European Glaucoma Society research priorities for glaucoma care.

BACKGROUND/AIMS: The goal of health research is to improve patients care and outcomes. Thus, it is essential that research addresses questions that are important to patients and clinicians. The aim of this study was to develop a list of priorities for glaucoma research involving stakeholders from different countries in Europe. METHODS: We used a three-phase method, including a two-round electronic Delphi survey and a workshop. The clinician and patient electronic surveys were conducted in parallel and independently. For phase I, the survey was distributed to patients from 27 European countries in 6 different languages, and to European Glaucoma Society members, ophthalmologists with expertise in glaucoma care, asking to name up to five research priorities. During phase II, participants were asked to rank the questions identified in phase I using a Likert scale. Phase III was a 1 day workshop with patients and clinicians. The purpose was to make decisions about the 10 most important research priorities using the top 20 priorities identified by patients and clinicians. RESULTS: In phase I, 308 patients and 150 clinicians were involved. In phase II, the highest-ranking priority for both patients and clinicians was 'treatments to restore vision'. In phase III, eight patients and four clinicians were involved. The top three priorities were 'treatments to stop sight loss', 'treatments to restore vision' and 'improved detection of worsening glaucoma'. CONCLUSION: We have developed a list of priorities for glaucoma research involving clinicians and patients from different European countries that will help guide research efforts and investment.

A prototype protocol for evaluating the real-world data set using a structured electronic health record in glaucoma.

PURPOSE: As the first step in monitoring and evaluating day-to-day glaucoma care, this study reports all real-world data recorded during the first full year after the implementation of a prototype for glaucoma-specific structured electronic healthcare record (EHR). METHODS: In 2019, 4618 patients visited Tays Medical Glaucoma Clinic at Tays Eye Centre, Tampere University Hospital, Finland, that serves a population of 0.53 M. Patient data were entered into a glaucoma-specific EHR by trained nurses to be checked by glaucoma specialists. Tays Eye Centre follows the Finnish Current Care Guideline for glaucoma in which glaucoma is defined using a '2 out of 3' rule, that is, ≥2 findings evaluated as glaucomatous in optic nerve head (ONH), retinal nerve fibre layer (RNFL) and visual field (VF). RESULTS: The clinical evaluations of ONH, RNFL and VF were recorded in 95%-100% of all eyes. ONH was evaluated as glaucomatous more often (44%) than RNFL (33%) and VF tests (30%). Progressive changes in any of the three tests were recorded in 35% of the '≥2/3 glaucoma group' compared to 2%-9% in the other groups. The mean IOP at visit was 15 mmHg. The mean target IOP was 17 mmHg, and it was recorded in 94% of eyes. CONCLUSION: The developed structured data presentation enables comparisons between different population-based real-world glaucoma data sets and glaucoma clinics. Compared to a data set from the UK, the proportion of glaucoma suspicion-related visits was smaller in Tays Eye Centre and test intervals were longer.

European Glaucoma Society - A guide on surgical innovation for glaucoma.

PROLOGUE: Glaucoma surgery has been, for many decades now, dominated by the universal gold standard which is trabeculectomy augmented with antimetabolites. Tubes also came into the scene to complement what we use to call conventional or traditional glaucoma surgery. More recently we experienced a changing glaucoma surgery environment with the "advent" of what we have become used to calling Minimally Invasive Glaucoma Surgery (MIGS). What is the unmet need, what is the gap that these newcomers aim to fill? Hippocrates taught us "bring benefit, not harm" and new glaucoma techniques and devices aim to provide safer surgery compared to conventional surgery. For the patient, but also for the clinician, safety is important. Is more safety achieved with new glaucoma surgery and, if so, is it associated with better, equivalent, or worse efficacy? Is new glaucoma surgery intended to replace conventional surgery or to complement it as an 'add-on' to what clinicians already have in their hands to manage glaucoma? Which surgery should be chosen for which patient? What are the options? Are they equivalent? These are too many questions for the clinician! What are the answers to the questions? What is the evidence to support answers? Do we need more evidence and how can we produce high-quality evidence? This EGS Guide explores the changing and challenging glaucoma surgery environment aiming to provide answers to these questions. The EGS uses four words to highlight a continuum: Innovation, Education, Communication, and Implementation. Translating innovation to successful implementation is crucially important and requires high-quality evidence to ensure steps forward to a positive impact on health care when it comes to implementation. The vision of EGS is to provide the best possible well-being and minimal glaucomainduced visual disability in individuals with glaucoma within an affordable healthcare system. In this regard, assessing the changes in glaucoma surgery is a pivotal contribution to better care. As mentioned, this Guide aims to provide answers to the crucial questions above. However, every clinician is aware that answers may differ for every person: an individualised approach is needed. Therefore, there will be no uniform answer for all situations and all patients. Clinicians would need, through the clinical method and possibly some algorithm, to reach answers and decisions at the individual level. In this regard, evidence is needed to support clinicians to make decisions. Of key importance in this Guide is to provide an overview of existing evidence on glaucoma surgery and specifically on recent innovations and novel devices, but also to set standards in surgical design and reporting for future studies on glaucoma surgical innovation. Designing studies in surgery is particularly challenging because of many subtle variations inherent to surgery and hence multiple factors involved in the outcome, but even more because one needs to define carefully outcomes relevant to the research question but also to the future translation into clinical practice. In addition this Guide aims to provide clinical recommendations on novel procedures already in use when insufficient evidence exists. EGS has a long tradition to provide guidance to the ophthalmic community in Europe and worldwide through the EGS Guidelines (now in their 5th Edition). The EGS leadership recognized that the changing environment in glaucoma surgery currently represents a major challenge for the clinician, needing specific guidance. Therefore, the decision was made to issue this Guide on Glaucoma Surgery in order to help clinicians to make appropriate decisions for their patients and also to provide the framework and guidance for researchers to improve the quality of evidence in future studies. Ultimately this Guide will support better Glaucoma Care in accordance with EGS's Vision and Mission. Fotis Topouzis EGS President

Ten-year real-world outcomes of antivascular endothelial growth factor therapy in neovascular age-related macular degeneration using pro re nata regimen.

BACKGROUND/AIMS: To analyse long-term outcomes of antivascular endothelial growth factor (anti-VEGF) therapy for the treatment of neovascular age-related macular degeneration (nAMD) using pro re nata (PRN) regimen in a single-centre clinical practice. METHODS: All patients receiving intravitreal injection (IVI) for nAMD between 1 January 2008 and 31 December 2020 were searched from electronic medical records. All 3844 treatment-naïve eyes of 3008 patients were included with a total of 50 146 IVIs (87% bevacizumab) administered. Main outcome measures were mean change in visual acuity (VA) from baseline, proportion of eyes within 15 letters of baseline, proportion of eyes with VA ≥20/40 Snellen and ≤20/200 Snellen, number of annual visits and number of annual IVIs. RESULTS: The mean baseline VA was 55 Early Treatment Diabetic Retinopathy Study (ETDRS) letters and the mean change in VA from baseline was +2, +2, ±0, -2, -2 and -4 ETDRS letters at year 1, 2, 3, 5, 7 and 10, respectively. Proportions of eyes within 15 letters of baseline were 88%, 87%, 82%, 80%, 76% and 72% at the end of years 1, 2, 3, 5, 7 and 10, respectively. The median number of annual IVI was 6 at years 1-7 and 5 at year 10. The median number of annual total visits was 10 at year 1, 9 at years 2-7 and 8 at year 10, respectively. CONCLUSIONS: VA was maintained short-term and long-term with anti-VEGF therapy using PRN treatment regimen.

A generalizable deep learning regression model for automated glaucoma screening from fundus images.

A plethora of classification models for the detection of glaucoma from fundus images have been proposed in recent years. Often trained with data from a single glaucoma clinic, they report impressive performance on internal test sets, but tend to struggle in generalizing to external sets. This performance drop can be attributed to data shifts in glaucoma prevalence, fundus camera, and the definition of glaucoma ground truth. In this study, we confirm that a previously described regression network for glaucoma referral (G-RISK) obtains excellent results in a variety of challenging settings. Thirteen different data sources of labeled fundus images were utilized. The data sources include two large population cohorts (Australian Blue Mountains Eye Study, BMES and German Gutenberg Health Study, GHS) and 11 publicly available datasets (AIROGS, ORIGA, REFUGE1, LAG, ODIR, REFUGE2, GAMMA, RIM-ONEr3, RIM-ONE DL, ACRIMA, PAPILA). To minimize data shifts in input data, a standardized image processing strategy was developed to obtain 30° disc-centered images from the original data. A total of 149,455 images were included for model testing. Area under the receiver operating characteristic curve (AUC) for BMES and GHS population cohorts were at 0.976 [95% CI: 0.967-0.986] and 0.984 [95% CI: 0.980-0.991] on participant level, respectively. At a fixed specificity of 95%, sensitivities were at 87.3% and 90.3%, respectively, surpassing the minimum criteria of 85% sensitivity recommended by Prevent Blindness America. AUC values on the eleven publicly available data sets ranged from 0.854 to 0.988. These results confirm the excellent generalizability of a glaucoma risk regression model trained with homogeneous data from a single tertiary referral center. Further validation using prospective cohort studies is warranted.

Glaucoma progression in patients receiving intravitreal anti-VEGF treatment for neovascular age-related macular degeneration.

PURPOSE: The purpose of this study was to investigate how often glaucoma and neovascular age-related macular degeneration (nAMD) occur in the same patient and to evaluate whether glaucoma progression is faster in eyes treated with intravitreal anti-VEGF medications for nAMD. METHODS: This single-centre retrospective real-world data (RWD) consists of medical records of 6314 glaucoma and 2166 nAMD patients treated in 2008-2017 in Tays Eye Centre, Finland. To study glaucoma progression, changes in visual fields (mean deviation [MD], dB/year), IOP (mmHg/year) and fundus photographs (progression, yes/no) were compared in glaucoma eyes with and without anti-VEGF treatment for nAMD and ≥1 year follow-up. RESULTS: During the 10-year period, 147 patients with glaucoma received intravitreal anti-VEGF treatment for nAMD corresponding to 2% of glaucoma and 7% of nAMD patients. The mean change in MD was -0.70 dB/year (SD 1.8) vs. -0.27 dB/year (SD 1.7) (p = 0.027) in glaucoma eyes with (n = 37) and without (n = 4304) anti-VEGF injections, respectively. In patients with bilateral glaucoma and unilateral nAMD treated with anti-VEGF injections (n = 20), MD declined at -0.62 dB/year (SD 1.9) vs 0.33 dB/year (SD 1.5) (p = 0.654), and glaucoma progression was detected in 14/20 vs 10/20 (p = 0.219) fundus photographs in eyes with anti-VEGF treatment compared with their untreated fellow eyes. CONCLUSION: nAMD and glaucoma were found co-existing in the same eye at rates that were similar to the age-corrected prevalence of the two diseases in the general population. Our results suggest that intravitreal anti-VEGF treatment for nAMD may accelerate glaucoma progression.

Immediate sequential bilateral cataract surgery: a 13-year real-life report of 56 700 cataract operations.

BACKGROUND/AIMS: To assess the frequency of immediate sequential bilateral cataract surgery (ISBCS) and endophthalmitis during 13-year period in Tays Eye Centre, Tampere University Hospital, Tampere, Finland. METHODS: All cataract surgeries performed between 1 January 2008 and 31 December 2020, and all endophthalmitis cases during the same period were searched from electronic patient records. Numbers and frequencies of ISBCS, and complications, including endophthalmitis and vitreous loss, were recorded and compared with unilateral operations. RESULTS: The study included 56 700 cataract surgeries in 34 797 patients of whom 39% (n=13 445) had ISBCS. The median age of the patients was 75 (IQR 68-80, range 0.08-99) years at the time of surgery. The proportion of ISBCS patients increased from 4.2% in 2008 to 46% in 2020. Vitreous loss occurred in 480 (0.9%) of cataract surgeries. There were no postoperative endophthalmitis after cataract surgery (n=0) during the 13-year period. CONCLUSION: The proportion of patients undergoing ISBCS increased from 4.2% in 2008 to 46% in 2020. No endophthalmitis were found to be associated with ISBCS.

A comprehensive model for measuring real-life cost-effectiveness in eyecare: automation in care and evaluation of system (aces-rwm™).

This paper describes a holistic, yet simple and comprehensible, ecosystem model to deal with multiple and complex challenges in eyecare. It aims at producing the best possible wellbeing and eyesight with the available resources. When targeting to improve the real-world cost-effectiveness, what gets done in everyday practice needs be measured routinely, efficiently and unselectively. Collection of all real-world data of all patients will enable evaluation and comparison of eyecare systems and departments between themselves nationally and internationally. The concept advocates a strategy to optimize real-life effectiveness, sustainability and outcomes of the service delivery in ophthalmology. The model consists of three components: (1) resource-governing principles (i.e., to deal with increasing demand and limited resources), (2) real-world monitoring (i.e., to collect structured real-world data utilizing automation and visualization of clinical parameters, health-related quality of life and costs), and (3) digital innovation strategy (i.e., to evaluate and benchmark real-world outcomes and cost-effectiveness). The core value and strength of the model lies in the consensus and collaboration of all Finnish university eye clinics to collect and evaluate the uniformly structured real-world outcomes data. In addition to ophthalmology, the approach is adaptable to any medical discipline to efficiently generate real-world insights and resilience in health systems.

Combined structure-function analysis in glaucoma screening.

AIM: To assess the applicability of a structure-function (S-F) analysis combining spectral-domain optical coherence tomography (SD-OCT) and standard automated perimetry (SAP) in glaucoma screening in a middle-aged population. METHODS: A randomised sample of 3001 Caucasian participants aged 45-49 years of the Northern Finland Birth Cohort Eye Study was examined. We performed an eye examination, including 24-2 SAP, optic nerve head (ONH) and retinal nerve fibre layer (RNFL) photography and SD-OCT of the peripapillary RNFL. The S-F report was generated by Forum Glaucoma Workplace software. OCT, SAP and the S-F analysis were evaluated against clinical glaucoma diagnosis, that is, the positive '2 out of 3' rule based on the clinician's evaluation of ONH and RNFL photographs and visual fields (VFs). RESULTS: At a specificity of 97.5%, the sensitivity for glaucomatous damage was 26% for abnormal OCT, 35% for SAP and 44% for S-F analysis. Estimated areas under the curve were 0.74, 0.85 and 0.76, and the corresponding positive predictive values were 8 %, 10% and 12%, respectively. By applying a classification tree approach combining OCT, SAP and defect localisation data, a sensitivity of 77% was achieved at 90% specificity. In a localisation analysis of glaucomatous structural and functional defects, the correlation with glaucoma increased significantly if the abnormal VF test points were located on borderline or abnormal OCT zones. CONCLUSION: SAP performs slightly better than OCT in glaucoma screening of middle-aged population. However, the diagnostic capability can be improved by S-F analysis.

False Positive Responses in Standard Automated Perimetry.

PURPOSE: To analyze the relationship between rates of false positive (FP) responses and standard automated perimetry results. DESIGN: Prospective multicenter cross-sectional study. METHODS: One hundred twenty-six patients with manifest or suspect glaucoma were tested with Swedish Interactive Thresholding Algorithm (SITA) Standard, SITA Fast, and SITA Faster at each of 2 visits. We calculated intervisit differences in mean deviation (MD), visual field index (VFI), and number of statistically significant test points as a function of FP rates and also as a function of general height (GH). RESULTS: Increasing FP values were associated with higher MD values for all 3 algorithms, but the effects were small, 0.3 dB to 0.6 dB, for an increase of 10 percentage points of FP rate, and for VFI even smaller (0.6%-1.4%). Only small parts of intervisit differences were explained by FP (r2 values 0.00-0.11). The effects of FP were larger in severe glaucoma, with MD increases of 1.1 dB to 2.0 dB per 10 percentage points of FP, and r2 values ranging from 0.04 to 0.33. The numbers of significantly depressed total deviation points were affected only slightly, and pattern deviation probability maps were generally unaffected. GH was much more strongly related to perimetric outcomes than FP. CONCLUSIONS: Across 3 different standard automated perimetry thresholding algorithms, FP rates showed only weak associations with visual field test results, except in severe glaucoma. Current recommendations regarding acceptable FP ranges may require revision. GH or other analyses may be better suited than FP rates for identifying unreliable results in patients who frequently press the response button without having perceived stimuli.

Diagnostic performance of modern imaging instruments in glaucoma screening.

AIM: To evaluate the applicability of imaging devices (spectral-domain optical coherence tomography (Cirrus SD-OCT), scanning laser polarimetry (GDx) and scanning laser ophthalmoscopy (Heidelberg Retinal Tomograph, HRT3)) for glaucoma screening in a middle-aged unselected population. METHODS: Participants of the population-based Northern Finland Birth Cohort Eye Study, aged 45 to 49 years, underwent a comprehensive eye examination including modern imaging with five methods (retinal nerve fibre layer (RNFL) and macular ganglion cell layer +inner plexiform layer (GCIPL) analysis and their combination with SD-OCT, GDx and HRT). The performance of the automated classification of the imaging devices was assessed using a clinical glaucoma diagnosis as reference, that is, the '2 out of 3' rule based on the evaluation of optic nerve head and RNFL photographs and visual fields. RESULTS: We examined 6060 eyes of 3039 subjects; in the clinical evaluation, glaucomatous damage was found in 33 subjects (1.1%) in 43 eyes. The following sensitivities were obtained; RNFL analysis (53%), GCIPL analysis (50%), OCT combination analysis (61%), GDx (56%) and HRT (31%) with corresponding specificities of 95%, 92%, 90%, 88% and 96%. The area under the curve values were 0.76, 0.73, 0.75, 0.75 and 0.73, respectively. Post-test probabilities of glaucoma after positive imaging finding with each of these methods in this unselected population were 11%, 7%, 6%, 5% and 7%, respectively. CONCLUSION: Screening capabilities of the OCT, GDx and HRT were rather similar. The accuracy of all evaluated parameters was only moderate and thus screening with these parameters alone is not reliable.

Expression of VEGFA-regulating miRNAs and mortality in wet AMD.

MicroRNAs (miRNAs) regulate gene expression; many of them act in the retinal pigment epithelium (RPE), and RPE degeneration is known to be a critical factor in age-related macular degeneration (AMD). Repeated injections with anti-VEGFA (vascular endothelial growth factor A) are the only effective therapy in wet AMD. We investigated the correlation between the expression of 18 miRNAs involved in the regulation of the VEGFA gene in serum of 76 wet AMD patients and 70 controls. Efficacy of anti-VEGFA treatment was evaluated by counting the number of injections delivered up to 12 years. In addition, we compared the relative numbers of deaths in patient with AMD and control groups. We observed a decreased expression of miR-34-5p, miR-126-3p, miR-145-5p and miR-205-5p in wet AMD patients as compared with controls. These miRNAs are involved in the regulation of angiogenesis, cytoprotection and protein clearance. No miRNA was significantly correlated with the treatment outcome. Wet AMD patients had greater mortality than controls, and their survival was inversely associated with the number of anti-VEGFA injections per year. No association was observed between miRNA expression and mortality. Our study emphasizes the need to clarify the role of miRNA regulation in AMD pathogenesis.

A New SITA Perimetric Threshold Testing Algorithm: Construction and a Multicenter Clinical Study.

PURPOSE: To describe a new time-saving threshold visual field-testing strategy-Swedish Interactive Thresholding Algorithm (SITA) Faster, which is intended to replace SITA Fast-and to report on a clinical evaluation of this new strategy. DESIGN: Description and validity analysis for modifications applied to SITA Fast. METHODS: Five centers tested 1 eye of each of 126 glaucoma and glaucoma suspect patients with SITA Faster, SITA Fast, and SITA Standard at each of 2 visits. Outcomes included test time, mean deviation, and the visual field index (VFI), significant test points in probability maps, and intertest threshold variability. RESULTS: Mean (standard deviation) test times were 171.9 (45.3) seconds for SITA Faster, 247.0 (56.7) for SITA Fast, and 369.5 (64.5) for SITA Standard (P < .001). SITA Faster test times averaged 30.4 % shorter than SITA Fast and 53.5 % shorter than SITA Standard. Mean deviation was similar among all 3 tests.VFI did not differ between SITA Fast and SITA Faster tests, mean difference 0%, but VFI values were 1.2% lower with SITA Standard compared to both SITA Fast (P = .007) and SITA Faster (P = .002). A similar trend was seen with a slightly higher number of significant test points with SITA Standard than with SITA Fast and SITA Faster. All 3 tests had similar test-retest variability over the entire range of threshold values. CONCLUSIONS: SITA Faster saved considerable test time. SITA Faster and SITA Fast gave almost identical results. There were small differences between SITA Faster and SITA Standard, of the same character as previously shown for SITA Fast vs SITA Standard.

Prevalence of glaucoma in the Northern Finland Birth Cohort Eye Study.

PURPOSE: To report the prevalence of glaucoma in the Northern Finland Birth Cohort (NFBC) Eye Study. METHODS: Subjects of the population-based Northern Finland 1966 Birth Cohort (NFBC), aged 45-49 years at the time of the field examination, were randomized to eye screening (50%) and control (50%) groups. The eye examination protocol included best corrected visual acuity (BCVA), measurements of intraocular pressure and central corneal thickness, Humphrey 24-2 perimetry, stereoscopic optic nerve head (ONH) and retinal nerve fibre layer (RNFL) photography and imaging with optical coherence tomography (OCT), scanning laser polarimetry (GDx) and scanning laser ophthalmoscopy (HRT). The diagnosis of glaucoma was made by two independent general ophthalmologists and three independent glaucoma experts based on the evaluation of the ONH and RNFL photographs and the visual fields. RESULTS: Totally, 10 321 subjects of the NFBC main study were alive in Finland in 2011, and they were randomized to the NFBC Eye Study group (n = 5155) and the control group (n = 5166). Of the randomized subjects, 3039 of 5155 (59%) responded and had sufficient data for the study. Glaucoma was suspected in 172 subjects (5.7%) at the first phase of the evaluation protocol. The interobserver agreement between two screening ophthalmologists was moderately good (kappa value 0.54 [95% confidence intervals (CI) 0.46-0.61]). Finally, definite glaucoma was found in 33 subjects (1.1% [95% CI 0.8-1.5]). CONCLUSION: The study provides up-to-date information on the prevalence of glaucoma in a middle-aged Caucasian population in Finland. The baseline data reported here allows the evaluation of the cost-effectiveness of screening later on.

Outcome of anti-vascular endothelial growth factor therapy for neovascular age-related macular degeneration in real-life setting.

AIMS: To evaluate outcome of anti-vascular endothelial growth factor (VEGF) therapy for the treatment of neovascular age-related macular degeneration (nAMD) in the real-life setting and to compare incidence of ocular serious adverse events (SAE) after injections administered by nurses and physicians. METHODS: Retrospective, single-centre study. Medical records of patients receiving anti-VEGF treatment for nAMD between 2008 and 2013 with three-loading-dose regimen were evaluated. Outcome measures were baseline visual acuity (VA), change in VA, number of intravitreal injections, incidence of ocular SAE and patients' baseline characteristics affecting VA change. In addition, the number of injections per 1000 citizens living in the serving area and per individuals over 65 years old were estimated. RESULTS: 1349 eyes in 1117 patients received a total of 11 562 intravitreal anti-VEGF injections. Twenty-one per cent of patients received treatment for both eyes. The mean baseline Snellen VA was 0.32. The mean change of VA from baseline was +2, +2 and ±0 Early Treatment Diabetic Retinopathy Study letters and the mean numbers of injections were 5.7, 4.7 and 4.9 at years 1, 2 and 3, respectively. There was a negative correlation between baseline VA and change of VA. Incidence of endophthalmitis was 0.086%. No difference in the incidence of ocular SAE was identified between injections given by nurses or by physicians. The number of intravitreal injections per all citizens was 9 per 1000 inhabitants and 45 per 1000 inhabitants over 65 years. CONCLUSION: The VA was maintained at the baseline level (±0 letters) with the mean of 15.3 anti-VEGF injections in real-world clinical practice during 3-year follow-up.

The Finnish national guideline for diagnosis, treatment and follow-up of patients with wet age-related macular degeneration.

Age-related macular degeneration (AMD) is the main cause of visual impairment in developed countries. Several improvements in the visualization of posterior segment of the eye together with the introduction of intravitreal anti-VEGF treatment have revolutionized the prognosis of the wet form of AMD (wAMD). Increasing incidence of wAMD together with the limited resources of society and of the healthcare system poses challenges for the provision and development of care. In context of these current aspects, we aimed to set evidence-based medical guidelines for diagnosis, treatment and follow-up of patients with wAMD.