Short-term-outcomes of idiopathic epiretinal membranes treated with pars-plana-vitrectomy - examination of visual function and OCT-morphology.

BACKGROUND: Epiretinal membranes (ERM) represent one of the most common findings in retinal examination. Structural changes of the retinal layers in patients with ERM can be visualized and classified using OCT. The purpose of this study is to evaluate structural and functional changes related to surgical treatment of ERM. METHODS: Monocentric retrospective analysis of 92 patients who underwent 23-gauge-pars plana vitrectomy (ppV) combined with cataract surgery for idiopathic ERM from 2015 to 2020. Visual acuity was determined directly preoperatively, at four weeks and three months postoperatively. Disease stage and tomographic biomarkers related to ERM were assessed in OCT imaging. RESULTS: 92 eyes of 92 patients were included. At the time of surgery, the mean patient age was 71 years. Visual acuity improved significantly by 2 lines postoperatively, on average from LogMar 0.4 to 0.2 (p < 0.001). Disease stage regressed from stage 3 to stage 2 postoperatively (p < 0.001). No patient had stage 4 postoperatively (n = 0). In the presence of preoperative intraretinal fluid, mean retinal thickness was 488 µm and decreased to 392 µm postoperatively (n = 32; p < 0.001). Preoperative presence of a Cotton Ball Sign (n = 30) was associated with better visual acuity (p = 0.009). This was also visible in patients with preoperative vitreomacular traction syndrome (p < 0.001). The presence of preoperative intraretinal fluid showed a tendency towards better disease staging after surgery (p = 0.080). CONCLUSION: Surgery was able to achieve visual improvement and morphological regression of the preoperative OCT findings related to ERM. ppV led to a reduction in retinal thickness and disease stage. The presence of the Cotton Ball Sign and vitreomacular traction was associated with better visual acuity in the follow-up period. In our cohort the preoperative presence of intraretinal fluid showed a tendency for better postoperative disease staging.

Characterizing Foveal Hypoplasia Using Optical Coherence Tomography Angiography: Evaluation of Microvascular Abnormalities and Clinical Significance.

This study aimed to evaluate foveal avascular zone (FAZ) features and macular flow density (FD) in various retinal layers in a cohort of patients with foveal hypoplasia (FH) using optical coherence tomography angiography (OCTA), in order to characterize microvascular abnormalities and explore their potential clinical significance. FAZ parameters and FD, as well as retinal thickness and volume values were analyzed and compared between patients with FH and an age- and gender-matched control cohort. Correlations between disease severity and visual acuity (VA), as well as between disease severity and FAZ features were evaluated. A total of 19 eyes with FH and 19 control eyes were included. The study group showed significantly higher FD values in the foveal sectors of the superficial and deep capillary plexus compared to controls. FAZ area, perimeter, and acircularity index (ACI) were noticeably altered in eyes with FH; however, they did not correlate with disease severity. Visual acuity was negatively correlated with disease severity. The results of this study provide evidence of altered microvasculature architecture specifically in the foveal sectors of patients with FH. The higher FD values in the foveal sectors of FH patients suggest a potential compensatory response of the retinal microvasculature. FAZ parameters and FD values of the foveal sectors could be used as part of an OCTA-based grading system in FH patients.

Descemet Membrane Endothelial Keratoplasty (DMEK) Reduces the Corneal Epithelial Thickness in Fuchs' Patients.

Fuchs' endothelial corneal dystrophy (FECD) is the occurrence of corneal edema due to endothelial cell dystrophy. Descemet membrane endothelial keratoplasty (DMEK) is considered to be the gold standard of treatment. The aim of this study was to investigate the changes in the corneal epithelial thickness of FECD patients before and after DMEK and to compare these results with a healthy control cohort. In this retrospective analysis, 38 eyes of patients with FECD that were treated with DMEK and 35 healthy control eyes received anterior segment optical coherence tomography (OCT; Optovue, XR-Avanti, Fremont, CA, USA). The corneal epithelial thicknesses in different locations were analyzed and compared between the preoperative, postoperative, and control cohorts. The median follow-up time was 9 months. There was a significant degression of the mean epithelial thickness after DMEK in the central, paracentral, and mid-peripheral zones (p < 0.01) of the cornea. The total corneal thickness and stromal thickness decreased significantly as well. No significant differences were observed between the postoperative and control cohorts. In conclusion, the FECD patients had an increased epithelial thickness compared to the healthy controls, which decreased significantly after DMEK and reached thickness levels comparable to those of healthy control eyes. This study emphasized the importance of distinguishing between the corneal layers in anterior segment pathologies and surgical procedures. Moreover, it accentuated the fact that the structural alterations in FECD extend beyond the corneal stroma.

High-Precision Optical Coherence Tomography Navigated Laser Retinopexy for Retinal Breaks.

The prevalent cause of retinal detachment is a full-thickness retinal break and the ingress of fluid into the subretinal space. To prevent progression of the detachment, laser photocoagulation (LPC) lesions are placed around the break in clinical practice to seal the tissue. Unlike the usual application under indirect ophthalmoscopy, we developed a semi-automatic treatment planning software based on a sequence of optical coherence tomography (OCT) scans to perform navigated LPC treatment. The depth information allows demarcation of the border where the neurosensory retina is still attached to the retinal pigment epithelium (RPE), which is critical for prevention of detachment progression. To evaluate the method, artificially provoked retinal breaks were treated in seven ex-vivo porcine eyes. Treatment outcome was assessed by fundus photography and OCT imaging. The automatically applied lesions surrounding each detachment (4.4-39.6 mm2) could be identified as highly scattering coagulation regions in color fundus photography and OCT. Between the planned and applied pattern, a mean offset of 68 µm (SD ± 16.5 µm) and a mean lesion spacing error of 5 µm (SD ± 10 µm) was achieved. The results demonstrate the potential of navigated OCT-guided laser retinopexy to improve overall treatment accuracy, efficiency, and safety.

U-Net-Based Segmentation of Current Imaging Biomarkers in OCT-Scans of Patients with Age Related Macular Degeneration.

Age-related macular degeneration (AMD) is the leading cause of blindness in the Western world. In this work, the non-invasive imaging technique spectral domain optical coherence tomography (SD-OCT) is used to acquire retinal images, which are then analyzed using deep learning techniques. The authors trained a convolutional neural network (CNN) using 1300 SD-OCT scans annotated by trained experts for the presence of different biomarkers associated with AMD. The CNN was able to accurately segment these biomarkers and the performance was further enhanced through transfer learning with weights from a separate classifier, trained on a large external public OCT dataset to distinguish between different types of AMD. Our model is able to accurately detect and segment AMD biomarkers in OCT scans, which suggests that it could be useful for prioritizing patients and reducing ophthalmologists' workloads.

FURTHER EVIDENCE AGAINST BILATERAL MANIFESTATION OF COATS DISEASE IN OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY OF THE MACULA.

PURPOSE: Recent studies have questioned the traditional view, which regards Coats disease as a strictly unilateral entity. Applying optical coherence tomography angiography, this prospective, monocentric study investigates quantitative capillary changes of the macula associated with Coats disease. METHODS: Twenty-four eyes (4 untreated, 8 pre-treated) of 12 patients with stage 2 Coats disease (age range: 9-61 years) and 15 eyes of healthy, age-matched controls from the University of Muenster Medical Center, Germany received macular optical coherence tomography angiography measurements of the superficial, deep, and choriocapillary capillary plexus. Flow density and parameters related to the foveal avascular zone were compared between Coats eyes and fellow eyes, and between fellow eyes and control eyes. Additional subanalyses investigated changes based on disease stage. RESULTS: Flow density did not differ between fellow eyes of Coats disease patients and control eyes in any of the parameters investigated. Comparison of Coats eyes to their respective fellow eyes revealed Coats disease to be associated with lower flow density in superficial, deep, and choriocapillary capillary plexus regions, irrespective of disease stage (all P < 0.03). There were no noticeable differences regarding the size or symmetry of the foveal avascular zone. CONCLUSION: In light of the recent discussion around the unilateral character of Coats disease, this trial provides evidence against a bilateral presentation of vascular changes in the macula.

A rabbit model for outer retinal atrophy caused by surgical RPE removal.

PURPOSE: We aimed to establish a rabbit model with retinal atrophy induced by an iatrogenic retinal pigment epithelium (RPE) removal, for future testing of the efficacy and safety of cell therapy strategies. METHODS: A localized detachment of the retina from the RPE/choroid layer was created in 18 pigmented rabbits. The RPE was removed by scraping with a custom-made extendable loop instrument. The resulting RPE wound was observed over a time course of 12 weeks with optical coherence tomography and angiography. After 4 days (group 1) and 12 weeks (group 2), histology was done and staining with hematoxylin and eosin, as well as immunofluorescence performed to further investigate the effects of debridement on the RPE and the overlying retina. RESULTS: Already after 4 days, we observed a closure of the RPE wound by proliferating RPE and microglia/macrophage cells forming a multilayered clump. This pattern continued over the observation time course of 12 weeks, whereby the inner and outer nuclear layer of the retina became atrophic. No neovascularization was observed in the angiograms or histology. The observed changes were limited to the site of the former RPE wound. CONCLUSIONS: Localized surgical RPE removal induced an adjacent progressive retinal atrophy. Altering the natural course of this model may serve as a basis to test RPE cell therapeutics.

Idiopathic Epiretinal Membranes - Pathophysiology, Classifications and OCT-Biomarkers. / Idiopathische epiretinale Membranen ­ Pathophysiologie, Klassifikationen und OCT-Biomarker.

Epiretinal membranes (ERMs) are a common finding in patients with increasing age. Diagnosis and treatment of ERMs have changed dramatically in recent years due to technological advances in ophthalmological care. In recent years, tomographic imaging has allowed for accurate visualization of ERMs and contributed to the growing understanding of the pathophysiology of this condition. The literature review conducted here summarizes recent innovations in diagnosis, classification, and treatment of idiopathic ERMs and specifically addresses novel optical coherence tomography (OCT) biomarkers that allow for the generation of prognoses regarding the clinical postoperative outcome.

SALUS-a non-inferiority trial to compare self-tonometry in glaucoma patients with regular inpatient intraocular pressure controls: study design and set-up.

PURPOSE: The SALUS study aims to improve the healthcare situation for glaucoma patients in Germany. In order to detect diurnal intraocular pressure (IOP) fluctuations, inpatient monitoring of IOP in an eye hospital for a minimum of 24 h is the current standard. SALUS assesses the benefits of a new form of outpatient care, where IOP can be measured by the patients themselves at home using a self-tonometer. This approach should promote the patient's health competence and empowerment within the healthcare system while reducing treatment costs. METHODS: The SALUS study is a randomized controlled, open non-inferiority trial, alongside an economic analysis, determining whether outpatient monitoring of IOP with self-tonometry is at least as effective as current standard care and would reduce treatment costs. Participants (n = 1980) will be recruited by local ophthalmologists in the area of Westphalia-Lippe, Germany, and randomized to receive 7-day outpatient or 24-h inpatient monitoring. Participants in both study arms will also receive 24-h blood pressure monitoring. Furthermore, patient data from both study groups will be collected in an electronic case file (ECF), accessible to practitioners, hospitals, and the study participants. The primary endpoint is the percentage of patients with IOP peaks, defined as levels 30% above the patient-specific target pressure. Data will also be collected during initial and final examinations, and at 3, 6, and 9 months after the initial examination. RESULTS: The study implementation and trial management are represented below. CONCLUSION: SALUS is a pioneering prospective clinical trial focused on the care of glaucoma patients in Germany. If SALUS is successful, it could improve the healthcare situation and health literacy of the patients through the introduction of various telemedical components. Furthermore, the approach would almost certainly reduce the treatment costs of glaucoma care. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT04698876, registration date: 11/25/2020. DRKS-ID: DRKS00023676, registration date: 11/26/2020.

Systemic Curcumin-Human Serum Albumin in Proliferative Vitreoretinal Retinopathy: A Pilot Study.

Objectives The purpose of this study is to compare the risks of novel postoperative curcumin infusion in patients with increased proliferative vitreoretinal retinopathy (PVR) after retinal detachment with steroid infusion or no treatment. Methods This was a prospective, non-randomized pilot study of 15 eyes of 15 patients (mean age 68 ± 7 years) with retinal detachment, macula off, and flare >15 pc/ms. Postoperatively, the patients received either curcumin-HSA (human serum albumin) infusion (C, n=5), prednisolone infusion (P, n=5), or no therapy (N, n=5) for three days. The outcome measures included postoperative PVR rate, the number of vitreoretinal surgeries (VRS) required, epiretinal membrane development, and visual acuity (VA).  Results All patients had a preoperative VA of hand movements, macula-off detachment situation, and two quadrants rhegmatogenous retinal detachment. Patients underwent VRS at a mean time of 5.6 ± 1.5 (C), 4.9 ± 2.0 (P), 4.7 ± 1.2 (N) days after first recognized symptoms. Postoperative PVR developed just in one eye (P) after 16 days and required VRS due to PVR retinal detachment. The remaining 14 patients of group C and N did not develop PVR. BCVA improved six months post surgery to 0.56 ± 0.31 (P), 0.53 ± 0.19 (D), 0.53 ± 0.17 (N) logMAR. There were no side effects nor complications related to the postoperative infusions.  Conclusions In this pilot study, we demonstrated that a postoperative application of curcumin infusion is a safe option in patients with an increased risk of PVR. Whether or not PVR can be reduced by curcumin infusion would require to be investigated in larger, randomized clinical trials.

Selective Large-Area Retinal Pigment Epithelial Removal by Microsecond Laser in Preparation for Cell Therapy.

Purpose: Cell therapy is a promising treatment for retinal pigment epithelium (RPE)-associated eye diseases such as age-related macular degeneration. Herein, selective microsecond laser irradiation targeting RPE cells was used for minimally invasive, large-area RPE removal in preparation for delivery of retinal cell therapeutics. Methods: Ten rabbit eyes were exposed to laser pulses 8, 12, 16, and 20 µs in duration (wavelength, 532 nm; top-hat beam profile, 223 × 223 µm²). Post-irradiation retinal changes were assessed with fluorescein angiography (FA), indocyanine green angiography (ICGA), and optical coherence tomography (OCT). RPE viability was evaluated with an angiographic probit model. Following vitrectomy, a subretinal injection of balanced salt solution was performed over a lasered (maximum 13.6 mm2) and untreated control area. Bleb retinal detachment (bRD) morphology was then evaluated by intraoperative OCT. Results: Within 1 hour after irradiation, laser lesions showed FA and ICGA leakage. OCT revealed that large-area laser damage was limited to the RPE. The angiographic median effective dose irradiation thresholds (ED50) were 45 µJ (90 mJ/cm2) at 8 µs, 52 µJ (104 mJ/cm2) at 12 µs, 59 µJ (118 mJ/cm2) at 16 µs, and 71 µJ (142 mJ/cm2) at 20 µs. Subretinal injection over the lasered area resulted in a controlled, shallow bRD rise, whereas control blebs were convex in shape, with less predictable spread. Conclusions: Large-area, laser-based removal of host RPE without visible photoreceptor damage is possible and facilitates surgical retinal detachment. Translational Relevance: Selective microsecond laser-based, large-area RPE removal prior to retinal cell therapy may reduce iatrogenic trauma.

Submacular integration of hESC-RPE monolayer xenografts in a surgical non-human primate model.

BACKGROUND: Human pluripotent stem cells (hPSCs) provide a promising cell source for retinal cell replacement therapy but often lack standardized cell production and live-cell shipment logistics as well as rigorous analyses of surgical procedures for cell transplantation in the delicate macula area. We have previously established a xeno- and feeder cell-free production system for hPSC differentiated retinal pigment epithelial (RPE) cells, and herein, a novel immunosuppressed non-human primate (NHP) model with a disrupted ocular immune privilege is presented for transplanting human embryonic stem cell (hESC)-derived RPE on a scaffold, and the safety and submacular graft integration are assessed. Furthermore, the feasibility of intercontinental shipment of live hESC-RPE is examined. METHODS: Cynomolgus monkeys were systemically immunosuppressed and implanted with a hESC-RPE monolayer on a permeable polyester-terephthalate (PET) scaffold. Microscope-integrated intraoperative optical coherence tomography (miOCT)-guided surgery, postoperative follow-up incorporated scanning laser ophthalmoscopy, spectral domain (SD-) OCT, and full-field electroretinography (ERG) were used as outcome measures. In addition, histology was performed after a 28-day follow-up. RESULTS: Intercontinental cell shipment, which took >30 h from the manufacturing to the transplantation site, did not alter the hESC-RPE quality. The submacular hESC-RPE xenotransplantation was performed in 11 macaques. The miOCT typically revealed foveal disruption. ERG showed amplitude and peak time preservation in cases with favorable surgical outcomes. Histology confirmed photoreceptor preservation above the grafts and in vivo phagocytosis by hESC-RPE, albeit evidence of cytoplasmic redistribution of opsin in photoreceptors and glia hypertrophy. The immunosuppression protocol efficiently suppressed retinal T cell infiltration and microglia activation. CONCLUSION: These results suggest both structural and functional submacular integrations of hESC-RPE xenografts. It is anticipated that surgical technique refinement will further improve the engraftment of macular cell therapeutics with significant translational relevance to improve future clinical trials.

REVISED PREDICTIVE BIOMARKER FOR OCRIPLASMIN THERAPY IN VITREOMACULAR TRACTION DISORDERS.

PURPOSE: To determine a statistically optimal limit of adhesion size in vitreomacular traction (VMT) syndrome for ocriplasmin treatment. METHODS: In this retrospective, consecutive, interventional study, we included 106 patients treated with ocriplasmin injection because of VMT between July 2013 and January 2018. A univariate and multivariate risk analysis was performed with grouped factors and continuous factors. We used a receiver operating characteristic curve to measure the prognostic relevance of each continuous factor for therapy success and determined the statistically optimal cutoff value at which specificity and sensitivity are simultaneously maximized. RESULTS: Among the grouped factors, only a phakic lens status showed a highly significant positive influence on the resolution of the VMT. For the continuous factors, only the adhesion diameter before injection was a good predictor of anatomical success. The statistically optimal threshold value for the adhesion size was calculated to be 480 µm. Eyes below this limit had a 6.84-fold better chance of VMT resolution compared with eyes with a larger adhesion diameter. CONCLUSION: The threshold value of the VMT diameter for ocriplasmin therapy could be statistically defined as 480 µm and may thus be a new quantitative biomarker to predict treatment success.

Ophthalmic Outpatient and Inpatient Care Under Pandemic Conditions: Hygiene, Triage and New Challenges. / Ambulante und stationäre Augenheilkunde unter Pandemiebedingungen: Hygiene, Triage und neue Herausforderungen.

BACKGROUND: The progression of the COVID-19 pandemic has caused significant changes in the environment for outpatient and inpatient care in ophthalmology, with limitations on access to medical care but also new observations and challenges. We now describe major developments in recent months and provide an outlook on the expected consequences. METHODS: PubMed literature search, clinical survey. RESULTS: To date, the course of the COVID-19 pandemic has been characterised by several new but overall rare ocular manifestations, the ophthalmological shared management of COVID-19 patients on intensive care units, and a significant decrease in case numbers, associated with an increase in case severity and relative proportion of emergencies, as a result of delayed presentation of patients and reduced treatment adherence. With the introduction of hygiene measures and infection control procedures, ophthalmic patient care was maintained - including emergencies and urgent treatments. Due to the extensive postponement of elective surgeries, scarce therapeutic and health care professional resources, and the prioritisation of critically ill patients from other specialties, there is a reasonable likelihood that urgent treatments will be delayed as infection rates rise. CONCLUSION: Outpatient and inpatient care in ophthalmology during the COVID-19 pandemic is primarily accompanied by additional organisational or medical challenges and a decline in case volume. Although to date emergency and urgent ophthalmic treatments have been maintained, long-term persistence of pandemic conditions will require additional strategies to provide continuation of ophthalmic care at the required level.

[Microbiological and infectious disease aspects of postoperative endophthalmitis]. / Mikrobiologische und infektiologische Aspekte der postoperativen Endophthalmitis.

Infectious postoperative or postinjection endophthalmitis is a medical emergency. Gram-positive bacteria, such as staphylococci, streptococci and enterococci are the predominant causative agents, whereas Gram-negative pathogens (e.g. Klebsiella pneumoniae, Pseudomonas aeruginosa) and fungi account for a minority of cases. Using modern diagnostic tools, which include polymerase chain reaction-based assays in addition to Gram staining and agar culturing, a causal agent can be detected in the majority of cases, which enables a targeted treatment and estimation of the prognosis. Endophthalmitis is treated with intravitreal and often also intravenous administration of antibiotics, with the combination of vancomycin and ceftazidime being most commonly used. This article presents and summarizes recent developments in the microbiological etiology and diagnostics of endophthalmitis as well as treatment options and perioperative antibiotic prophylaxis in the light of emerging resistance patterns.

Assessment of Macular Function Following Internal Limiting Membrane Peeling With ILM Blue®.

Purpose To evaluate clinical outcome after surgery of idiopathic epiretinal membranes (ERM) with internal limiting membrane (ILM) peeling using a commercial combination of Brilliant blue G (BBG, 0.25 mg/ml) with 4% polyethylene glycol (PEG). Methods It was a prospective, single-center study. Macular surgery was performed due to ERM (n = 18) by two experienced surgeons. Exclusion criteria were secondary ERM, previous retinal surgery and pharmacological treatment. Best-corrected visual acuity (BCVA), optical coherence tomography (OCT), and multifocal ERG (RETIscan) were assessed at baseline and three months after surgery. Results The BCVA improved from baseline 0.4 ± 0.13 logMAR to 0.3 ± 0.2 logMAR after three months (p > 0.05). The mean central foveal thickness was reduced from 407 ± 85 µm to 366 ± 56 µm after three months (p > 0.05). At baseline, the mean P1 amplitude (nV/deg2) was 53.5 ± 32.1 in ring 1 and 35.9 ± 20.1 in ring 2. Three months after surgery the mean P1 amplitude was comparable with 57.2 ± 16.3 in ring 1 and 38.0 ± 11.7 in ring 2 compared with the initial situation (p = 0.22 and p = 0.3, respectively). Conclusion BBG with 4% PEG can be used for ILM peeling in patients with idiopathic epiretinal membranes without any sign of short-term toxicity.

Surgical Approaches for Cell Therapeutics Delivery to the Retinal Pigment Epithelium and Retina.

Developing successful surgical strategies to deliver cell therapeutics to the back of the eye is an essential pillar to success for stem cell-based applications in blinding retinal diseases. Within this chapter, we have attempted to gather all key considerations during preclinical animal trials.Guidance is provided for choices on animal models, options for immunosuppression, as well as anesthesia. Subsequently we cover surgical strategies for RPE graft delivery, both as suspension as well as in monolayers in small rodents, rabbits, pigs, and nonhuman primate. A detailed account is given in particular on animal variations in vitrectomy and subretinal surgery, which requires a considerable learning curve, when transiting from human to animal. In turn, however, many essential subretinal implantation techniques in large-eyed animals are directly transferrable to human clinical trial protocols.A dedicated subchapter on photoreceptor replacement provides insights on preparation of suspension as well as sheet grafts, to subsequently outline the basics of subretinal delivery via both the transscleral and transvitreal route. In closing, a future outlook on vision restoration through retinal cell-based therapeutics is presented.