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Background/aim: To examine the relationship between baseline blood flow biomarkers and long-term open-angle glaucoma (OAG) progression., Methods: 112 patients with early to moderate OAG (mean age 64.9±11.0 years; 68 female) were evaluated at baseline and every 6 months from 2008 to 2013. Biomarkers of retinal capillary blood flow were assessed by Heidelberg retinal flowmetry. Functional disease progression was monitored via Humphrey visual field examinations, defined as two consecutive visits with a mean deviation decrease ≥2 decibels and/or Advanced Glaucoma Intervention Study score increase ≥2 compared with baseline. Structural progression was monitored with optical coherence tomography and Heidelberg retinal tomograph, defined as two consecutive visits with retinal nerve fibre layer thickness decrease ≥8% and/or horizontal or vertical cup/disk ratio increase ≥0.2 compared with baseline. Mixed-model analysis of covariance was used to test for significant change from baseline to 5-year follow-up. Times to functional and structural progression were analysed using Cox proportional hazards models., Results: Lower HRF retinal capillary blood flow in the superior retina was significantly associated with structural progression (p=0.0009)., Conclusion: In our OAG sample, baseline lower retinal capillary perfusion in the superior retina was predictive of structural progression after 5 years., Trial Registration Number: NCT01145911., Competing Interests: Competing interests: There are no competing interests. Professor Alon Harris would like to disclose that he received remuneration from AdOM, Qlaris, Cipla for serving as a consultant, and he serves on the board of AdOM and Qlaris. Professor Alon Harris holds an ownership interest in AdOM, Oxymap, Qlaris and SlitLed. All relationships listed above are pursuant to Icahn School of Medicine’s policy on outside activities. The contribution of the author Francesco Oddone was supported by Fondazione Roma and by the Italian Ministry of Health. None of the other authors listed have any financial disclosures., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Carbonic anhydrase inhibitors (CAIs) have been used for many decades in the treatment of glaucoma. Systemic CAIs were an early treatment option to lower intraocular pressure by reducing aqueous humour production; however, frequent side effects including polyuria and paresthesia contributed to the eventual development of topical CAIs. As topical drug development evolved over time, prostaglandin analogues and beta-blockers have become the gold standard of glaucoma therapies. Although prescribed less often than other classes of topical glaucoma therapies, topical CAIs continue to be used in combination therapies with beta-blockers and alpha agonists. Topical CAIs have also been demonstrated to alter biomarkers of ocular haemodynamics, which have relevance in glaucoma. The purpose of this review is to review and summarise the current state of topical CAI prescribing trends, known efficacy and suggested mechanisms and potential influence on ocular haemodynamics for the future of glaucoma management., Competing Interests: Competing interests: AH would like to disclose that he received remuneration from AdOM, Qlaris, Luseed and Cipla for serving as a consultant, and he serves on the board of AdOM, Qlaris and Phileas Pharma. AH holds an ownership interest in AdOM, Luseed, Oxymap, Qlaris, Phileas Pharma and QuLent. All relationships listed above are pursuant to Icahn School of Medicine’s policy on outside activities. IJ would like to disclose that she received remuneration from Santen and Thea for serving as a consultant. The contribution of the author Francesco Oddone was supported by Fondazione Roma and by the Italian Ministry of Health. None of the other authors listed have any financial disclosures., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To evaluate morphological differences in retinal nerve fibers layers (RNFL), optic nerve head (ONH), ganglion cell complex (GCC), and macular thickness between amblyopic and normal eyes from spectral domain optical coherence tomography (SD-OCT)., Methods: Of 234 eyes of 117 children, four groups emerged: group A (162 eyes of 81 non-amblyopic subjects); group B (32 fellow eyes of 32 subjects with monolateral amblyopia); group C (32 amblyopic eyes of 32 subjects affected by monolateral amblyopia); group D (8 amblyopic eyes of 4 subjects with bilateral amblyopia). Patients underwent SD-OCT for ONH parameters, RNFL, GCC and macular thickness, retina map, and ONH scan quality index (SQI). Two-sided p values <0.05 were taken as statistically significant. (Analysis: STATA v.13)., Results: Parameters with a significant difference between groups ( p  < 0.005) with their Standard Deviation (SD) are presented: rim area, 2.08 (0.49) mm 2 in group A and 1.76 (0.68) mm 2 in group C; disk area, 2.43 (0.45) mm 2 in group A and 2.02 (0.71) mm 2 in group C; central macular thickness, 250.99 (19.74) µm in group A and 267.16 (23.52) µm in group C; nerve fiber ONH SQI, 62.82 (13.15) in group A, 51.26 (15.55) in group C, 48.29 (14.37) in group D; retina map SQI, 63.34 (10.34) in group A and 57.34 (9.84) in group C. For other parameters no significant difference was observed ( p  > 0.005)., Conclusions: Amblyopia may influence optic nerve morphology, central macular thickness, and OCT scan quality. RNFL and GCC are not affected by monolateral amblyopia.

Competing Interests: Declaration of interest G Guidoboni would like to disclose that she received remuneration from Foreside Healthcare, LLC and Qlaris Bio, Inc for serving as a consultant. These relationships are pursuant to the University of Missouri’s policy on outside activities. A Harris would like to disclose that he received remuneration from AdOM, Qlaris, Luseed, and Cipla for serving as a consultant, and he serves on the board of AdOM, Qlaris, and Phileas Pharma. A Harris holds an ownership interest in AdOM, Luseed, Oxymap, Qlaris, Phileas Pharma, SlitLed and QuLent. All relationships listed above are pursuant to Icahn School of Medicine’s policy on outside activities. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

We developed a mathematical model to characterize how macular oxygenation may be affected by abnormalities in the retinal and choroidal oxygen supplies. The macular region is modeled as a layered structure including: ganglion cell and nerve fiber layers, inner plexiform layer, inner nuclear layer, outer plexiform layer, outer nuclear layer, inner segment of photoreceptors layer and retinal pigmented epithelium. Each layer is characterized by specific levels of oxygen consumption. The vitreous and the choroid are located at the macula boundary and provide oxygen via boundary conditions of Dirichlet type. The three capillary plexi (superficial, intermediate, and deep) of the retinal circulation pierce the macular layers and provide oxygen via a volumetric source that depends on the retinal blood flow. Oxygen profiles through the macular tissue are calculated by simulating the balance among oxygen supply, consumption and diffusion in: (a) physiological baseline conditions; (b) retinal blood flow reduced by 10%, 30% and 50% with respect to baseline; (c) choroidal oxygen level diminished by 10%, 30% and 50% with respect to baseline. Model simulations predict that: (1) the oxygenation of the foveal avascular zone is not affected by reduction in retinal blood flow; (2) a reduction in choroidal oxygen supply significantly affects the outer layers, especially the photoreceptors and outer nuclear layers; (3) the impact of reduction in choroidal oxygen supply is larger in the region more proximal to the macular center; (4) the impact of reduction in retinal blood flow is larger in the region more proximal to the macular periphery. The proposed mathematical model suggests that changes in retinal and choroidal oxygen supplies impact the oxygenation of the macular tissue differentially. These results may help better understand the pathogenesis of macular degeneration., Competing Interests: Declaration of Competing Interest The Authors declare that there is no conflict of interest. Professor A. Harris would like to disclose that he received remuneration from AdOM, Qlaris, Luseed, and Cipla for serving as a consultant, and he serves on the board of AdOM, Qlaris, and Phileas Pharma. Professor A. Harris holds an ownership interest in AdOM, Luseed, Oxymap, Qlaris, Phileas Pharma, and QuLent. All relationships listed above are pursuant to Icahn School of Medicine’s policy on outside activities. Dr. G. Guidoboni would like to disclose that she received remuneration from Foresite Healthcare LLC for serving as a consultant. Dr. G. Guidoboni holds an ownership interest in Gspace LLC., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Glaucoma patients often suffer from ocular surface disease (OSD) caused by the chronic administration of topical anti-glaucoma medications, especially in cases of long-term therapy with preserved or multiple drugs. Additionally, glaucoma surgery may determine ocular surface changes related to the formation and location of the filtering bleb, the application of anti-mitotic agents, and the post-operative wound-healing processes within the conjunctiva. Recently, several studies have evaluated the role of advanced diagnostic imaging technologies such as in vivo confocal microscopy (IVCM) and anterior segment-optical coherence tomography (AS-OCT) in detecting microscopic and macroscopic features of glaucoma therapy-related OSD. Their clinical applications are still being explored, with recent particular attention paid to analyzing the effects of new drug formulations and of minimally invasive surgical procedures on the ocular surface status. In this review, we summarize the current knowledge about the main changes of the ocular surface identified at IVCM and AS-OCT in glaucoma patients under medical therapy, or after surgical treatment.

Purpose: To assess the structure-function relationship in glaucoma using Humphrey visual field (HVF) perimetry and a three-dimensional neuroretinal rim parameter derived from spectral domain optical coherence tomography (SD-OCT) volume scans., Methods: Structure-function correlation was analyzed globally and regionally (four quadrants and four sectors). Structural data included peripapillary retinal nerve fiber layer (RNFL) thickness and minimum distance band (MDB) neuroretinal rim thickness, defined as the shortest distance between the inner cup surface and the outer retinal pigment epithelium/Bruch's membrane complex. Logarithmic regression analyses were performed and Pearson correlation coefficients determined to assess relationship strength., Results: The study consisted of 102 open-angle glaucoma patients and 58 healthy subjects. The Pearson correlation coefficient for global MDB thickness (R = 0.585) was higher than for global RNFL thickness (R = 0.492), but the difference was not statistically significant (P = 0.18). The correlation coefficients for regional MDB thicknesses and corresponding HVF sensitivities were higher than those for regional RNFL thicknesses and HVF in six out of eight regions (P = 0.08 to 0.47). In the remaining two out of eight regions, the correlation coefficients were higher for RNFL thickness than for MDB thickness (P = 0.15 to 0.20)., Conclusions: Three-dimensional MDB neuroretinal rim thickness relates to visual function as strongly as the most commonly used SD-OCT parameter for glaucoma, two-dimensional peripapillary RNFL thickness., Translational Relevance: This paper illustrates the potential for 3D OCT algorithms to improve in vivo imaging in glaucoma.

Competing Interests: Disclosure: A.H. would like to disclose that he received remuneration from Adom, Qlaris, and Luseed for serving as a consultant, and he serves on the board of Adom and Phileas Pharma. A.H. also holds an ownership interest in AdOM, Luseed, Oxymap, Phileas Pharma, and QuLent. All relationships listed above are pursuant to Icahn School of Medicine’s policy on outside activities. J.C.T. is a paid consultant for Eyenovia and ReNetX Bio. The contribution of the author A.C.V.V. was supported by Fondazione Roma and by the Italian Ministry of Health. The remaining authors declare no conflict of interest.

Neurodegenerative disorders (NDD) such as Alzheimer's and Parkinson's diseases are significant causes of morbidity and mortality worldwide. The pathophysiology of NDD is still debated, and there is an urgent need to understand the mechanisms behind the onset and progression of these heterogenous diseases. The eye represents a unique window to the brain that can be easily assessed via non-invasive ocular imaging. As such, ocular measurements have been recently considered as potential sources of biomarkers for the early detection and management of NDD. However, the current use of ocular biomarkers in the clinical management of NDD patients is particularly challenging. Specifically, many ocular biomarkers are influenced by local and systemic factors that exhibit significant variation among individuals. In addition, there is a lack of methodology available for interpreting the outcomes of ocular examinations in NDD. Recently, mathematical modeling has emerged as an important tool capable of shedding light on the pathophysiology of multifactorial diseases and enhancing analysis and interpretation of clinical results. In this article, we review and discuss the clinical evidence of the relationship between NDD in the brain and in the eye and explore the potential use of mathematical modeling to facilitate NDD diagnosis and management based upon ocular biomarkers., (Copyright © 2020 Guidoboni, Sacco, Szopos, Sala, Verticchio Vercellin, Siesky and Harris.)

Studies have confirmed that optic disc haemorrhage (ODH) is a significant risk factor for the development and progression of primary open-angle glaucoma (POAG). Various populations have differing risk factors for developing POAG. As such, a literature review was conducted examining seven studies published in India, China, Japan, Australia, Korea and the USA. The goal of this review was to better identify ODH risk factors and their relationship to development and progression of POAG. Ultimately, patients with ODH have a greater risk for developing POAG across all populations analysed in this review. However, some populations demonstrated additional risk factors for ODH, such as increasing age and female gender. Paradoxically, data from several studies show that people of African descent have a reduced risk of ODH despite having increased risk of open-angle glaucoma than their Caucasian counterparts. By parsing out the complex relations between ODH and open-angle glaucoma stratified by age, gender and race, we may gain a broader understanding of glaucoma pathogenesis and derive individualised treatment strategies., Competing Interests: Competing interests: AH would like to disclose that he receives remuneration from AdOM for serving as a consultant and a board member, and from Thea for a speaking engagement. AH also holds an ownership interest in AdOM, Luseed, Oxymap and QuLent. LRP would like to disclose that he on the advisory Boards for Eyenovia, Emerald Bioscience, Nicox and Bausch + Lomb. He also consults for Verily., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Traumatic brain injury is represented by a penetrating or non-penetrating head injury, which causes disruption in the normal functioning of the brain. Traumatic brain injury has been an ardently debated topic of discussion due to its prevalence in media centric persons such as military personnel and athletes. Current assessments for traumatic brain injury have looked at vestibulo-ocular and vascular parameters to aid in diagnosis. Innovations in non-invasive ophthalmic imaging have allowed for the visualization of specific tissue structure/function relationships in a variety of ophthalmic and neurodegenerative diseases. As the eye and brain share significant embryological and physiological pathways, ocular imaging modalities may provide a novel and impactful tool in advancing assessment of traumatic brain injury. Herein, we examined the available literature and data on visual fields, mean retinal nerve fiber layer thickness, retinal ganglion cell layer thickness, and cerebral blood flow following traumatic brain injury. This review of published individual and population-based studies was performed in order to explore the feasibility and importance of considering ocular imaging biomarkers following traumatic brain injury.

Introduction: To identify novel velocity waveform parameters of the ophthalmic artery and central retinal artery by computer-aided image processing of Doppler ultrasonography measurements, and to evaluate correlations between the waveform parameters and different demographics and disease severity of open-angle glaucoma patients., Methods: Thirty-six images of 36 open-angle glaucoma patients were considered. A semiautomated image processing code was used to detect the digitalized ophthalmic artery and central retinal artery velocity waveforms and to extract the waveform parameters. Concordance correlation coefficient, two-sample t-test, and Pearson's correlation coefficient were used to test for similarities, differences, and associations among variables., Results: Female glaucoma patients showed a statistically higher ophthalmic artery normalized distance between ascending and descending limb (p = 0.004), hypertensive glaucoma patients a statistically higher ophthalmic artery peak systolic velocity time (p = 0.025), glaucoma patients with hyperlipidemia a statistically higher ophthalmic artery resistivity index (p = 0.023) and a statistically higher ophthalmic artery peak systolic velocity acceleration (p = 0.025), glaucoma patients with cardiovascular diseases a statistically lower central retinal artery normalized distance between ascending and descending limb of the wave (p = 0.033) and a statistically higher central retinal artery period (p = 0.028), and patients with different body mass index a statistically different central retinal artery normalized distance between ascending and descending limb of the wave (p = 0.016). Groups with different disease severity, classified following the Brusini glaucoma staging system 2, showed statistically different central retinal artery normalized distance between ascending and descending limb of the wave (p < 0.001) and central retinal artery period (p = 0.016). No statistical differences were found in regard to race, diabetes status, glaucoma family history, and smoking., Discussion: Ophthalmic artery and central retinal artery computer-aided analysis of velocity waveforms could identify novel waveform parameters capable of differentiating among different demographics and disease severity of open-angle glaucoma patients.

Aims: To examine the relationship between baseline structural characteristics of the optic nerve head (ONH) and retinal nerve fiber layer (RNFL) and functional disease progression in patients with open-angle glaucoma (OAG) over 5 years., Methods: 112 OAG patients were prospectively examined at baseline and every 6 months over a period of five years. Structural glaucomatous changes were examined with optical coherence tomography (OCT) and Heidelberg retinal tomography-III (HRT-III), and functional disease progression with automated perimetry (Humphrey visual fields). Cox proportional hazard models were used to assess the relationship between baseline structural measurements and functional disease progression., Results: From baseline over a 5-year period, statistically significant increases were found in OCT disc (D) area (p<0.001), cup (C) area (p<0.001), C/D area ratio (p<0.001), C/D horizontal ratio (p<0.001), C/D vertical ratio (p = 0.018), and a decrease in superior RNFL thickness (p = 0.008). Statistically significant increases were found in HRT-III C volume (p = 0.021), C/D area ratio (p = 0.046), mean C depth (p = 0.036), C shape (p = 0.008), and height variation contour (p = 0.020). Functional disease progression was detected in 37 of the 112 patients (26 of European descent and 11 of African descent; 33%). A statistically significant shorter time to functional progression was seen in patients with larger baseline OCT D area (p = 0.008), C area (p = 0.003), thicker temporal RNFL (p = 0.003), and in patients with a larger HRT-III C area (p = 0.004), C/D area ratio (p = 0.004), linear C/D ratio (p = 0.007), C shape (p = 0.032), or smaller rim area (p = 0.039), rim volume (p = 0.005), height variation contour (p = 0.041), mean RNFL thickness (p<0.001), or RNFL cross-sectional area (p = 0.002)., Conclusion: Baseline ONH and RNFL structural characteristics were associated with a significantly shorter time to functional glaucomatous progression and visual field loss through the five-year period in OAG patients., Competing Interests: The authors have declared that no competing interests exist. Dr. Alon Harris would like to disclose that he received remuneration from Adom and Luseed for serving as a consultant, and he serves on the board of Adom and Phileas Pharma. Dr. Harris also holds an ownership interest in AdOM, Luseed, Oxymap, Phileas Pharma, and QuLent. All relationships listed above are pursuant to Icahn School of Medicine’s policy on outside activities. Dr. Ingrida Januleviciene would like to disclose that she receives honoraria from Santen, and she receives remuneration from Santen and Thea for serving as a consultant. The contribution of the author Dr. Alice C. Verticchio Vercellin was supported by Fondazione Roma and by the Italian Ministry of Health. There are no patents, products in development or marketed products to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Assessment and monitoring of intracranial pressure (ICP) are important in the management of traumatic brain injury and other cerebral pathologies. In the eye, ICP elevation and depression both correlate with optic neuropathies, the former because of papilledema and the latter related to glaucoma. While the relationship between ICP elevation and papilledema is well established, the relationship between low ICP and glaucoma is still poorly understood. So far, ICP monitoring is performed invasively, but this entails risks including infection, spurring the study of non-invasive alternatives. We review 11 methods of non-invasive estimation of ICP including correlation to optic nerve sheath diameter, intraocular pressure, ophthalmodynamometry and two-depth transcranial Doppler of the ophthalmic artery. While none of these methods can fully replace invasive techniques, certain measures show great potential for specific applications. Although only used in small studies to date, a MRI based method known as MR-ICP, appears to be the best non-invasive technique for estimating ICP, with two-depth transcranial ultrasound and ophthalmodynamometry showing potential as well., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background/aims: To evaluate diurnal variations in optic nerve head (ONH) vessel density assessed by optical coherence tomography angiography (OCT-A) in healthy subjects, ocular hypertension (OHT), and open-angle glaucoma (OAG) patients., Methods: Forty subjects (OAG, 21; OHT, 6; healthy, 13) were assessed for vessel density percentage (VD%) and flow index in the ONH (NH VD%, NH index), and in the radial peripapillary capillary layer (RPC VD%, RPC index) at 9:00, 11:00, 14:00, 16:00, and 18:00 on a single day. Repeated measures ANOVAs were used to test for changes in the parameters measured at multiple time points., Results: All OCT-A parameters analyzed at the different time points were statistically lower in the OAG patients compared to both the OHT and healthy groups (p < 0.05). In the OAG group, the NH index, RPC index, NH VD%, and RPC VD% were statistically lower at 18:00 compared to 14:00, and the RPC VD% was statistically lower at 9:00 than 14:00. In the OHT group, the RPC index was statistically lower at 9:00 than 11:00. In the healthy group, the NH VD% and RPC VD% were statistically lower at 16:00 than 18:00, and the RPC index was statistically lower at 9:00 than 11:00. No other statistically significant difference was found in none of the three groups comparing any other time point (p > 0.05)., Conclusion: In healthy subjects, OHT and OAG patients, the variations in the OCT-A derived parameters were relatively small. These results suggest that in the clinical practice the OCT-A assessment can be performed independently of the time of the day, contrasting IOP evaluation.

Purpose: The current understanding of circadian regulation disorders and their involvement in glaucoma pathophysiology are poorly understood, yet they may have a substantial impact on the onset and progression of glaucoma. Herein, we review and summarize all the available literature on circadian rhythm disorder and glaucoma to uncover the impact on glaucoma risk, and we highlight future research and potential novel targets for glaucoma management., Materials and Methods: A review of the relevant literature was performed through PubMed through August 1, 2019., Results: Within a normal circadian rhythm, intraocular pressure (IOP) peaks at night, whereas blood pressure (BP) troughs at night. High nocturnal IOP coupled with low nocturnal systemic BP results in low ocular perfusion pressure and potential for unobserved damage to retinal tissues and the optic nerve. Circadian-related melatonin and sleep disorders also result in changes in IOP and ocular perfusion pressure that lead to the progression of glaucoma. In addition, impaired perception of light input due to glaucoma can subsequently lead to abnormal serum levels of melatonin, resulting in circadian rhythm misalignment. This disruption of the circadian rhythm also contributes to sleep and mood disorders, common in individuals with glaucoma. As regards treatment, glaucoma medications that lower nocturnal IOP without influencing nocturnal BP or diminishing circadian variation seem most effective., Conclusions: Glaucoma progression is influenced by multiple physiological factors regulated by the circadian rhythm. Progression of the disease may also cause physiological changes that lead to circadian-related issues. Further research is warranted on the diurnal cycle, melatonin-mediated processes, and their influence on glaucoma management.

Alterations in ocular blood flow have been identified as important risk factors for the onset and progression of numerous diseases of the eye. In particular, several population-based and longitudinal-based studies have provided compelling evidence of hemodynamic biomarkers as independent risk factors for ocular disease throughout several different geographic regions. Despite this evidence, the relative contribution of blood flow to ocular physiology and pathology in synergy with other risk factors and comorbidities (e.g., age, gender, race, diabetes and hypertension) remains uncertain. There is currently no gold standard for assessing all relevant vascular beds in the eye, and the heterogeneous vascular biomarkers derived from multiple ocular imaging technologies are non-interchangeable and difficult to interpret as a whole. As a result of these disease complexities and imaging limitations, standard statistical methods often yield inconsistent results across studies and are unable to quantify or explain a patient's overall risk for ocular disease. Combining mathematical modeling with artificial intelligence holds great promise for advancing data analysis in ophthalmology and enabling individualized risk assessment from diverse, multi-input clinical and demographic biomarkers. Mechanism-driven mathematical modeling makes virtual laboratories available to investigate pathogenic mechanisms, advance diagnostic ability and improve disease management. Artificial intelligence provides a novel method for utilizing a vast amount of data from a wide range of patient types to diagnose and monitor ocular disease. This article reviews the state of the art and major unanswered questions related to ocular vascular anatomy and physiology, ocular imaging techniques, clinical findings in glaucoma and other eye diseases, and mechanistic modeling predictions, while laying a path for integrating clinical observations with mathematical models and artificial intelligence. Viable alternatives for integrated data analysis are proposed that aim to overcome the limitations of standard statistical approaches and enable individually tailored precision medicine in ophthalmology., Competing Interests: Declaration of competing interest There are no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The ciliary epithelium (CE) is the primary site of aqueous humor (AH) production, which results from the combined action of ultrafiltration and ionic secretion. Modulation of ionic secretion is a fundamental target for drug therapy in glaucoma, and therefore it is important to identify the main factors contributing to it. As several ion transporters have been hypothesized as relevant players in CE physiology, we propose a theoretical approach to complement experimental methods in characterizing their role in the electrochemical and fluid-dynamical conditions of CE. As a first step, we compare two model configurations that differ by (i) types of transporters included for ion exchange across the epithelial membrane, and by (i) presence or absence of the intracellular production of carbonic acid mediated by the carbonic anhydrase enzyme. The proposed model configurations do not include neurohumoral mechanisms such as P2Y receptor-dependent, cAMP, or calcium-dependent pathways, which occur in the ciliary epithelium bilayer and influence the activity of ion transporters, pumps, and channels present in the cell membrane. Results suggest that one of the two configurations predicts sodium and potassium intracellular concentrations and transmembrane potential much more accurately than the other. Because of its quantitative prediction power, the proposed theoretical approach may help relate phenomena at the cellular scale, that cannot be accessed clinically, with phenomena occurring at the scale of the whole eye, for which clinical assessment is feasible.

Purpose: To investigate potential associations between intraocular pressure (IOP) and cerebrospinal fluid pressure (CSFP) in patients with primary open-angle glaucoma (POAG) and healthy subjects., Methods: Forty-three subjects were recruited. Weight and height were measured to calculate body mass index (BMI), along with blood pressure, heart rate, visual acuity, and IOP. Biometrics exam, corneal pachymetry, peripapillary retinal nerve fiber layer (RNFL) thickness, and macular thickness were assessed. The visual field exam was performed on all patients, and both pattern standard deviation (PSD) and mean deviation (MD) were considered. CSFP was estimated indirectly by using the mathematical formula CSFP = 0.44 × BMI + 0.16 × diastolic pressure - 0.18 × age - 1.91, based on the previous scientific studies. The TLCPD was calculated as follows: IOP-CSFP., Results: A significant ( p < 0.05) difference was found between the two groups for several parameters. Specifically, the CSFP was lower in patients with POAG than in healthy subjects (8.14 ± 4.52 and 7.43 ± 2.06, p < 0.001, respectively). Anamnestic TLCPD was found to be significantly ( p < 0.001) higher in patients with POAG compared to healthy subjects. A significant ( p < 0.05) correlation was found between anamnestic TLCPD and MD ( r  = -0.31), inferior RNFL thickness ( r  = -0.29), superior RNFL thickness ( r  = -0.27), IOP ( r  = 0.22), and CSFP ( r  = -0.46)., Conclusion: The CSFP was lower in glaucomatous patients compared to healthy subjects, whereas the TLCPD was higher in glaucomatous patients compared to healthy subjects, even though this difference was not statistically significant. A higher TLCPD may damage the RNFL, resulting in functional visual field impairment., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2019 Laura Landi et al.)

PRéCIS:: Neuroretinal rim minimum distance band (MDB) thickness is significantly lower in older subjects and African Americans compared with whites. It is similar in both sexes., Purpose: To evaluate the relationship between age, race, and sex with the neuroretinal rim using high-density spectral-domain optical coherence tomography optic nerve volume scans of normal eyes., Methods: A total of 256 normal subjects underwent Spectralis spectral-domain optical coherence tomography optic nerve head volume scans. One eye was randomly selected and analyzed for each subject. Using custom-designed software, the neuroretinal rim MDB thickness was calculated from volume scans, and global and quadrant neuroretinal rim thickness values were determined. The MDB is a 3-dimensional neuroretinal rim band comprised of the shortest distance between the internal limiting membrane and the termination of the retinal pigment epithelium/Bruch's membrane complex. Multiple linear regression analysis was performed to determine the associations of age, race, and sex with neuroretinal rim MDB measurements., Results: The population was 57% female and 69% white with a mean age of 58.4±15.3 years. The mean MDB thickness in the normal population was 278.4±47.5 µm. For this normal population, MDB thickness decreased by 0.84 µm annually (P<0.001). African Americans had thinner MDBs compared with whites (P=0.003). Males and females had similar MDB thickness values (P=0.349)., Conclusion: Neuroretinal rim MDB thickness measurements decreased significantly with age. African Americans had thinner MDB neuroretinal rims than whites.

The relationship between ocular haemodynamics and retinitis pigmentosa (RP) has not been fully understood. Reductions in blood flow have been established in RP patients by a variety of studies; however, questions have yet to be answered regarding the role of vascular dysfunction in photoreceptors (PR) degeneration, the causes of vascular dysfunction in RP, as well as the diagnostic, prognostic and perhaps therapeutic potential of measuring ocular haemodynamics in RP patients. While significant evidence supports the theory that vascular dysfunction is associated with but not the cause of PR death in retinitis pigmentosa, evidence suggests that vascular abnormalities in the foveal and parafoveal regions may exacerbate cone cell loss. Additional evidence demonstrates that vascular dysfunction likely results from changes in metabolic demand due to death of PR cells in the retina. Detection and monitoring of ocular blood flow, retinal oxygen saturation, endothelin-1 levels and vascular structural abnormalities could provide diagnostic, prognostic and therapeutic potential for patients with RP., (© 2019 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background/aim: Blood flow deficiencies of the retinal and retrobulbar circulations have been previously reported in open-angle glaucoma (OAG) and other eye diseases. Herein we investigated the effects of image brightness and contrast dynamic altering stimuli (DAS) when viewing a video content on ocular blood flow, intraocular pressure (IOP) and ocular perfusion pressure (OPP) in OAG and healthy subjects., Methods: Thirty-five subjects, 25 with OAG (mild to moderate) and 10 healthy controls, were evaluated for blood pressure, IOP, OPP and retinal capillary blood flow before, immediately after, 30 min after and 60 min after using ReviView (a dichoptic video goggles device), which stimulates one eye with a DAS video image that is brighter and with greater contrast than the fellow eye (duration of exposure 30 min). Differences between each subject's eyes and between OAG and healthy subjects were evaluated using repeated-measures analysis of variance with p<0.05 considered statistically significant., Results: All subjects demonstrated a significant increase in OPP in both eyes immediately following viewing. In all DAS eyes, retinal capillary blood flow rose immediately after stimulation and remained elevated for an hour postviewing. Viewing DAS increased retinal blood flow compared with control eyes (p=0.0014, 0.0135 superiorly and p=0.0094, 0.0001 inferiorly, at 30 and 60 min, respectively). OAG eyes had a significant reduction in the number of dormant retinal capillaries (p=0.0174), while healthy eyes demonstrated a larger increase in retinal capillary blood flow (p=0.0006 and p=0.0093 at 60 min, superior and inferior, respectively) following DAS viewing., Conclusion: Viewing DAS video for 30 min using ReviView increased retina blood flow both in healthy subjects and in patients with OAG., Trial Registration Number: NCT02959593., Competing Interests: Competing interests: AH would like to disclose that he receives remuneration from CIPLA, AdOM and Shire for serving as a consultant. AH also holds an ownership interest in AdOM and Oxymap. All relationships listed above are pursuant to Indiana University’s policy on outside activities.​ The contribution of ACVV was supported by Fondazione Roma and by the Italian Ministry of Health., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: To investigate the effects of a lutein complex supplementation on ocular blood flow in healthy subjects. Materials and Methods: Sixteen healthy female patients (mean age 36.8 ± 12.1 years) were enrolled in this randomized, placebo-controlled, double-blinded, two-period crossover study. Subjects received daily an oral dose of the lutein with synergistic phytochemicals complex (lutein (10 mg), ascorbic acid (500 mg), tocopherols (364 mg), carnosic acid (2.5 mg), zeaxanthin (2 mg), copper (2 mg), with synergistic effects in reducing pro-inflammatory mediators and cytokines when administered together in combination) and placebo during administration periods. Measurements were taken before and after three-week supplementation periods, with crossover visits separated by a three-week washout period. Data analysis included blood pressure, heart rate, intraocular pressure, visual acuity, contrast sensitivity detection, ocular perfusion pressure, confocal scanning laser Doppler imaging of retinal capillary blood flow, and Doppler imaging of the retrobulbar blood vessels. Results: Lutein complex supplementation produced a statistically significant increase in mean superior retinal capillary blood flow, measured in arbitrary units (60, p = 0.0466) and a decrease in the percentage of avascular area in the superior (-0.029, p = 0.0491) and inferior (-0.023, p = 0.0477) retina, as well as reduced systolic (-4.06, p = 0.0295) and diastolic (-3.69, p = 0.0441) blood pressure measured in mmHg from baseline. Data comparison between the two supplement groups revealed a significant decrease in systemic diastolic blood pressure (change from pre- to post-treatment with lutein supplement (mean (SE)): -3.69 (1.68); change from pre- to post-treatment with placebo: 0.31 (2.57); p = 0.0357) and a significant increase in the peak systolic velocity (measured in cm/sec) in the central retinal artery (change from pre- to post-treatment with lutein supplement: 0.36 (0.19); change from pre- to post-treatment with placebo: -0.33 (0.21); p = 0.0384) with lutein complex supplement; data analyses from the placebo group were all non-significant. Discussion: In healthy participants, oral administration of a lutein phytochemicals complex for three weeks produced increased ocular blood flow biomarkers within retinal vascular beds and reduced diastolic blood pressure compared to placebo.

Primary open-angle glaucoma (POAG) is a multifactorial optic neuropathy characterized by progressive retinal ganglion cell death and visual field loss. Some speculate that sex plays a role in the risk of developing POAG and that the physiological differences between men and women may be attributed to the variable effects of sex hormones on intraocular pressure, ocular blood flow, and/or neuroprotection. Estrogen, in the form of premenopausal status, pregnancy, and postmenopausal hormone therapy is associated with an increase in ocular blood flow, decrease in intraocular pressure and neuroprotective properties. The vasodilation caused by estrogen and its effects on aqueous humor outflow may contribute. In contrast, although testosterone may have known effects in the cardiovascular and cerebrovascular systems, there is no consensus as to its effects in ocular health or POAG. With a better understanding of sex hormones in POAG, sex hormone-derived preventative and therapeutic considerations in disease management may provide for improved sex-specific patient care.

Purpose: To compare the diagnostic capability of three-dimensional (3D) macular parameters against traditional two-dimensional (2D) retinal nerve fiber layer (RNFL) thickness using spectral domain optical coherence tomography. To determine if manual correction and interpolation of B-scans improve the ability of 3D macular parameters to diagnose glaucoma., Methods: A total of 101 open angle glaucoma patients (29 with early glaucoma) and 57 healthy subjects had peripapillary 2D RNFL thickness and 3D macular volume scans. Four parameters were calculated for six different-sized annuli: total macular thickness (M-thickness), total macular volume (M-volume), ganglion cell complex (GCC) thickness, and GCC volume of the innermost 3 macular layers (retinal nerve fiber layer + ganglion cell layer + inner plexiform layer). All macular parameters were calculated with and without correction and interpolation of frames with artifacts. The areas under the receiver operating characteristic curves (AUROC) were calculated for all the parameters., Results: The 3D macular parameter with the best diagnostic performance was GCC-volume-34, with an inner diameter of 3 mm and an outer of 4 mm. The AUROC for RNFL thickness and GCC-volume-34 were statistically similar for all regions (global: RNFL thickness 0.956, GCC-volume-34 0.939, P value = 0.3827), except for the temporal GCC-volume-34, which was significantly better than temporal RNFL thickness (P value = 0.0067). Correction of artifacts did not significantly change the AUROC of macular parameters (P values between 0.8452 and 1.0000)., Conclusions: The diagnostic performance of best macular parameters (GCC-volume-34 and GCC-thickness-34) were similar to or better than 2D RNFL thickness. Manual correction of artifacts with data interpolation is unnecessary in the clinical setting.

Purpose: To describe new software tools for quantifying optic nerve head drusen volume using 3-dimensional (3D) swept-source optical coherence tomography (SS-OCT) volumetric scans., Materials and Methods: SS-OCT was used to acquire raster volume scans of 8 eyes of 4 patients with bilateral optic nerve head drusen. The scans were manually segmented by 3 graders to identify the drusen borders, and thereafter total drusen volumes were calculated. Linear regression was performed to study the relationships between drusen volume, retinal nerve fiber layer thickness, and Humphrey visual field mean deviation., Results: In the 8 study eyes, drusen volumes ranged between 0.24 to 1.05 mm. Visual field mean deviation decreased by ∼20 dB per cubic millimeter increase in drusen volume, and the coefficient of correlation of the linear regression was 0.92. In this small patient series, visual field defects were detected when drusen volume was larger than about 0.2 mm., Conclusions: Software tools have been developed to quantify the size of OHND using SS-OCT volume scans.

[This corrects the article DOI: 10.1007/s40477-016-0194-5.].

Background/aims: Previous studies suggest that vascular abnormalities are involved in the pathogenesis of open-angle glaucoma. This study aims to examine the relationship of baseline retrobulbar blood flow measurements with functional and structural glaucomatous progression in patients with open-angle glaucoma over 4 years., Methods: In this study, 112 patients with open-angle glaucoma were examined at baseline and 78 with retrobulbar blood flow assessments were followed to 4 years. Colour Doppler imaging was used to evaluate retrobulbar blood flow. Structural disease progression was examined with optical coherence tomography and Heidelberg Retinal Tomography III. Functional disease progression was monitored with automated perimetry using Humphrey visual fields. Mixed-model analysis of covariance was used to test for significance of changes from baseline to 4-year follow-up. Two-sample t tests and χ 2 tests were used to test for baseline blood flow differences between patients who progressed and those who did not progress., Results: Patients who progressed structurally had a statistically significant lower baseline mean ophthalmic artery peak systolic velocity (PSV) (p=0.024) and ophthalmic artery end diastolic velocity (EDV) (p=0.012) compared with those who did not progress. Similarly, a lower baseline mean ophthalmic artery PSV (p=0.031) and ophthalmic artery EDV (p=0.005) were associated with patients who progressed functionally compared with those who did not progress after 4 years., Conclusions: In this study population, lower baseline ophthalmic artery blood flow velocities were associated with simultaneous structural and functional glaucoma progression after 4 years., Competing Interests: Competing interests: AH would like to disclose that he receives remuneration from Stemnion, Biolight, Nano Retina, AdOM, Science Based Health, Isarna Therapeutics, and Ono Pharmaceuticals for serving as a consultant. He also holds an ownership interest in AdOM, Nano Retina and Oxymap. All relationships listed above are pursuant to Indiana University's policy on outside activities., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Glaucoma is an optic neuropathy characterized by retinal ganglion cells (RGC) loss and retinal nerve fiber layer (RNFL) injury: this results in functional and morphological changes. The first can be observed by Standard Automated Perimetry (SAP), the second by Optic Coherence Tomography (OCT) that measures the RNFL and ganglion cell complex (GCC) thicknesses. Nevertheless, diagnosis of early glaucoma may be difficult. Recently, Medeiros et al. derived an empirical formula combining the measurement of structural and functional tests to provide an estimate of RGC. The aim of the current study is to analyse the correlation between RGC count, estimated by Medeiros' formula, and the structural and functional parameters in patients examined for glaucoma and to evaluate SAP, OCT and RGC counts capability to discriminate the weight of the disease itself., Methods: Ninety four eyes of 50 consecutive patients clinically referring to glaucoma service of the Universitary Eye Clinic were submitted to a complete ophthalmic evaluation including SAP and Spectral Domain OCT (SD-OCT) of RNFL and macular GCC. Average thickness of RNFL and macular GCC, parameters Global Loss Volume (GLV) and Focal Loss Volume (FLV) over the entire GCC map were taken into account. Estimates of RGC were obtained with the help of a model already published by Medeiros et al. combining light sensitivities from SAP and retinal thickness from OCT. The RGC count was estimated in the entire visual field (central 24°) and in the GCC macular area and then compared with functional and morphological parameters applying Pearson's correlation coefficient., Results: After the classification of the patients by the Glaucoma Staging System 2 of Brusini, we noticed a good correlation among the functional parameters considered, even if the Visual Field Index is unable to identify early glaucoma. An analogous result can be observed for structural data (RNFL and GCC). The correlation detected between functional and structural parameters was moderate. Great differences in RGC counts were found between groups at various stages of glaucoma. GLV showed highest level of correlation (r > -0.8) with RCG counts., Conclusions: Estimate circumpapillary and macular RGC counts can discriminate various stages of the disease and there is also a good/very good correlation with both functional and structural parameters. GLV could be used instead of RGC counts in clinical practice.

Purpose: This study was done to evaluate the intra- and inter-operator reproducibility of colour Doppler imaging (CDI) in assessing blood flow velocity in the ophthalmic (OA), central retinal (CRA) and short posterior ciliary arteries (SPCA) in healthy subjects., Materials and Methods: The right eye of two groups of eight healthy volunteers was examined. Two radiologists and two ophthalmologists, divided into pairs, measured peak systolic velocity (PSV), end-diastolic velocity (EDV) and resistivity index (RI) of each vessel using a different CDI device for each group. The concordance between two measurements was evaluated with Lin's concordance correlation coefficient (CCC)., Results: Globally, very good degrees of intra-operator concordance were obtained for the PSV (0.859 cm/s), EDV (0.834 cm/s) and RI (0.859) of the OA. There was moderate concordance for PSV (0.574 cm/s) and EDV (0.594 cm/s) and good concordance for RI (0.694) for the CRA. Good degrees of concordance were obtained for the SPCA measurements. However, inter-operator concordance was found globally poor., Conclusions: These data show that CDI measurements in retrobulbar vessels are operator dependent. To increase the intra-operator and inter-operator concordance, rules should be adopted for timing of the examination and positioning of the probe to minimise the pressure applied on the eye.

Purpose. Dupuytren disease is an inherited proliferative and progressive connective disease. Ectopic disease may, however, be located distant from the palmar fascia. 
Methods. Case report and review of the literature. 
Results. We describe a case of symmetric bilateral posterior subcapsular cataracts associated with symmetric bilateral Dupuytren disease and symmetric bilateral Ledderhose disease in a 56-year-old Caucasian man. His medical history was negative for glucocorticoids intake, diabetes, and exposure to radiation. Serum transforming growth factor β (TGF-β)1 concentration has been evaluated and was found to be almost double compared to the controls. 
Conclusions. We speculate that the TGF-β plays an important role for ocular and connective tissue disorders.