion in this TREX regimen, and the recurrence risk after treatment cessation. This indicates that eyes with VMA should be monitored carefully for new disease activity after treatment cessation.

Purpose: To identify spectral-domain optical coherence tomography (SD-OCT) features associated with exudative conversion in fellow eyes of patients treated for neovascular age-related macular degeneration (nAMD) in their first eye. Methods: Retrospective observational study. Spectral-domain optical coherence tomography images of converting fellow eyes (study eyes) from 83 patients with nAMD were compared to fellow eyes of age- and sex-matched patients with nAMD who did not convert (control eyes). Parameters related to drusen, pigment epithelium detachment, hyperreflective foci (HRF), retinal pigment epithelium atrophy, small cystic cavities, and vitreoretinal interface were graded. Longitudinal analysis in study eyes and cross-sectional comparison with control eyes at the last 3 semiannual visits before nAMD conversion were performed. Results: For most biomarkers, the prevalence in study eyes increased and imaging findings worsened more than in control eyes. Drusen size and reticular pseudodrusen presence were significantly greater in converting eyes at all 3 time points. Outer retinal small cystic cavities were significantly more common in study eyes shortly before conversion. Binary logistic regression revealed that biggest drusen width was significantly associated with nAMD at all 3 time points (odds ratio [OR] > 1.010; P < .001). The presence of soft drusen was strongly associated with nAMD 18 months before conversion (OR: 7.034; P = .040). Clustering HRF in the inner retina were significantly associated with nAMD both 12 (OR: 1.324; P = .049) and 6 months (OR: 2.161; P = .035) before conversion. Conclusions: Emergence of HRF in fellow eyes, particularly in the inner retina, are sensitive SD-OCT features indicating conversion to exudative disease in patients treated unilaterally for nAMD.

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.

The aim of this observational study was to assess the use and outcome of intravitreal aflibercept in a treat and extend regimen in treatment-naïve neovascular AMD patients in routine practice. This both retrospective and prospective study was conducted in four larger Swiss retina clinics (ASTERIA study). The primary endpoint was the mean change in best-corrected visual acuity (BCVA) in ETDRS letters from baseline to 12 months. Between December 2017 and August 2018, 160 patients were included. For patients with available data, the mean change in BCVA was + 8.4 (± 14.4) letters at month 12 (n = 139) and + 5.0 (± 11.4) letters at month 24 (n = 95). A mean number of 8.3 (± 2.4) injections were administered within the first year and 5.4 (± 2.9) injections during the second year. On average, the observed treatment interval at month 12 was 63.3 (± 22.0) days and increased to 69.1 (± 28.6) days at month 24. For 37% of the patients, a treatment interval ≥ 12 weeks was attained at month 24. In conclusion, intravitreal aflibercept in a Swiss real-life treat and extend regimen resulted in comparable anatomic and functional outcomes as were observed in the prospective registration trials of aflibercept for nAMD treatment.

The role of microglia in retinal inflammation is still ambiguous. Branch retinal vein occlusion initiates an inflammatory response whereby resident microglia cells are activated. They trigger infiltration of neutrophils that exacerbate blood–retina barrier damage, regulate postischemic inflammation and irreversible loss of neuroretina. Suppression of microglia‐mediated inflammation might bear potential for mitigating functional impairment after retinal vein occlusion (RVO). To test this hypothesis, we depleted microglia by PLX5622 (a selective tyrosine kinase inhibitor that targets the colony‐stimulating factor‐1 receptor) in fractalkine receptor reporter mice (Cx3cr1 gfp/+) subjected to various regimens of PLX5622 treatment and experimental RVO. Effectiveness of microglia suppression and retinal outcomes including retinal thickness as well as ganglion cell survival were compared to a control group of mice with experimental vein occlusion only. PLX5622 caused dramatic suppression of microglia. Despite vein occlusion, reappearance of green fluorescent protein positive cells was strongly impeded with continuous PLX5622 treatment and significantly delayed after its cessation. In depleted mice, retinal proinflammatory cytokine signaling was diminished and retinal ganglion cell survival improved by almost 50% compared to nondepleted animals 3 weeks after vein occlusion. Optical coherence tomography suggested delayed retinal degeneration in depleted mice. In summary, findings indicate that suppression of cells bearing the colony‐stimulating factor‐1 receptor, mainly microglia and monocytes, mitigates ischemic damage and salvages retinal ganglion cells. Blood–retina barrier breakdown seems central in the disease mechanism, and complex interactions between different cell types composing the blood–retina barrier as well as sustained hypoxia might explain why the protective effect was only partial., Main points Microglia have been depleted in ischemic retina by colony‐stimulating factor‐1 receptor inhibition (PLX5622).Three weeks after branch vein occlusion, depleted retinas showed increased retinal ganglion cell survival and delayed inner retina atrophy.

To compare drusen volume between Heidelberg Spectral Domain (SD-) and Zeiss Swept-Source (SS) PlexElite Optical Coherence Tomography (OCT) determined by manual and automated segmentation methods. Thirty-two eyes of 24 patients with Age-Related Macular Degeneration (AMD) and drusen maculopathy were included. In the central 1 and 3 mm ETDRS circle drusen volumes were calculated and compared. Drusen segmentation was performed using automated manufacturer algorithms of the two OCT devices. Then, the automated segmentation was manually corrected and compared and finally analyzed using customized software. Though on SD-OCT, there was a significant difference of mean drusen volume prior to and after manual correction (mean difference: 0.0188 &plusmn, 0.0269 mm3, p &lt, 0.001, corr. p &lt, 0.001, correlation of r = 0.90), there was no difference found on SS-OCT (mean difference: 0.0001 &plusmn, 0.0003 mm3, p = 0.262, corr. p = 0.524, r = 1.0). Heidelberg-acquired mean drusen volume after manual correction was significantly different from Zeiss-acquired drusen volume after manual correction (mean difference: 0.1231 &plusmn, 0.0371 mm3, p &lt, 0.001, r = 0.68). Using customized software, the difference of measurements between both devices decreased and correlation among the measurements improved (mean difference: 0.0547 &plusmn, 0.0744 mm3, p = 0.02, corr. p = 0.08, r = 0.937). Heidelberg SD-OCT, the Zeiss PlexElite SS-OCT, and customized software all measured significantly different drusen volumes. Therefore, devices/algorithms may not be interchangeable. Third-party customized software helps to minimize differences, which may allow a pooling of data of different devices, e.g., in multicenter trials.

Background To evaluate retinal ganglion cell (RGC) loss and axonal affection in branch retinal vein occlusion (BRVO).Methods 13 eyes of 12 non-glaucomatous BRVO patients were included. Thickness of peripapillary and macular retinal nerve fiber layer (pRNFL, mRNFL), ganglion cell-inner plexiform layer (GCIPL), inner nuclear layer, outer and total retina were measured at baseline and after a mean follow-up of 14 months. We compared the thickness between the affected and their internal reference regions. Additionally, pRNFL thickness was compared between the occluded and the healthy fellow eyes in the 11 unilateral cases.Results Significant degeneration of the pRNFL was observed in the affected sector of the BRVO eyes (P < 0.01 versus reference sector and versus fellow eye). In contrast, mRNFL and GCIPL thickness showed no difference between affected and reference regions and no correlation with pRNFL thickness. Degenerative microcystic macular edema (MME) was present in 25% of the eyes with macular edema following BRVO.Conclusion Axonal degeneration occurs in pRNFL, which suggests that anterograde degeneration is the mechanism of RGC affection in BRVO. Our results emphasized the importance of pRNFL monitoring in BRVO treatment, and considering degenerative MME in persistent edema following BRVO.

Selective retina therapy (SRT) is a short pulse (μs-regime) alternative to conventional laser photocoagulation (LPC) for treatment of retinal diseases. LPC leads to collateral damage of retinal layers adjacent to the retinal pigment epithelium (RPE), including healthy, non-regenerative photoreceptors due to the high thermal load, whereas in SRT, RPE cells are destroyed by microbubbles without damaging the neuronal retina. A novel experimental SRT laser operating at 532 nm wavelength can deliver 2 – 20 μs pulse sequences. Its tight integration into an upgraded diagnostic SPECTRALIS system combines beam control for treatment planning with real-time optical coherence tomography (OCT) overexposure protection of the photoreceptors. This “Spectralis Centaurus” system, was built and preliminary tested on porcine ex-vivo samples, reaching an unprecedented accuracy with unique planning and follow-up capabilities for upcoming clinical cellular level micro-surgery. The combination of OCT with SRT selectively limits cell death to the RPE by precisely controlling energy deposition while optically monitoring tissue response.

PURPOSE To investigate the prevalence and impact of ganglion cell layer cysts (GCLC) in patients with diabetic macular oedema (DME) under continuous anti-vascular endothelial growth factor (VEGF) therapy. METHODS The clinical findings and spectral domain optical coherence devices of baseline visits and follow-up after 12-24 and 36 months of DME patients under continuous anti-VEGF therapy were retrospectively collected and analysed for the impact of GCLC cysts. Previously established prognostic parameters were also assessed. RESULTS A total of 110 eyes of 110 DME patients (mean age 64 ± 10 years) were included. At baseline, 17% eyes had GCLC. With GCLC, the best-corrected visual acuity (BCVA) improvement was in mean 8.4 ± 2.4 Early-Treatment-Diabetic-Retinopathy-Study (ETDRS) letters less over the course of 36 months compared to the group lacking GCLC (p = 0.0009). Eyes with GCLC showed 68 ± 23.4 μm less central retinal thickness (CRT) decrease than eyes lacking GCLC (p

PURPOSE To assess whether iris-claw intraocular lenses (IOLs) undergo gravitation-dependent changes in position and refraction. SETTING Tertiary referral center, Bern, Switzerland. DESIGN Observational case study. METHODS Patients with a history of pars plana vitrectomy and IOL exchange with implantation of an aphakic iris-claw IOL (Artisan) were included in this study. Objective refraction was obtained with a handheld autorefractometer, and the IOL position was measured by ultrasound biomicroscopy with the patient prone, sitting, and supine. RESULTS Twenty-one eyes of 19 patients with retropupilary IOLs (13) or prepupillary IOLs (8) were included. The mean spherical equivalent (SE) in the sitting position was -0.81 diopter (D) ± 0.95 (SD), and the mean distance from the endothelium to the anterior edge of the IOL was 3.35 ± 0.72 mm. The mean SE in the supine position was -0.61 ± 1.28 D, whereas the mean SE in the prone position was -1.34 ± 1.17 D (P = .0030). The IOL position changed from 3.50 mm in the supine position to 3.06 mm in the prone position (P

PURPOSE To identify the prevalence and progression of macular atrophy (MA) in neovascular age-related macular degeneration (AMD) patients under long-term anti-vascular endothelial growth factor (VEGF) therapy and to determine risk factors. METHOD This retrospective study included patients with neovascular AMD and ≥30 anti-VEGF injections. Macular atrophy (MA) was measured using near infrared and spectral-domain optical coherence tomography (SD-OCT). Yearly growth rate was estimated using square-root transformation to adjust for baseline area and allow for linearization of growth rate. Multiple regression with Akaike information criterion (AIC) as model selection criterion was used to estimate the influence of various parameters on MA area. RESULTS Forty-nine eyes (47 patients, mean age 77 ± 14) were included with a mean of 48 ± 13 intravitreal anti-VEGF injections (ranibizumab:37 ± 11, aflibercept:11 ± 6, mean number of injections/year 8 ± 2.1) over a mean treatment period of 6.2 ± 1.3 years (range 4-8.5). Mean best-corrected visual acuity improved from 57 ± 17 letters at baseline (= treatment start) to 60 ± 16 letters at last follow-up. The MA prevalence within and outside the choroidal neovascularization (CNV) border at initial measurement was 45% and increased to 74%. Mean MA area increased from 1.8 ± 2.7 mm(2) within and 0.5 ± 0.98 mm(2) outside the CNV boundary to 2.7 ± 3.4 mm(2) and 1.7 ± 1.8 mm(2) , respectively. Multivariate regression determined posterior vitreous detachment (PVD) and presence/development of intraretinal cysts (IRCs) as significant factors for total MA size (R(2) = 0.16, p = 0.02). Macular atrophy (MA) area outside the CNV border was best explained by the presence of reticular pseudodrusen (RPD) and IRC (R(2) = 0.24, p = 0.02). CONCLUSION A majority of patients show MA after long-term anti-VEGF treatment. Reticular pseudodrusen (RPD), IRC and PVD but not number of injections or treatment duration seem to be associated with the MA size.

PURPOSE To evaluate macular retinal ganglion cell thickness in patients with neovascular age-related macular degeneration (AMD) and intravitreal anti-vascular endothelial growth factor (VEGF) therapy. DESIGN Retrospective case series with fellow-eye comparison METHODS: Patients with continuous unilateral anti-VEGF treatment for sub- and juxtafoveal neovascular AMD and a minimum follow-up of 24 months were included. The retinal nerve fiber (RNFL) and retinal ganglion cell layer (RGCL) in the macula were segmented using an ETDRS grid. RNFL and RGCL thickness of the outer ring of the ETDRS grid were quantified at baseline and after repeated anti-VEGF injections, and compared to the patients' untreated fellow eye. Furthermore, best-corrected visual acuity (BCVA), age, and retinal pigment epithelium (RPE) atrophy were recorded and correlated with RNFL and RGCL. RESULTS Sixty eight eyes of 34 patients (23 female and 11 male; mean age 76.7 (SD±8.2) with a mean number of 31.5 (SD ±9.8) anti-VEGF injections and a mean follow-up period of 45.3 months (SD±10.5) were included. Whereas the RGCL thickness decreased significantly compared to the non-injected fellow eye (p=0.01) the decrease of the RNFL was not significant. Visual acuity gain was significantly correlated with RGCL thickness (r=0.52, p

PURPOSE To identify individual retinal layer thickness changes associated with visual acuity gain in diabetic macular edema treated with ranibizumab using layer segmentation on high-resolution optical coherence tomography scans. METHODS Retrospective observational case series. Thirty-three treatment-naive eyes with diabetic macular edema were imaged by spectral domain optical coherence tomography at monthly visits while receiving intravitreal ranibizumab treatment as needed, guided by visual acuity. Thickness changes of individual layers after 1 year were quantitatively analyzed and correlated with visual acuity gain. RESULTS The mean best-corrected visual acuity improvement at 1 year was 6.2 (SEM ± 1.5) Early Treatment Diabetic Retinopathy Study letters, and central retinal thickness decreased by 66 ± 18 μm. In the central subfield, there was a significant decrease of thickness for all layers (P < 0.05) except the outer nuclear layer. Multiple linear regression analysis revealed that thickness decrease of the inner retina was associated with better visual acuity, whereas for the outer retina the opposite was true. The best estimate of final visual acuity (R = 0.817, P < 0.001) was obtained, by including baseline visual acuity and thickness change of the inner and outer plexiform layers in the model. CONCLUSION Whereas thickness decrease of the inner retina was positively associated with visual acuity gain, the opposite was found for the outer retina. This might be indirect evidence for recovery of the outer retina during ranibizumab treatment.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.

Although sutureless techniques for 20-gauge vitrectomy had previously been described, it was not until the advent of 25-gauge vitrectomy that transconjunctival sutureless vitrectomy became popular. The development of less invasive methods had been motivated by the desire to avoid typical complications of 20-gauge pars plana vitrectomy, spare the conjunctiva from scarring, and shorten procedural time. During the early stages of small gauge vitrectomy, the lack of stiffness and the limited range of the instruments provoked skepticism among retina specialists and dampened initial enthusiasm. However, ingenious design, improved materials and adaptation of operating techniques lately led to rapid progress and much improved performance of small gauge vitrectomy systems. In fact, some surgeons now use 27-gauge systems almost exclusively for nearly the entire spectrum of vitreoretinal pathology. This chapter discusses performance characteristics and limitations of some popular small gauge vitrectomy platforms. Handling techniques and tricks to avoid common complications specific to minimally invasive pars plana vitrectomy are explained.

In ophthalmology, retinal biological markers, or biomarkers, play a critical role in the management of chronic eye conditions and in the development of new therapeutics. While many imaging technologies used today can visualize these, Optical Coherence Tomography (OCT) is often the tool of choice due to its ability to image retinal structures in three dimensions at micrometer resolution. But with widespread use in clinical routine, and growing prevalence in chronic retinal conditions, the quantity of scans acquired worldwide is surpassing the capacity of retinal specialists to inspect these in meaningful ways. Instead, automated analysis of scans using machine learning algorithms provide a cost effective and reliable alternative to assist ophthalmologists in clinical routine and research. We present a machine learning method capable of consistently identifying a wide range of common retinal biomarkers from OCT scans. Our approach avoids the need for costly segmentation annotations and allows scans to be characterized by biomarker distributions. These can then be used to classify scans based on their underlying pathology in a device-independent way.

IMPORTANCE: Despite the unquestionable effectiveness of anti–vascular endothelial growth factor therapy (VEGF), there is ongoing controversy about potential systemic adverse effects. Besides the direct adverse effects of anti-VEGF agents, other factors associated with the injection itself, such as perioperative blood pressure fluctuations, may contribute to adverse events. OBJECTIVE: To determine blood pressure fluctuations during intravitreal injections. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational study at a tertiary referral center (Department of Ophthalmology, University Hospital Bern, Bern, Switzerland). Consecutive patients scheduled for intravitreal injections were recruited. Data were analyzed between October 2017 and January 2018. MAIN OUTCOMES AND MEASURES: Systolic and diastolic blood pressure, pulse rate, and oxygen saturation were recorded before, during, and after the intravitreal injection. An anxiety questionnaire was completed by all participants. Multivariate regression analysis was used to investigate potential factors associated with blood pressure rise during injections. RESULTS: Two hundred one patients (92 women and 109 men) were included in this study, with a mean age of 68 years (range, 18-93 years). Mean (SD) systolic blood pressure increased from a baseline of 150 (20) mm Hg to 162 (24) mm Hg following the preparation procedure to 168 (24) mm Hg during the injection (P

PURPOSE To evaluate the outcome of an exit strategy in a treat-and-extend regimen for neovascular age-related macular degeneration. METHODS Five hundred and ninety-eight eyes of 488 patients with neovascular age-related macular degeneration receiving intravitreal anti-vascular endothelial growth factor injections according to a treat-and-extend regimen were included in this retrospective study. A treat-and-extend regimen with either interval extension by 2 weeks or shortening by 1 week was used. "Exit criteria" were defined as 3 consecutive injections 16 weeks apart with stable findings after which the patient was exited from treatment and followed up at 3 to 4 monthly intervals without therapy. Best-corrected visual acuity, central retinal thickness at treatment initiation and termination, incidence of recurrence after treatment termination, presence of characteristics in the optical coherence tomography, duration of therapy, number and intervals of injections were analyzed. RESULTS Seventeen percent of all included eyes met the exit criteria. The mean number of anti-vascular endothelial growth factor injections was 23.7 ± 14.7 with a mean treatment duration of 4.5 ± 2.5 years. Twelve percent reached exit with the minimal number of injections. Thirteen percent had recurrent disease after a mean of 37 ± 16 weeks. In the subgroup with recurrent disease, rate of pigment epithelial detachment at treatment termination was significantly higher than without recurrence (77% vs. 30%, P = 0.0018) with a significant higher proportion of serous pigment epithelial detachment (31% vs. 7%, P = 0.0247). CONCLUSION The high percentage of patients meeting the exit criteria and the relatively low incidence of recurrences underline the usefulness of a predefined exit strategy. However, in a subgroup of patients, continuation of therapy may be advisable.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Background Microglia-associated inflammation is closely related to the pathogenesis of various retinal diseases such as uveitis and diabetic retinopathy, which are associated with increased vascular permeability. In this study, we investigated the effect of systemic lipopolysaccharide (LPS) exposure to activation and proliferation of retinal microglia /macrophages. Methods Balb/c and Cx3cr1gfp/+ mice were challenged with LPS (1 mg/kg) daily for four consecutive days. For microglia depletion, mice were treated with colony-stimulating factor 1 receptor (CSF-1R) inhibitor PLX5622 1 week before the first LPS challenge and until the end of the experiment. In vivo imaging of the retina was performed on days 4 and 7 after the first LPS challenge, using optical coherence tomography and fluorescein angiography. Flow cytometry analysis, retinal whole mount, and retinal sections were used to investigate microglia and macrophage infiltration and proliferation after LPS challenge. Cytokines were analyzed in the blood as well as in the retina. Data analysis was performed using unpaired t tests, repeated measures one-way ANOVA, or ordinary one-way ANOVA followed by Tukey’s post hoc analysis. Kruskal-Wallis test followed by Dunn’s multiple comparison tests was used for the analysis of non-normally distributed data. Results Repeated LPS challenge led to activation and proliferation of retinal microglia, infiltration of monocyte-derived macrophages into the retina, and breakdown of the blood-retina barrier (BRB) accompanied by accumulation of sub-retinal fluid. Using in vivo imaging, we show that the breakdown of the BRB is highly reproducible but transitory. Acute but not chronic systemic exposure to LPS triggered a robust release of inflammatory mediators in the retina with minimal effects in the blood plasma. Inhibition of the CSF-1R by PLX5622 resulted in depletion of retinal microglia, suppression of cytokine production in the retina, and prevention of BRB breakdown. Conclusions These findings suggest that microglia/macrophages play an important role in the pathology of retinal disorders characterized by breakdown of the BRB, and suppression of their activation may be a potential therapeutic target for such retinopathies. Electronic supplementary material The online version of this article (10.1186/s12974-018-1373-4) contains supplementary material, which is available to authorized users.

Neovascular age-related macular degeneration is one of the leading causes of blindness. Microglia and macrophages play a critical role in choroidal neovascularization (CNV) and may, therefore, be potential targets to modulate the disease course. This study evaluated the effect of the colony-stimulating factor-1 receptor inhibitor PLX5622 on experimental laser-induced CNV. A 98% reduction of retinal microglia cells was observed in the retina 1 week after initiation of PLX5622 treatment, preventing accumulation of macrophages within the laser site and leading to a reduction of leukocytes within the choroid after CNV induction. Mice treated with PLX5622 had a significantly faster decrease of the CNV lesion size, as revealed by in vivo imaging and immunohistochemistry from day 3 to day 14 compared with untreated mice. Several inflammatory modulators, such as chemokine (C-C motif) ligand 9, granulocyte-macrophage colony-stimulating factor, soluble tumor necrosis factor receptor-I, IL-1α, and matrix metallopeptidase-2, were elevated in the acute phase of the disease when microglia were ablated with PLX5622, whereas other cytokines (eg, interferon-γ, IL-4, and IL-10) were reduced. Our results suggest that colony-stimulating factor-1 receptor inhibition may be a novel therapeutic target in patients with neovascular age-related macular degeneration.

Purpose: We evaluated the repeatability of wide-field en face swept-source optical coherence tomography angiography (SS-OCTA) in healthy subjects. Methods: Healthy subjects underwent two imaging sessions, on average 8 days apart, with a 100 kHz SS-OCTA instrument. The imaging protocol included a central 3 × 3 and 12 × 12 mm scans of the four quadrants resulting in more than a 70° wide-field OCTA of the posterior pole. Quantitative analysis was performed using the inbuilt Macular Density Algorithm Version v0.6.1 and AngioTool software. Consistency for the foveal avascular zone (FAZ), vessel density, and perfusion density of the superficial and deep capillary plexus slabs and the wide-field OCTA superficial slab, and the number of artefacts on the wide-field images were assessed. Results: A total of 21 healthy volunteers (seven men and 14 women; mean age 32 years; range, 18-61; standard deviation, 10.28 years) were included in this analysis. Internal consistency was highest for FAZ area with an intraclass correlation (ICC) = 0.998 (95% confidence interval [CI], 0.997-0.999), a FAZ perimeter with an ICC = 0.995 (95% CI, 0.990-0.997), a FAZ circularity with an ICC= 0.976 (95% CI, 0.956-0.987), followed by the vessel density of the inner ring in the superficial slab with an ICC = 0.834 (95% CI, 0.691-0.911), and a vessel density of the inner ring in the deep slab with an ICC = 0.523 (95% CI, 0.113-0.744).The reproducibility of the average vessels length of the wide-field OCTA cropped images was strong (ICC = 0.801; 95% CI, 0.624-0.895), followed by the reproducibility of total number of junctions (ICC = 0.795; 95% CI, 0.613-0.892) and the vessels percentage area (ICC = 0.662; 95% CI, 0.361-0.821). Conclusions: The level of reproducibility for assessing the microvascular anatomy in wide-field OCTA is strong and can be used to quantify microvascular changes over time. Refinements in analysis strategies and a consensus of which parameters are most useful for quantitative assessment of wide-field OCTA images would be useful in the future. Translational Relevance: These findings bridge the gap between basic imaging research and clinical use for quantitative wide-field OCTA.

PURPOSE To analyze retinal blood flow before and after cataract surgery using swept-source optical coherence tomography angiography (SS-OCTA). METHODS Prospective observational study. Consecutive patients were recruited and scanned using SS-OCTA before and after cataract surgery. Laser flare photometry were performed post-surgery. Perfusion and vessel density of superficial (SCP) and deep capillary plexuses (DCP) of the 3 × 3 mm images as well as foveal avascular zone (FAZ) measurements were assessed. Vessel continuity, vessel visibility and presence of artefacts were evaluated by two blinded graders using a predefined grading protocol. RESULTS Thirteen eyes of 12 patients met the inclusion criteria. There was a significant increase of perfusion and vessel densities in both the SCP and the DCP after cataract surgery within the 3 × 3 mm images. Significantly better distinguishability of FAZ border was observed postoperatively in both SCP and DCP, however, FAZ area and perimeter measurements did not significantly change after cataract surgery. Mean number of motion artifacts in SCP and DCP numerically decreased by 37% (P = .089) and 42% (P = .080). CONCLUSIONS Lens opacities have a significant influence on retinal blood flow measurements in SS-OCTA and should be considered in quantitative vessel analysis. Inflammation may also impact the assessment of density parameters. FAZ measurements seems to be the most robust parameters in terms of media opacity.

Purpose: We investigate which spectral domain-optical coherence tomography (SD-OCT) setting is superior when measuring subfoveal choroidal thickness (CT) and compared results to an automated segmentation software. Methods: Thirty patients underwent enhanced depth imaging (EDI)-OCT. B-scans were extracted in six different settings (W+N = white background/normal contrast 9; W+H = white background/maximum contrast 16; B+N = black background/normal contrast 12; B+H = black background/maximum contrast 16; C+N = Color-encoded image on black background at predefined contrast of 9, and C+H = Color-encoded image on black background at high/maximal contrast of 16), resulting in 180 images. Subfoveal CT was manually measured by nine graders and by automated segmentation software. Intraclass correlation (ICC) was assessed. Results: ICC was higher in normal than in high contrast images, and better for achromatic black than for white background images. Achromatic images were better than color images. Highest ICC was achieved in B+N (ICC = 0.64), followed by B+H (ICC = 0.54), W+N, and W+H (ICC = 0.5 each). Weakest ICC was obtained with Spectral-color (ICC = 0.47). Mean manual CT versus mean computer estimated CT showed a correlation of r = 0.6 (P = 0.001). Conclusion: Black background with white image at normal contrast (B+N) seems the best setting to manually assess subfoveal CT. Automated assessment of CT seems to be a reliable tool for CT assessment. Translational Relevance: To define optimized OCT analysis settings to improve the evaluation of in vivo imaging.

AIMS To investigate the prognostic significance of macular capillary drop-out and previous panretinal laser photocoagulation in diabetic macular oedema treated with intravitreal ranibizumab. METHODS Retrospective observational case series. Treatment-naive patients with diabetic macular oedema that had been treated with intravitreal ranibizumab as per the RESTORE study protocol for at least 12 months were included. Some patients (n=15) had previous panretinal laser photocoagulation. Best-corrected visual acuity and central retina thickness were recorded monthly. The foveal avascular zone and the perifoveal capillaries were quantitatively and qualitatively assessed on fluorescein angiography on two occasions during the observational period. RESULTS From the 46 eyes (46 patients) in this study, 13 (28%) had evidence of perifoveal capillary drop-out. Central retinal thickness was significantly thinner at baseline (p=0.02) and throughout the study period in these eyes compared with those with normal perifoveal capillaries. Both groups responded with a significant gain of best-corrected visual acuity to ranibizumab treatment (7.6±3.3 and 6.3±1.3 ETDRS letters, respectively). Eyes with previous panretinal laser photocoagulation displayed a comparable final outcome regarding function and morphology, requiring a similar intensity of intravitreal injections. CONCLUSIONS Perifoveal capillary drop-out did not limit the gain of visual acuity from intravitreal ranibizumab treatment. The reduction of central retina thickness was similar to that seen in eyes with normal perifoveal capillaries. Central retinal thickness in eyes with perifoveal capillary drop-out was generally reduced. However, this did not affect their benefit from treatment. Ranibizumab did not increase the amount of perifoveal capillary loss.

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.

Spectral domain optical coherence tomography (SD-OCT) and scanning laser ophthalmoscopy (SLO) are extensively used in experimental ophthalmology. In the present protocol, mice expressing green fluorescent protein (gfp) under the promoter of Cx3cr1 (BALB/c-Cx3cr1gfp/gfp) were used to image microglia cells in vivo in the retina. Microglia are resident macrophages of the retina and have been implicated in several retinal diseases1,2,3,4,5,6. This protocol provides a detailed approach for generation of retinal B-scans, with SD-OCT, and imaging of microglia cell distribution in Cx3cr1gfp/gfp mice with SLO in vivo, using an ophthalmic imaging platform system. The protocol can be used in several reporter mouse lines. However, there are some limitations to the protocol presented here. First, both SLO and SD-OCT, when used in the high-resolution mode, collect data with high axial resolution but the lateral resolution is lower (3.5 µm and 6 µm, respectively). Moreover, the focus and saturation level in SLO is highly dependent on parameter selection and correct alignment of the eye. Additionally, using devices designed for human patients in mice is challenging due to the higher total optical power of the mouse eye compared to the human eye; this can lead to lateral magnification inaccuracies7, which are also dependent on the magnification by the mouse lens among others. However, despite that the axial scan position is dependent upon lateral magnification, the axial SD-OCT measurements are accurate8.

BACKGROUND: To report patients with age-related macular degeneration and atypical central retinal pigment epithelium (RPE) defects not attributable to geographic atrophy (GA) or RPE-tears with overlying preserved photoreceptor layers.METHODS: Multimodal imaging case-series evaluating the course of atypical RPE- defects in patients with AMD using Color fundus images, Optical coherence tomography (OCT), OCT-Angiography, fundus autofluorescence (FAF) and fluorescein-angiography (FA).RESULTS: Ten patients were identified. Three patients had a prior RPE-rip and were excluded. Seven patients with a mean follow-up period of 47 ± 38 months after the occurrence of the RPE-defect were included (age range 71-87 years). Mean distance Best corrected visual acuity (BCVA) at initial presentation was 0.36 ± 0.29logMAR and at last follow-up visit 0.51 ± 0.43logMAR. Patients presented with clinically apparent GA on funduscopy and FAF, but preserved photoreceptor layers on optical coherence tomography (OCT). On FA there was early hyperfluorescence and late pooling visible. Over time, migration of RPE/drusenoid material right above the Bruch's membrane with concomitant decrease of hypoautofluorescence was detectable in 4 cases. An enlargement of the RPE-defect was apparent in the remaining 3 cases. The majority (n = 4) showed a drusenoid pigment epithelium detachment (PED) preceding the lesion.CONCLUSIONS: Beside GA and characteristic RPE-tears, another atypical form of RPE-defect with overlying preserved photoreceptor layers are found in AMD. This so far disregarded subgroup of patients present with reasonable visual function and long-term survival of photoreceptors layers. Repair mechanisms such as ingrowth of RPE/drusenoid material and persistent subretinal fluid (SRF), but also a RPE-independent visual cycle for cone photopigment within the neurosensory retina may contribute to their favorable course.