Preservative-Free Bimatoprost 0.01% Ophthalmic Gel for Glaucoma Therapy: A Phase III Randomized Controlled Trial.

PRCIS: Noninferiority of efficacy was demonstrated for a preservative-free bimatoprost 0.01% compared with BAK-containing bimatoprost 0.01% following a 12-week treatment period in patients with open angle glaucoma or ocular hypertension. Improved tolerability, in particular conjunctival hyperemia, was also observed. PURPOSE: To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of a preservative-free bimatoprost 0.01% ophthalmic gel (PFB 0.01% gel) compared with preserved bimatoprost 0.01% (PB 0.01%). DESIGN: Phase III, international, multicenter, randomized, 2-parallel group, investigator-masked, 3-month treatment duration. METHODS: Patients with glaucoma or ocular hypertension were randomized after a 7-week run-in/washout period to receive once-daily PFB 0.01% gel (n=236) or PB 0.01% (n=249) for 3 months. The primary efficacy measure was changed from baseline in IOP at week 12. Safety measures included adverse events (AEs) and assessment of conjunctival hyperemia. RESULTS: The mean changes from baseline in IOP at week 12 in the PFB 0.01% gel and PB 0.01% were -9.72±2.97 and -9.47±3.06 mm Hg, respectively, at 8 am , -9.41±3.03 and -9.19±3.12 mm Hg at 10 am , and -8.99±3.36 and -8.54±3.44 mm Hg at 4 pm . Noninferiority of PFB 0.01% gel to PB 0.01% was demonstrated at week 12 based on predetermined criteria (upper 95% CI margin of 1.5 mmHg at all time points). The most frequently reported AE was conjunctival hyperemia; 13 (5.5%) patients with PFB 0.01% gel and 17 (6.8%) patients with PB 0.01%. The percentage of patients experiencing a worsening from baseline in conjunctival hyperemia score was lower with PFB 0.01% gel compared to PB 0.01% at week 6 (20.1% vs. 29.3%, respectively) and week 12 (18.3% vs. 30.4%, respectively). CONCLUSIONS: PFB 0.01% ophthalmic gel has the same efficacy in lowering IOP as PB 0.01% and demonstrated less aggravation of conjunctival hyperemia at weeks 6 and 12.

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.

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

Fellow of the European board of ophthalmology glaucoma examination and diploma (FEBOS-Gl): update on 8 years of experience and future perspectives.

Glaucoma is the leading cause of irreversible blindness worldwide. Early diagnosis and appropriate management of the disease are essential to avoid a significant impact on the quality of life of millions of patients and the socioeconomic impact on societies. Education is the hallmark of good medical care. The European Glaucoma Society (EGS) has dedicated significant efforts to provide means of improving education, training, and testing knowledge in the field of glaucoma. The Fellow of the European Board of Ophthalmology Subspecialty (FEBOS)-Glaucoma examination, introduced and organized yearly by the EGS since 2015 in collaboration with the European Board of Ophthalmology (EBO), has become a valuable tool for increasing overall knowledge in the field. Over the 8 years of experience, several updates and new projects have emerged around the examination to further increase the overall quality of education, training, and knowledge in the field of glaucoma in Europe, particularly in UEMS and associated countries. This article discusses in detail the various projects and measures introduced by the EGS.

Rethinking Prophylactic Laser Peripheral Iridotomy in Primary Angle-Closure Suspects: A Review.

PURPOSE: To examine the generalizability, discuss limitations, and critically appraise recommendations on the management of primary angle-closure suspects (PACSs) that emerged as a result of recent randomized clinical trials challenging the widely accepted clinical practice of offering laser peripheral iridotomy (LPI) to PACS patients. To synthetize findings from these and other studies. DESIGN: Narrative review. SUBJECTS: Patients classified as PACS. METHODS: The Zhongshan Angle-Closure Prevention (ZAP)-Trial and the Singapore Asymptomatic Narrow Angle Laser Iridotomy Study (ANA-LIS) along with accompanying publications were reviewed. Epidemiologic studies reporting on the prevalence of primary angle-closure glaucoma and other precursor forms of the disease were also analyzed along with publications reporting on the natural course of the disease or studies reporting on outcomes after prophylactic LPI. MAIN OUTCOME MEASURES: Incidence of progression to more severe forms of angle closure. RESULTS: Patients recruited in recent randomized clinical trials are asymptomatic, do not have cataracts, may be younger, and have, on average, deeper anterior chambers depth compared with patients treated with LPI in clinics. CONCLUSIONS: The ZAP-Trial and ANA-LIS clearly represent the best available data on PACS management, additional parameters however may need to be considered when physicians face patients in clinic. PACS patients encountered at tertiary referral centers may represent more advanced cases with respect to ocular biometric parameters and may be at higher risk for disease progression compared with those recruited through population-based screening. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Association of Systemic Medication Use with Glaucoma and Intraocular Pressure: The European Eye Epidemiology Consortium.

PURPOSE: To investigate the association of commonly used systemic medications with glaucoma and intraocular pressure (IOP) in the European population. DESIGN: Meta-analysis of 11 population-based cohort studies of the European Eye Epidemiology Consortium. PARTICIPANTS: The glaucoma analyses included 143 240 participants and the IOP analyses included 47 177 participants. METHODS: We examined associations of 4 categories of systemic medications-antihypertensive medications (ß-blockers, diuretics, calcium channel blockers [CCBs], α-agonists, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers), lipid-lowering medications, antidepressants, and antidiabetic medications-with glaucoma prevalence and IOP. Glaucoma ascertainment and IOP measurement method were according to individual study protocols. Results of multivariable regression analyses of each study were pooled using random effects meta-analyses. Associations with antidiabetic medications were examined in participants with diabetes only. MAIN OUTCOME MEASURES: Glaucoma prevalence and IOP. RESULTS: In the meta-analyses of our maximally adjusted multivariable models, use of CCBs was associated with a higher prevalence of glaucoma (odds ratio [OR], 1.23; 95% confidence interval [CI], 1.08 to 1.39). This association was stronger for monotherapy of CCBs with direct cardiac effects (OR, 1.96; 95% CI, 1.23 to 3.12). No other antihypertensive medications, lipid-lowering medications, antidepressants, or antidiabetic medications were associated with glaucoma. Use of systemic ß-blockers was associated with a lower IOP (ß coefficient, -0.33 mmHg; 95% CI, -0.57 to -0.08 mmHg). Monotherapy of both selective systemic ß-blockers (ß coefficient, -0.45 mmHg; 95% CI -0.74 to -0.16 mmHg) and nonselective systemic ß-blockers (ß coefficient, -0.54 mmHg; 95% CI, -0.94 to -0.15 mmHg) was associated with lower IOP. A suggestive association was found between use of high-ceiling diuretics and lower IOP (ß coefficient, -0.30 mmHg; 95% CI, -0.47 to -0.14 mmHg) but not when used as monotherapy. No other antihypertensive medications, lipid-lowering medications, antidepressants, or antidiabetic medications were associated with IOP. CONCLUSIONS: We identified a potentially harmful association between use of CCBs and glaucoma prevalence. Additionally, we observed and quantified the association of lower IOP with systemic ß-blocker use. Both findings potentially are important, given that patients with glaucoma frequently use systemic antihypertensive medications. Determining causality of the CCB association should be a research priority. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Survival of Visual Function in Patients with Advanced Glaucoma after Standard Guarded Trabeculectomy with MMC.

Surgical intervention in patients with severe glaucoma remains controversial, especially in unilateral cases with a minimally affected fellow eye. Many question the benefit of trabeculectomy in such cases due to high complication rates and prolonged recovery. In this retrospective, non-comparative, interventional case series we aimed to determine the effect of trabeculectomy or combined phaco-trabeculectomy on the visual function of advanced glaucoma patients. Consecutive cases with perimetric mean deviation loss worse than -20 dB were included. Survival of visual function according to five predetermined visual acuity and perimetric criteria was set as the primary outcome. Qualified surgical success utilizing two different sets of criteria commonly used in the literature constituted secondary outcomes. Forty eyes with average baseline visual field mean deviation -26.3 ± 4.1 dB were identified. The average pre-operative intraocular pressure was 26.5 ± 11.4 mmHg and decreased to 11.4 ± 4.0 mmHg (p < 0.001) after an average follow-up of 23.3 ± 15.5 months. Visual function was preserved at two years in 77% or 66% of eyes respectively according to two different sets of visual acuity and perimetric criteria. Qualified surgical success was 89%, 72% at 1 and 3 years respectively. Trabeculectomy and/or phaco-trabeculectomy is associated with meaningful visual outcomes in patients with uncontrolled advanced glaucoma.

The effect of citicoline oral solution on quality of life in patients with glaucoma: the results of an international, multicenter, randomized, placebo-controlled cross-over trial.

PURPOSE: This study aims to evaluate whether the use of citicoline oral solution could improve quality of life in patients with chronic open-angle glaucoma (OAG). DESIGN: Randomized, double-masked, placebo-controlled, cross-over study was used. Patients were randomized to one of the two sequences: either citicoline 500 mg/day oral solution-placebo or placebo-citicoline 500 mg/day oral solution. Switch of treatments was done after 3 months; patients were then followed for other 6 months. Follow-up included 3-month, 6-month, and 9-month visits. OUTCOMES: The primary outcome was the mean change of "intra-patient" composite score of the Visual Function Questionnaire-25 (VFQ-25). after citicoline oral solution vs placebo at 6-month visit as compared with baseline. METHODS: The trial was multicenter, conducted at 5 European Eye Clinics. OAG patients with bilateral visual field damage, a mean deviation (MD) ranging from - 5 to - 13 dB in the better eye, and controlled IOP were included. VFQ-25 and SF-36 questionnaires were administered at baseline and at 3-, 6-, and 9-month visits. A mixed effect model, with a random effect on the intercept, accounted for correlations among serial measurements on each subject. RESULTS: The primary pre-specified outcome of the analysis reached statistical significance (p = 0.0413), showing greater improvement after citicoline oral solution. There was an increase in the composite score in both arms compared to baseline, but it was significant only for the placebo-citicoline arm (p = 0.0096, p = 0.0007, and p = 0.0006 for the three time-points compared to baseline). The effect of citicoline was stronger in patients with vision-related quality of life more affected by glaucoma at baseline. CONCLUSIONS: This is the first placebo-controlled clinical study evaluating the effect of a medical treatment aiming at improving vision-related quality of life in glaucomatous patients.

Association of lipid-lowering drugs and antidiabetic drugs with age-related macular degeneration: a meta-analysis in Europeans.

BACKGROUND/AIMS: To investigate the association of commonly used systemic medications with prevalent age-related macular degeneration (AMD) in the general population. METHODS: We included 38 694 adults from 14 population-based and hospital-based studies from the European Eye Epidemiology consortium. We examined associations between the use of systemic medications and any prevalent AMD as well as any late AMD using multivariable logistic regression modelling per study and pooled results using random effects meta-analysis. RESULTS: Between studies, mean age ranged from 61.5±7.1 to 82.6±3.8 years and prevalence ranged from 12.1% to 64.5% and from 0.5% to 35.5% for any and late AMD, respectively. In the meta-analysis of fully adjusted multivariable models, lipid-lowering drugs (LLD) and antidiabetic drugs were associated with lower prevalent any AMD (OR 0.85, 95% CI=0.79 to 0.91 and OR 0.78, 95% CI=0.66 to 0.91). We found no association with late AMD or with any other medication. CONCLUSION: Our study indicates a potential beneficial effect of LLD and antidiabetic drug use on prevalence of AMD across multiple European cohorts. Our findings support the importance of metabolic processes in the multifactorial aetiology of AMD.

Association Between Dietary Salt Intake and Open Angle Glaucoma in the Thessaloniki Eye Study.

PRCIS: In the Thessaloniki Eye Study (TES) incidence phase population, frequent dietary salt intake was potentially associated with increased risk of open angle glaucoma in antihypertensive users. PURPOSE: The aim was to examine the association between dietary salt intake and glaucoma by antihypertensive use in the TES population. MATERIALS AND METHODS: The study population included TES incidence phase participants. Dietary salt intake frequency was assessed by self-report. Outcomes included prevalence of any open angle glaucoma (OAG), primary open angle glaucoma (POAG), and pseudoexfoliation (PEX). Covariates included demographics, cardiovascular disease, migraines, diabetes, steroid use, smoking, history of cataract surgery, central corneal thickness, intraocular pressure, blood pressure, and antihypertensive use. Logistic regression was used to examine associations between frequency of salt intake and glaucoma, controlling for covariates and stratified by antihypertensive use. RESULTS: The study included 1076 participants 80.5±4.4 years old, of whom 518 were female. There were 89/1076 (8.3%) participants with any OAG, 46/789 (5.8%) with POAG, and 287/1030 (27.9%) with PEX. In participants with antihypertensive use, frequent versus never salt intake was associated with increased risk of any OAG [adjusted odds ratio (aOR)=2.65, 95% confidence interval (CI)=1.12, 6.28; n=784] and POAG (aOR=3.59, 95% CI=1.16, 11.11; n=578) overall, and additionally in participants with diastolic blood pressure <90 mm Hg (aOR=2.42, 95% CI=1.00, 5.84; n=735) for OAG. There were no statistically significant adjusted associations between salt intake and PEX, or in participants without antihypertensive use. CONCLUSIONS: In TES participants assessed for OAG in the prevalence and incidence phases, frequent salt intake may be associated with increased OAG in those who take antihypertensive medication. Further investigation is needed of salt intake and glaucoma in hypertensive individuals.

Emerging Treatment Modalities for Neovascular Age-Related Macular Degeneration: A Systematic Overview.

INTRODUCTION: Neovascular age-related macular degeneration (nAMD) represents a leading cause of irreversible visual loss affecting the quality of life of millions of elderly patients worldwide. Although the introduction of intravitreal injections with anti-vascular endothelial growth factors (anti-VEGF) agents has revolutionized the management of nAMD, their effectiveness and ultimate success are limited by several therapeutic challenges. Consequently, real-world efficacy appears significantly inferior to that reported by randomized controlled trials. Therefore, further innovative, long-term treatment options are essential to improve the prognosis and outcome of nAMD therapy. METHODS: Emerging pharmacological therapies for nAMD and those currently in clinical trials are reviewed and their mechanism of action, safety, and efficacy are discussed. The evidence presented herein has been collected from online databases PubMed, Cochrane library, and the ClinicalTrials.gov site. RESULTS: A number of promising technologies and novel anti-VEGF therapies are currently being tested and some have already reached phase III trials. Anti-VEGF agents with enhanced durability and possibly efficacy, gene therapy, angiogenic targets, alternative drug delivery routes such as sustained delivery implants, drug carriers, and encapsulated cell technology are currently being explored. We briefly discuss the potential value of these options. CONCLUSION: Several options may optimize future nAMD management. On the basis of current, albeit limited evidence, the most promising technology to reach clinical practice soon appears to be the sustained drug delivery options, which may improve visual outcome and reduce the socioeconomic burden of nAMD.

An interpretable multiple-instance approach for the detection of referable diabetic retinopathy in fundus images.

Diabetic retinopathy (DR) is one of the leading causes of vision loss across the world. Yet despite its wide prevalence, the majority of affected people lack access to the specialized ophthalmologists and equipment required for monitoring their condition. This can lead to delays in the start of treatment, thereby lowering their chances for a successful outcome. Machine learning systems that automatically detect the disease in eye fundus images have been proposed as a means of facilitating access to retinopathy severity estimates for patients in remote regions or even for complementing the human expert's diagnosis. Here we propose a machine learning system for the detection of referable diabetic retinopathy in fundus images, which is based on the paradigm of multiple-instance learning. Our method extracts local information independently from multiple rectangular image patches and combines it efficiently through an attention mechanism that focuses on the abnormal regions of the eye (i.e. those that contain DR-induced lesions), thus resulting in a final image representation that is suitable for classification. Furthermore, by leveraging the attention mechanism our algorithm can seamlessly produce informative heatmaps that highlight the regions where the lesions are located. We evaluate our approach on the publicly available Kaggle, Messidor-2 and IDRiD retinal image datasets, in which it exhibits near state-of-the-art classification performance (AUC of 0.961 in Kaggle and 0.976 in Messidor-2), while also producing valid lesion heatmaps (AUPRC of 0.869 in the 81 images of IDRiD that contain pixel-level lesion annotations). Our results suggest that the proposed approach provides an efficient and interpretable solution against the problem of automated diabetic retinopathy grading.

Twelve-Year Incidence of Open-angle Glaucoma: The Thessaloniki Eye Study.

OBJECTIVE: The objective of this study was to determine the 12-year incidence of open-angle glaucoma (OAG), with further classification into primary open-angle glaucoma (POAG) and pseudoexfoliative glaucoma (PEXG), in an elderly White population. DESIGN: A longitudinal, population-based study in urban Northern Greece. PARTICIPANT: Surviving cohort of the 2554 Thessaloniki Eye Study subjects 60 years and above who had the baseline examination. METHODS: The surviving cohort was re-examined 12 years after baseline, using the same methodology and the same standard operating procedures as in the baseline examination. The definitions of glaucoma and pseudoexfoliation were consistent throughout the study. The 12-year incidences of OAG, POAG, and PEXG with corresponding 95% confidence intervals (CIs) were calculated for the whole study population, consisting of clinic-visit and home-visit participants. The population at risk was defined as those who did not meet the study criteria for the diagnosis of glaucoma in either eye at baseline. MAIN OUTCOME MEASURES: Twelve-year incidence of OAG, with further classification into POAG and PEXG. RESULTS: Of 1468 eligible subjects in the surviving cohort, 1092 were examined (participation rate 74%). Mean age at baseline was 68.9±4.6 years. Mean follow-up time was 11.6±1.6 years. The 12-year incidence of OAG was 4.4% (95% CI: 3.3-5.8); 0.37% per year. In the overall population the incidence of POAG and PEXG was 2.1% (95% CI: 1.3-3.2) and 2.3% (95% CI: 1.5-3.4), respectively. The corresponding incidence proportions were 2.9 (95% CI: 1.8-4.3) in those without PEX and 8.9 (95% CI: 5.8-12.9) in those with PEX at baseline and/or incidence. The latter was strongly associated with higher odds for incident glaucoma (odds ratio=3.34, 95% CI: 1.83-6.08, P<0.001). Of all incident OAG cases, 11.1% (95% CI: 4.4-24) had baseline intraocular pressure >21 mm Hg. CONCLUSIONS: The incidence of OAG was similar or higher compared with other White populations. The incidence of glaucoma in those with PEX was higher compared with the incidence of glaucoma in those without PEX.

Ocular biomarkers and their role in the early diagnosis of neurocognitive disorders.

Given the fact that different types of dementia can be diagnosed only postmortem or when the disease has progressed enough to cause irreversible damage to certain brain areas, there has been an increasing need for the development of sensitive and reliable methods that can detect early preclinical forms of dementia, before the symptoms have even appeared. Ideally, such a method would have the following characteristics: to be inexpensive, sensitive and specific, Non-invasive, fast and easily accessible. The ophthalmologic examination and especially the study of the retina, has caught the attention of many researchers, as it can provide a lot of information about the CNS and it fulfills many of the aforementioned criteria. Since the introduction of the non-invasive optical coherence tomography (OCT) and the newly developed modality OCT-angiography (OCT-A) that can demonstrate the structure and the microvasculature of the retina and choroid, respectively, there have been promising results regarding the value of the ophthalmologic examination in the early diagnosis of Alzheimer's disease. In this review paper, we summarize and discuss the ocular findings in patients with cognitive impairment disorders and we highlight the importance of the ophthalmologic examination to the diagnosis of these disorders.

Association of Rare CYP39A1 Variants With Exfoliation Syndrome Involving the Anterior Chamber of the Eye.

Importance: Exfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness. Objective: To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function. Design, Setting, and Participants: A 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome. Exposures: Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function. Main Outcomes and Measures: The primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 × 10-6. The secondary outcomes included biochemical enzymatic assays and gene expression analyses. Results: The discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 × 10-7). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4% [interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < .001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome. Conclusions and Relevance: In this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants. Further research is needed to understand the clinical implications of these findings.

The Contribution of Ocular Biomarkers in the Differential Diagnosis of Alzheimer's Disease versus Other Types of Dementia and Future Prospects.

With dementia becoming increasingly prevalent, there is a pressing need to become better equipped with accurate diagnostic tools that will favorably influence its course via prompt and specific intervention. The overlap in clinical manifestation, imaging, and even pathological findings between different dementia syndromes is one of the most prominent challenges today even for expert physicians. Since cerebral microvasculature and the retina share common characteristics, the idea of identifying potential ocular biomarkers to facilitate diagnosis is not a novel one. Initial efforts included studying less quantifiable parameters such as aspects of visual function, extraocular movements, and funduscopic findings. However, the really exciting prospect of a non-invasive, safe, fast, reproducible, and quantifiable method of pinpointing novel biomarkers has emerged with the advent of optical coherence tomography (OCT) and, more recently, OCT angiography (OCTA). The possibility of analyzing multiple parameters of retinal as well as retinal microvasculature variables in vivo represents a promising opportunity to investigate whether specific findings can be linked to certain subtypes of dementia and aid in their earlier diagnosis. The existing literature on the contribution of the eye in characterizing dementia, with a special interest in OCT and OCTA parameters will be reviewed and compared, and we will explicitly focus our effort in advancing our understanding and knowledge of relevant biomarkers to facilitate future research in the differential diagnosis between Alzheimer's disease and common forms of cognitive impairment, including vascular dementia, frontotemporal dementia, and dementia with Lewy bodies.

Brinzolamide/brimonidine fixed-dose combination bid as an adjunct to a prostaglandin analog for open-angle glaucoma/ocular hypertension.

PURPOSE: To evaluate the additive intraocular pressure-lowering effect of twice-daily brinzolamide 1%/brimonidine 0.2% fixed-dose combination (BBFC) as an adjunct to a prostaglandin analog (PGA) in patients with open-angle glaucoma or ocular hypertension insufficiently controlled with PGA monotherapy. METHODS: In this Phase 4, double-masked trial, patients aged ⩾18 years, with a mean intraocular pressure of ⩾19 and <32 mm Hg in at least one eye were randomized (1:1) to receive BBFC + PGA (n = 96) or vehicle + PGA (n = 92) for 6 weeks. The primary endpoint was the mean change in diurnal intraocular pressure from baseline (averaged over 09:00 and 11:00 h) at Week 6. RESULTS: The mean diurnal intraocular pressure at baseline was similar in the BBFC + PGA (22.8 mm Hg) and vehicle + PGA (22.9 mm Hg) groups. The least squares mean change in diurnal intraocular pressure from baseline at Week 6 was greater with BBFC + PGA (-5.59 mm Hg (95% confidence interval: -6.2 to -5.0)) than with vehicle + PGA (-2.15 mm Hg (95% confidence interval: -2.7 to -1.6)); the treatment difference was statistically significant in favor of BBFC + PGA (-3.44 mm Hg, (95% confidence interval: -4.2 to -2.7); p < 0.001). Ocular adverse events were reported in 21.1% and 8.7% of patients in the BBFC + PGA and vehicle + PGA groups, respectively. The most frequent ocular adverse event was ocular hyperemia (5.3%) in the BBFC + PGA group and blurred vision (2.2%) in the vehicle + PGA group. CONCLUSION: BBFC + PGA significantly reduced mean diurnal intraocular pressure than PGA alone in patients with open-angle glaucoma or ocular hypertension. The safety findings with BBFC + PGA were consistent with the known safety profile of the individual medications.

Factors associated with non-active retinal capillary density as measured with Confocal Scanning Laser Doppler Flowmetry in an elderly population: the Thessaloniki Eye Study (TES).

PURPOSE: To identify factors associated with retinal capillary density as measured with Confocal Scanning Laser Doppler Flowmetry (Heidelberg retina flowmeter (HRF)) in the Thessaloniki Eye Study (TES). METHODS: Participants of the TES (age ≥60 years, cross-sectional population-based study) were assessed for active capillary density in the superior and inferior peripapillary retina using the HRF. Pixel-by-pixel analysis was performed to quantify the percentage of zero flow pixels (ZFPs; surrogate for % retinal area with non-active capillaries). Multivariable regression analyses were performed to assess the association of non-active vascular density with ophthalmic and systemic variables. Glaucoma, late age-related macular degeneration and diabetic retinopathy subjects were excluded. RESULTS: 1189 subjects were included in the analysis. Older age (per year) was associated with higher percentage of ZFP in both the superior (slope estimate (SE)=0.0020) and the inferior (SE=0.0019) peripapillary retina (p<0.0001). History of migraine was associated with lower percentage of ZFP (SE=-0.0166) compared with no history of migraine in the superior peripapillary retina only (p<0.05). Higher intraocular pressure ((IOP) per mm Hg) and height (per cm) were associated with higher percentage of ZFP in the inferior peripapillary retina only (SE=0.0012, p<0.05 and SE=0.0005, p<0.05, respectively). The group consuming vegetables one to three times per week compared with the group consuming vegetables at least once a day had higher percentage of ZFP only in the inferior peripapillary retina (SE=0.0080, p<0.05). CONCLUSION: At a population level, our study revealed associations of older age, higher IOP and taller height with lower active retinal capillary density and of migraine with higher capillary density. Looking further into these associations may provide insight into disease mechanisms.

Twelve-Year Incidence and Baseline Risk Factors for Pseudoexfoliation: The Thessaloniki Eye Study (An American Ophthalmological Society Thesis).

PURPOSE: To determine the 12-year incidence of pseudoexfoliation (PEX), baseline risk factors for incident PEX and risk factors for incident pseudoexfoliative glaucoma (PEXG) among those with PEX in an elderly white population. METHODS: Longitudinal, population-based study in Thessaloniki, the major urban center in Northern Greece. The baseline cohort included 2554 participants ≥60 years old. The surviving cohort was re-examined 12 years later using the same methodology. PEX was defined as typical fibrillar material at the pupil margin and/or on the lens capsule. Glaucoma was defined as both structural and functional damage, irrespective of intraocular pressure (IOP). RESULTS: Of 1468 eligible subjects in the surviving cohort, 1092 (74%) participated in the follow-up study. The mean age ± standard deviation (SD) at baseline was 68.9 ± 4.6 years. The mean follow-up time was 11.6 ± 1.6 years. The 12-year incidence of PEX was 19.6% (95% confidence interval (CI), 17.1-22.2), with women more likely to be affected than men (Fisher's exact test, P = .0197). Higher axial length was associated with lower odds of incident PEX (odds ratio [OR], 0.72 per mm; 95% CI, 0.57-0.92). PEX at baseline was not associated with an increased likelihood of major vascular disease (P = .9038). Higher baseline IOP (OR, 1.26 per mm Hg; 95% CI, 1.07-1.48) and history of heart attack at baseline (OR, 13.49; 95% CI, 2.85-63.87) were associated with a greater likelihood of developing PEXG among those with PEX. A history of alcohol consumption at baseline was protective of individuals developing PEXG if they had PEX at baseline. CONCLUSION: This is one of the very few longitudinal population-based studies that has specifically assessed the incidence of PEX. The association with axial length was previously found only in a cross-sectional study. The associations with heart attack and alcohol consumption are new findings. In individuals with baseline PEX, higher IOP at baseline, history of heart attack at baseline, and no alcohol consumption were associated with a greater likelihood of developing glaucomatous damage approximately 12 years later. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

Factors Associated With Retinal Vessel Diameters in an Elderly Population: the Thessaloniki Eye Study.

Purpose: To identify the factors associated with retinal vessel diameters in the population of the Thessaloniki Eye Study. Methods: Cross-sectional population-based study (age ≥ 60 years). Subjects with glaucoma, late age-related macular degeneration, and diabetic retinopathy were excluded from the analyses. Retinal vessel diameters were measured using the IVAN software, and measurements were summarized to central retinal artery equivalent (CRAE), central retinal vein equivalent (CRVE), and arteriole to venule ratio (AVR). Results: The analysis included 1614 subjects. The hypertensive group showed lower values of CRAE (P = 0.033) and AVR (P = 0.0351) compared to the normal blood pressure (BP) group. On the contrary, the group having normal BP under antihypertensive treatment did not have different values compared to the normal BP group. Diastolic BP (per mm Hg) was negatively associated with CRAE (P < 0.0001) and AVR (P < 0.0001), while systolic BP (per mm Hg) was positively associated with CRAE (P = 0.001) and AVR (P = 0.0096). Other factors significantly associated included age, sex, alcohol, smoking, cardiovascular disease history, ophthalmic medication, weight, and IOP; differences were observed in a stratified analysis based on BP medication use. Conclusions: Our study confirms previous reports about the association of age and BP with vessel diameters. The negative correlation between BP and CRAE seems to be guided by the effect of diastolic BP as higher systolic BP is independently associated with higher values of CRAE. The association of BP status with retinal vessel diameters is determined by diastolic BP status in our population. Multiple other factors are also independently associated with retinal vessel diameters.