[Fixed combination of latanoprost and timolol in the long-term treatment of patients with normal-tension glaucoma]. / Fiksirovannaya kombinatsiya latanoprost/timolol v dolgosrochnom lechenii patsientov s glaukomoi normal'nogo davleniya.

The most well-studied and widely prescribed fixed-combination drug for open-angle glaucoma is latanoprost/timolol. Its significant hypotensive effect is especially important in challenging cases, among which are patients with normal-tension glaucoma. With long life expectancy and the constant need for treatment, requirements are high for both the effectiveness of the drug and its tolerability. This paper presents a follow-up of 7 patients with normal-tension glaucoma who have been using the fixed combination of latanoprost/timolol for 10 years. All patients showed very good tolerability to the drug and their quality of life was preserved. A moderate rate of disease progression according to static perimetry was noted in one case. A mild degree of dry eye syndrome according to the OSDI questionnaire and an objective assessment of the state of the ocular surface was observed in one patient. The latanoprost/timolol fixed combination is a well-tolerated, highly effective and safe long-term treatment choice for normal-tension glaucoma.

Visual and structural prognosis of the untreated fellow eyes of unilateral normal tension glaucoma patients.

PURPOSE: To investigate the visual and structural prognosis of untreated initial non-glaucomatous fellow eyes of unilateral normal tension glaucoma (NTG) patients. METHODS: In this retrospective observational cohort study, 50 NTG patients with unilateral visual field (VF) loss and no VF defect, retinal nerve fiber layer (RNFL) defect or neuroretinal rim (NRR) notching in the fellow eyes, and those who had initial non-glaucomatous fellow eyes untreated were included. For the fellow eyes, the development of VF defect, RNFL defect, and NRR notching was inspected retrospectively by two observers. Baseline clinical characteristics including initial intraocular pressure (IOP), central corneal thickness, and spherical equivalent (SE) were compared between glaucomatous and fellow eyes. RESULTS: During the mean follow-up period of 8.77 ± 2.92 years, five patients (10 %) developed RNFL defect and four patients (8 %) developed NRR notching in the fellow eye. Among six patients (12 %) who had developed either RNFL defect or NRR notching, only three patients (6 %) developed VF loss in 1.81, 3.09, and 9.27 years respectively. The initial IOP was significantly higher (p = 0.031), SE was more myopic (p = 0.025), and the occurrence of disc hemorrhage (p = 0.049) was significantly higher in glaucomatous eyes than that in fellow eyes. CONCLUSIONS: The incidence of glaucoma development in the fellow eye is rather low. Therefore, the initial non-glaucomatous fellow eye of the unilateral NTG patient may be observed without treatment until glaucoma develops.

[Aiming for zero blindness].

Glaucoma is the leading cause of acquired blindness in Japan. One reason that it often leads to blindness is that it can continue to worsen even after effective medical reduction of intraocular pressure (IOP), the only evidence-based treatment. The limitations of current treatments make it critical to identify IOP-independent factors that can cause glaucoma and develop new drugs to target these factors. This is a challenging task, as the pathology of glaucoma is thought to be very complex, with different combinations of factors underlying its development and progression in different patients. Additionally, there is a deficiency in methods to efficiently perform clinical evaluations and reliably probe the state of the disease over relatively short periods. In addition, newly developed drugs need to be evaluated with clinical trials, for which human and financial resources are limited, before they can be widely used for treatment. Taking all these issues into consideration, it is evident that there are two urgent issues to consider: the development of methods to classify glaucoma in detail based on its pathology, and the improvement of clinical evaluation methods. In this review, we discuss some of our efforts to develop new neuroprotective agents for glaucoma, with a focus on the following three areas: 1. Clinical research and development of methods to classify glaucoma in detail based on IOP-independent factors, and the exploration of possibilities for the improvement of clinical evaluation of glaucoma. 2. Pathology-based research and development of new drugs for glaucoma, focusing on comprehensive gene expression analysis and the development of molecule-targeting drugs, using murine optic nerve crush as a disease model. 3. Development of next generation in vivo imaging modalities and the establishment of infrastructure enabling "big-data" analysis. First, we discuss our clinical research and the development of methods to classify glaucoma in detail based on IOP-independent factors, as well as our investigation of ways to improve the clinical evaluation of the disease. Our research was prompted by the multifactorial nature of glaucoma. There is a high degree of variability in the pattern and speed of the progression of visual field defects in individual patients, presenting a major obstacle for successful clinical trials. To overcome this, we classified the eyes of glaucoma patients into 4 types, corresponding to the 4 patterns of glaucomatous optic nerve head morphology described: by Nicolela et al. and then tested the validity of this method by assessing the uniformity of clinical features in each group. We found that in normal tension glaucoma (NTG) eyes, each disc morphology group had a characteristic location in which the loss of circumpapillary retinal nerve fiber layer thickness (cpRNFLT; measured with optical coherence tomography: OCT) was most likely to occur. Furthermore, the incidence of reductions in visual acuity differed between the groups, as did the speed of visual field loss, the distribution of defective visual field test points, and the location of test points that were most susceptible to progressive damage, measured by Humphrey static perimetry. These results indicate that Nicolela's method of classifying eyes with glaucoma was able to overcome the difficulties caused by the diverse nature of the disease, at least to a certain extent. Building on these findings, we then set out to identify sectors of the visual field that correspond to the distribution of retinal nerve fibers, with the aim of detecting glaucoma progression with improved sensitivity. We first mapped the statistical correlation between visual field test points and cpRNFLT in each temporal clock-hour sector (from 6 to 12 o'clock), using OCT data from NTG patients. The resulting series of maps allowed us to identify areas containing visual field test points that were prone to be affected together as a group. We also used a similar method to identify visual field sectors within a 10 x 10 grid displayed by an OCT map of the macula. By analyzing both the visual field and the macular map sectors, we anticipate that a more accurate and sensitive detection of glaucoma progression can become possible. We also used laser speckle flowgraphy (LSFG) to assess optic nerve blood flow. We found that compared to healthy eyes, eyes with early-stage NTG had decreased blood flow, and the peak of the blood flow wave form of each heartbeat was delayed. Finally, we used a method combining swept source OCT (SS-OCT) and newly developed analysis software to reconstruct the entire lamina cribrosa, a structure situated deep in the optic nerve head. This morphological analysis returned preliminary data suggesting that alterations in the morphology of the lamina cribrosa are already present in the early stages of glaucoma. This result indicates that axonal injury, mediated by morphological abnormalities of the lamina cribrosa, is involved in the pathogenesis of glaucoma. The next topic discussed is the pathology-based drug research and development, focusing on the use of comprehensive gene expression analysis and the development of molecule-targeting drugs in a murine model of optic nerve injury. Learning from clinical data on glaucoma and the lamina cribrosa, we carried out basic research to first determine what factors regulate axonal injury, and then develop drugs targeting these factors. Specifically, we performed a comprehensive gene expression analysis, using a next generation sequencer, and pathway analysis of retinal samples obtained from a murine model of axonal injury. This analysis revealed a characteristic upregulation of genes (such as Chop) that belongs to the endoplasmic reticulum stress pathway. An immunohistological analysis revealed that these changes in gene expression took place in the retinal ganglion cells, suggesting that endoplasmic reticulum stress molecules may be suitable therapeutic targets. Among these molecules, we chose CHOP as our primary target for drug development. Currently, we are in the process of screening a library of 1274 drugs, all of which are already used in human subjects, for CHOP inhibitors. The last topic of our discussion is future possibilities for glaucoma management. First, we discuss the development of next generation in vivo imaging modalities that allow detailed description of pathomechanisms of this multifactorial disease, glaucoma. The purpose of this research was to improve the efficacy of glaucoma diagnosis and to visualize its pathology at a cellular/molecular level and develop molecule-specific therapies. Currently available visual field tests are subjective, since they rely on a determination of the threshold of light perception, and are affected by poor reproducibility. The current dependence on visual field tests to ascertain the progression of glaucoma is thus a serious limitation on an important task of ophthalmologists. We, therefore, turned our focus to the establishment of an in vivo imaging method to detect dying retinal ganglion cells, which would highlight the pathologic state of glaucoma with high sensitivity. To this end, we used confocal scanning ophthalmoscopy to assess the usefulness of SYTOX Orange as a cell death probe. Our results showed that this probe could reveal dying retinal ganglion cells clearly, quickly and with high sensitivity. We, therefore, believe that the clinical application of probes that can sensitively detect dying retinal ganglion cells is a highly promising approach. This also applies to the use of molecular tools that can provide information on the molecular pathology of glaucoma. Finally, we would like to introduce our national collaborative work on the analysis of "big-data". The project aims to collect as wide a range of data as possible at an unprecedented scale. The data to be registered ranges from basic glaucoma data, such as IOP and visual field test results, to data from the most sophisticated comprehensive expression analyses or imaging data. This is an important area of research, since it promises to enable the exploration of targets for drug discovery and the identification of new biomarkers to efficiently detect glaucoma progression by applying new analysis strategies to the complex mass data. The project not only depends on the collaborative efforts of various types of clinical settings including private practices, medical centers and university hospitals, but also contributions of the pharmaceutical and the medical device industries. Thus, uniting a wide range of Japanese interests and resources is the key for success. In summary, in order to aim for ZERO BLINDNESS, a drastic improvement in the quality of our patient care, drug development research for unmet medical demands, and a strategic collaboration of various professionals in the ophthalmic industry are essential. With the deep appreciation we fell towards the selfless support extended during the earthquake disaster, we wish to translate our "gratitude" into "power" from Tohoku. In doing so, we as academicians are determined to keep on contributing to the society by making progress in the medicine.

Retinal vessel diameter in normal-tension glaucoma patients with asymmetric progression.

PURPOSE: To investigate the longitudinal changes in the central retinal vessel diameter in asymmetric progressive normal-tension glaucoma (NTG) patients. METHODS: This study included 27 patients with bilateral NTG without any systemic vascular disease who showed glaucomatous progression in one eye at the mean follow-up of 24.3 months (range, 18-29 months). Progression was determined by the development of new retinal nerve fiber layer (RNFL) defects or widening of pre-existing defects on red-free RNFL photographs. The central retinal arteriolar equivalent (CRAE) and the central retinal venular equivalent (CRVE) were measured at baseline and at the mean follow-up of 24.3 months. We classified the eyes of each patient as either progressed or stable eyes, and compared the differences and changes in the CRAE and CRVE. RESULTS: No significant inter-eye difference was observed at baseline in the mean CRAE (167.5 ± 22.2 µm vs. 168.2 ± 15.5 µm, p = 0.809) and in the mean CRVE (276.3 ± 18.2 µm vs. 281.6 ± 21.9 µm, p = 0.267) between the progressed and stable eyes. There were significant changes in CRAE in the progressed eyes between baseline and 2 years after baseline (from 167.5 ± 22.2 µm to 146.9 ± 18.0 µm, p < 0.0001), but there were no significant changes in the stable eyes (from 168.2 ± 15.5 µm to 167.5 ± 14.8 µm, p = 0.084). CONCLUSIONS: In our series of NTG patients with asymmetric progression, central retinal artery diameter decreased over time in the progressed eyes, whereas no significant decrease in the central retinal artery diameter was seen in the stable eyes.

Higher optic nerve sheath diameters are associated with lower ocular blood flow velocities in glaucoma patients.

PURPOSE: To investigate the relationship between optic nerve sheath diameter (ONSD) and retrobulbar blood flow velocities, as measured by color Doppler imaging (CDI) in glaucoma patients. METHODS: We performed a prospective, randomized, observer-masked study involving a total of 197 subjects. Once enrolled, they were divided by three groups: healthy controls (n = 51), normal-tension glaucoma patients (NTG, n = 58), and primary, open-angle glaucoma patients (POAG, n = 88). All subjects underwent a general ophthalmological examination, an ultrasound-based assessment of the ONSD, and a hemodynamic study of the retrobulbar vascularization using CDI. Non-parametric tests, chi-square contingency tables, and the Deming correlations were used to explore differences and correlations between variables in the diagnostic groups. RESULTS: ONSD was not different between experimental groups (p = 0.28). ONSD correlated positively with the pulsatility index of the ophthalmic artery in healthy individuals (p = 0.007), but not in glaucoma patients (NTG: p = 0.41; POAG: p = 0.22). In NTG patients, higher ONSD values were associated with lower end-diastolic and mean flow velocities in the short ciliary arteries (p = 0.005 in both correlations). No such correlation was found in healthy nor POAG groups (p range between 0.15 to 0.96). ONSD was not associated with any CDI-related variable of the central retinal artery in any cohort. Venous outflow velocities were not associated with ONSD in any of the three groups. CONCLUSIONS: ONSD is negatively correlated with retrobulbar blood flow velocities in glaucoma patients, but not in healthy controls.

Results of long-term monitoring of normal-tension glaucoma patients receiving medical therapy: results of an 18-year follow-up.

PURPOSE: To conduct a ≥15-year follow-up assessment of the visual field (VF) in normal-tension glaucoma (NTG) patients receiving medical therapy and to identify risk factors for VF progression. DESIGN: A retrospective clinical study. METHODS: Medical records of 78 eyes of 78 NTG patients monitored for ≥15 years were reviewed. VF progression was defined by a mean deviation (MD) deteriorated twice by 3.00 dB from baseline (MD criterion) and an annual decrease in the MD slope exceeding -0.5 dB/year (MD slope criterion). Logistic regression analysis was employed to identify risk factors for VF progression. RESULTS: The mean follow-up period was 18.3 years. The average intraocular pressure (IOP) before treatment was 15.1 ±1.9 mmHg and the average treated IOP was 13.5 ±1.5 mmHg with 2.0 medications. Forty-two eyes (53.8%) showed VF progression using the MD criterion and 15 eyes (19.2%) showed a negative MD slope less than -0.5 dB/year. Disc hemorrhage (DH) was observed in 30 eyes (38.5%). The mean VF progression rate was -0.38 ±0.30 dB/year in the DH group and -0.24 ±0.28 dB/year in the non-DH group (P = 0.012). Multiple logistic regression analysis identified DH [relative risk (RR) 4.28; P = 0.028] as a risk factor for VF progression using the MD criterion. DH (RR 8.77; P = 0.007) and IOP fluctuation during follow-up (RR 5.03; P = 0.048) were detected as risk factors using the MD slope criterion. CONCLUSIONS: DH and IOP fluctuation were associated with VF progression in NTG during long-term therapy.

Three-year efficacy and safety of omidenepag isopropyl in patients with normal tension glaucoma.

PURPOSE: To retrospectively evaluate the 3-year efficacy and safety of single-agent omidenepag isopropyl in patients with normal tension glaucoma (NTG). STUDY DESIGN: Retrospective. METHODS: One hundred patients (100 eyes) who had newly been administered omidenepag isopropyl were enrolled in this study. Intraocular pressure (IOP) was compared at baseline and 6, 9, 12, 18, 24, 30, and 36 months after administration. The mean deviation values at baseline and 12, 24, and 36 months measured using the Humphrey visual field test (30-2 Swedish Interactive Threshold Algorithm standard) were compared. Adverse reactions and dropouts were assessed. RESULTS: IOP significantly decreased from 15.5±2.7 mmHg at baseline to 13.8 ±2.3 mmHg after 6 months, 13.9± 2.3 mmHg after 12 months, 13.9±2.3 mmHg after 18 months, 13.8±2.1 mmHg after 24 months, 13.9±2.0 mmHg after 30 months, and 13.6±1.7 mmHg after 36 months (P < 0.0001). There was no significant difference in the mean deviation values at baseline (-3.66±3.49 dB), 12 months (-3.41±3.80 dB), 24 months (-3.13±3.81 dB), and 36 months (-3.06±3.30 dB). Adverse reactions occurred in 11 patients (11.0%), including conjunctival hyperemia in 6 patients. Fifty-two patients (52.0%) were excluded from the analysis because they discontinued treatment either due to IOP measurement by NCT or the use of additional drugs. CONCLUSION: After the administration of omidenepag isopropyl, IOP in patients with NTG decreased within 3 years, visual fields were maintained, and safety was satisfactory. Thus, omidenepag isopropyl can be used as the first-line treatment for patients with NTG.

Relationship of change in central corneal thickness to visual field progression in eyes with glaucoma.

BACKGROUND: To assess the relationship between baseline central corneal thickness (CCT) and/or ongoing CCT change over time with subsequent visual field progression. METHODS: One hundred sixty three eyes of 163 patients with medically treated glaucoma were followed up for 6.8 ± 1.8 years. Exclusion criteria was laser or intraocular surgery. Baseline and follow up CCT, confocal scanning laser tomography and visual fields were performed. CCT and CCT change related to visual field progression using Glaucoma Progress Analysis were assessed. Multivariate logistic regression analysis for predictive factors of glaucoma progression was used to analyze data. RESULTS: Thinner baseline CCT was associated with more advanced damage at presentation, mean deviation (MD) (r=0.17, p=0.02) and neuroretinal rim area (NRR) (r=0.20, p=0.02). Progressing eyes had significantly thinner (p=0.01) baseline CCT compared to non-progressing eyes. The slope of visual field change was significantly greater (p=0.05) for thinner (<540 µm) as compared to thicker eyes. A small but significant CCT reduction (12.78 ± 13.35 µm, p<0.0001) was noted in all eyes; however, there was no significant difference (p=0.95) in the amount of change between progressing and non-progressing eyes. CCT change did not correlate with MD or NRR change. A thinner CCT (Odds ratio=1.80, p=0.02), but not CCT change (Odds ratio=1.07, p=0.69), was a significant risk factor for glaucoma progression. CONCLUSIONS: CCT correlates significantly with the amount of glaucomatous damage at presentation. Thinner corneas may be associated with increased risk of visual field progression. CCT reduced slightly over time in eyes with glaucoma; but the magnitude of this change was not related to visual field progression.

Longitudinal effect of topical antiglaucoma medications on central corneal thickness.

BACKGROUND: To determine the change in central corneal thickness over time and whether the use of long-term topical antiglaucoma medications influences central corneal thickness. DESIGN: Case control study with retrospective and prospective data collection. PARTICIPANTS: One hundred eighty-seven eyes of 187 glaucoma patients (mean follow up 6.92 ± 1.67 years) being treated with topical antiglaucoma medications (at least 3 years) with no history of surgery or laser were included and compared with 100 eyes of 100 age-matched, untreated control subjects (mean follow up 6.58 ± 1.93 years) who were glaucoma suspects with normal intraocular pressure not on any treatment. METHODS: Demographic data, central corneal thickness and intraocular pressure were collected at initial glaucoma diagnosis and at most recent visit, and findings were compared between two groups. MAIN OUTCOME MEASURES: Mean change in central corneal thickness in microns (µm). RESULTS: Central corneal thickness fell significantly (P < 0.0001) in treated eyes but not in control eyes (P = 0.18); mean central corneal thickness reduction was 12.29 ± 13.65 µm in treated eyes and 1.17 ± 8.75 µm in controls. Among treated eyes, central corneal thickness reduction was significant (P < 0.0001) in those treated with either prostaglandins or a combination of prostaglandin and beta-blockers, while no significant reduction occurred in eyes treated with only beta-blockers (P = 0.15) when compared with control eyes. CONCLUSIONS: Prostaglandins appear to be associated with a small but significant central corneal thickness reduction over time. Serial central corneal thickness measurements might be helpful in glaucoma patients, particularly those on prostaglandins.

Influence of 0.002% Omidenepag Isopropyl on Intraocular Pressure and the Cornea in Normal Tension Glaucoma.

PRCIS: Although Omidenepag isopropyl drops elicited stable intraocular pressure reductions in NTG patients, transient changes in refraction and corneal endothelial cells, significant increase of central corneal thickness, and corneal erosion should be considered. PURPOSE: To analyze the efficacy and safety of 0.002% omidenepag Isopropyl (OMDI) eye drops in patients with normal tension glaucoma (NTG). METHODS: Medical records for 62 eyes treated with OMDI for ≥6 months were analyzed. Intraocular pressure (IOP), refraction, keratometry, central corneal thickness (CCT), endothelial cell count, coefficient of variation of endothelial cell area (CV), corneal erosion, and central retinal thickness were compared at baseline and 1, 3, and 6 months. RESULTS: IOP significantly decreased from 13.4±3.8 to 11.9±3.0, 11.7±2.9, and 12.2±3.3 mm Hg at each follow-up ( P <0.001). Endothelial cell count did not change, but CV transiently increased from 12.6 to 17.0 at 1 month, CCT increased from 531.5 to 538.4 µm, myopia changed from -1.5 to -1.9 D, and keratometry changed from 44.5 to 44.7 D. CV, myopia, and keratometry recovered to baseline at 6 months; however, CCT remained high. Significant corneal erosion was observed at 6 months. Central retinal thickness changes were not observed. There were improvements in prostaglandin-associated skin pigmentation (86.7%), eyelash elongation (40.0%), and deepening of the upper eyelid sulcus and ptosis (~30%) at 3 months after exchange to OMDI. Adverse reactions were corneal erosion (27.4%), corneal thickening (21.0%), conjunctival hyperemia (11.3%), photophobia (5.7%), blurred vision (5.7%), and anterior chamber cells (4.8%). CONCLUSIONS: OMDI eye drops elicited significant and stable IOP reductions after 6 months in NTG patients with low IOP. However, transient myopic and corneal endothelial cell changes, development of corneal thickening, and corneal erosion should be considered when using OMDI.

Clinical Efficacy of Omidenepag Isopropyl for Primary Open-Angle Glaucoma, Normal Tension Glaucoma, or Ocular Hypertension: A Meta-Analysis.

Purpose: To investigate the clinical efficacy of omidenepag isopropyl (OMDI) among glaucoma patients in terms of increased intraocular pressure (IOP) changes through a meta-analysis. Methods: Studies investigating the clinical efficacy of OMDI toward glaucoma patients were systemically searched. Inclusion criteria include recruiting studies that consisted of glaucoma or normal tension glaucoma patients who received OMDI treatment at least 4 weeks in duration. The primary outcome was to compare changes in IOP levels at baseline before OMDI treatment and after OMDI treatment. Results: Six studies were included with a total of 358 eyes. Our results showed OMDI monotherapy resulted in significant decreased IOP among patients with ocular hypertension, with weighted mean difference post-OMDI treatment being -4.684 (95% confidence interval: -6.010 to -3.358) and I2 of 91.092%. Separate subgroup analyses also showed initial IOP greater than 21 mmHg and those within the age group greater than 65 years old to be correlated with significant reduction in IOP post-OMDI. Randomized control trial (RCTs) design was also found to be superior compared with non-RCT in terms of investigating IOP changes after OMDI. The country of origin of the recruited studies and OMDI dosage frequencies were also found to have no effect on overall IOP changes after OMDI treatment. Conclusions: The current meta-analysis indicates OMDI to be a clinically effective treatment for glaucoma patients in terms of lowering IOP levels.

Morning Blood Pressure Surge and Glaucomatous Visual Field Progression in Normal-Tension Glaucoma Patients With Systemic Hypertension.

PURPOSE: To investigate the impact of a morning blood pressure surge (MBPS) at baseline on subsequent visual field (VF) progression in hypertensive, normal-tension glaucoma (NTG) patients receiving oral anti-hypertensive treatment. DESIGN: Retrospective cohort study. METHODS: A total of 127 eyes from 127 newly diagnosed NTG patients treated for systemic hypertension and followed up for at least 2 years were analyzed. All patients underwent baseline 24-hour ambulatory blood pressure monitoring (ABPM) and at least 5 serial VF examinations during the follow-up period. VF progression was defined according to the Early Manifest Glaucoma Trial criteria. The associations of VF progression with 24-hour ABPM-based blood pressure (BP) parameters (including MBPS) and other clinical variables were analyzed using Cox regression analyses. Kaplan-Meier survival analysis was used to compare VF survival estimates in patients with and without MBPS. RESULTS: VF progression was detected in 38 eyes (29.9%) over a 5.2-year mean follow-up. In the multivariate Cox regression model, a greater MBPS (hazard ratio [HR] = 1.033; P = .024) and lower nighttime mean arterial pressure (MAP) trough (HR = 0.965; P = .031) at baseline were significant independent predictors of subsequent VF progression. The likelihood of VF progression was significantly greater in patients with higher MBPS (P = .021) at baseline according to Kaplan-Meier survival analysis. CONCLUSIONS: An increased MBPS at baseline is a significant independent predictor of subsequent VF progression in NTG patients with systemic hypertension. This may be another relevant BP parameter associated with VF progression in hypertensive NTG patients receiving oral anti-hypertensive treatment.

Differentiating Branch Retinal Artery Occlusion From Normal Tension Glaucoma With Optical Coherence Tomography Angiography.

BACKGROUND: To describe a patient with branch retinal artery occlusion that was misdiagnosed as normal tension glaucoma (NTG). CASE PRESENTATION: A female 76-year-old patient presenting inferior nasal visual field scotoma, neuroretinal thinning in the optic disk of the right eye with corresponding atrophy of superior retinal nerve fiber layer in optical coherence tomography (OCT). She was treated with latanoprost eye drops for NTG. However macular OCT angiography showed a localized thinning of the inner retina following the superior temporal branch retinal artery path, along with a superficial and medium capillary plexus reduction and superior macular ganglion cell layer atrophy. Further investigation with carotid arteries angio-tomography revealed an atheromatous lesion in the right and left carotid bulb with stenosis of 50-60%, in addition to aneurysms of the cavernous, pituitary and communicating segments of the left and right internal carotid artery, reinforcing the diagnosis of superior temporal branch retinal artery ischemic. CONCLUSION: This case highlights the importance of establishing differential diagnosis in cases of presumed NTG and reinforces the use of the OCT angiography in clinical practice.

Ginkgo biloba: an adjuvant therapy for progressive normal and high tension glaucoma.

Gingko biloba has been used for hundreds of years to treat various disorders such as asthma, vertigo, fatigue and, tinnitus or circulatory problems. Two of the main extracts are EGb761 and LI 1370. Most pharmacological, toxicological and clinical studies have focused on the neuroprotective value of these two main extracts. Neuroprotection is a rapidly expanding area of research. This area is of particular interest due to the fact that it represents a new avenue of therapy for a frustrating disease that may progress despite optimal treatment. One such disease is glaucoma.Glaucoma leads to the loss of retinal ganglion cells and their axons but also to tissue remodelling which involves both the optic nerve head and the retina. In the retina the astrocytes get activated. In addition, the optic nerve gets thinner and the cells of the lateral geniculate ganglion disappear partially. On average, ocular blood flow (OBF) is reduced in glaucoma patients in various tissues of the eye. Increased intraocular pressure (IOP) is a major risk factor for glaucomatous damage. Nevertheless, there is little doubt that other risk factors besides IOP are involved. One such risk factor is a primary vascular dysregulation (PVD) occurring in patients with a disturbed autoregulation, another risk factor is oxidative stress.

Recent clinical pearls from clinical trials in glaucoma.

PURPOSE OF REVIEW: Over the past several years, numerous clinical trials in glaucoma have contributed to our understanding of the medical and surgical treatment of the disease. The goal of this review is to summarize the findings and conclusions of what the authors feel are the key clinical trials in glaucoma. RECENT FINDINGS: One of the major findings of Low-Pressure Glaucoma Treatment study was that patients randomized to the brimonidine group were statistically less likely to have progressive visual field loss than those randomized to the timolol group, even though there was no significant difference between the intraocular pressure (IOP)-lowering effect of these two drugs. The Ocular Hypertension Treatment Study has effectively demonstrated that patients with ocular hypertension should be risk stratified prior to initiation of treatment and that it appears to be relatively safe to delay treatment in low-risk patients. The 3-year canaloplasty study demonstrates the long-term safety and efficacy of this surgery. However, it also demonstrates that canaloplasty can deliver a modest IOP reduction and therefore is likely more suited for patients with mild damage and a higher target IOP. The 1-year results from the Ahmed Baerveldt Comparison Study do not demonstrate a clear superiority of one implant over the other. These findings are consistent with prior retrospective studies in the literature. SUMMARY: These four studies have furthered our understanding of the field of glaucoma and provided key insights into the medical and surgical management of patients with this complex disease.

Clinical use of multifocal visual-evoked potentials in a glaucoma practice: a prospective study.

PURPOSE: To test a framework that describes how the multifocal visual-evoked potential (mfVEP) technique is used in a particular glaucoma practice. METHODS: In this prospective, descriptive study, glaucoma suspects, ocular hypertensives and glaucoma patients were referred for mfVEP testing by a single glaucoma specialist over a 2-year period. All patients underwent standard automated perimetry (SAP) and mfVEP testing within 3 months. Two hundred and ten patients (420 eyes) were referred for mfVEP testing for the following reasons: (1) normal SAP tests suspected of early functional loss (ocular hypertensives, n = 43; and glaucoma suspects on the basis of suspicious optic disks, n = 52); (2) normal-tension glaucoma patients with suspected central SAP defects (n = 33); and (3) SAP abnormalities needing confirmation (n = 82). RESULTS: All the glaucoma suspects with normal SAP and mfVEP results remained untreated. Of those with abnormal mfVEP results, 68 % (15/22) were treated because the abnormal regions on the mfVEP were consistent with the abnormal regions seen during clinical examination of the optic disk. The mfVEP was abnormal in 86 % (69/80) of eyes with glaucomatous optic neuropathy and SAP damage, even though it did not result in an altered treatment regimen. In NTG patients, the mfVEP showed central defects in 44 % (12 of 27) of the eyes with apparently normal central fields and confirmed central scotomata in 92 % (36 of 39), leading to more rigorous surveillance of these patients. CONCLUSIONS: In a clinical practice, the mfVEP was used when clinical examination and subjective visual fields provided insufficient or conflicting information. This information influenced clinical management.

Bilateral upper eyelid retraction caused by topical bimatoprost therapy.

The authors report a case with upper eyelid retraction caused by topical bimatoprost therapy. Topical bimatoprost 0.03% was administered to a 69-year-old woman with bilateral normal-tension glaucoma. It was first administered to the left eye, and 3 weeks later, therapy on the right side of the eye was initiated. One week after the initiation of therapy on the right side, right upper eyelid retraction occurred, and 63 days after starting treatment on the left side (42 days after initiation on the right side), conspicuous bilateral upper eyelid retraction was observed. Bimatoprost instillation was then stopped and the medication was switched to latanoprost 0.005%. Upper eyelid retraction was reversed to normal levels approximately 1 week after cessation of bimatoprost therapy. In conclusion, a rare case of upper eyelid retraction caused by topical bimatoprost therapy, which was reversed after discontinuation of the medication, is reported.

One-Year Efficacy and Safety of Omidenepag Isopropyl in Patients with Normal-Tension Glaucoma.

Purpose: To retrospectively evaluate the 1-year efficacy and safety of single-agent of omidenepag isopropyl in patients with normal-tension glaucoma (NTG). Methods: One hundred patients (100 eyes) newly administered omidenepag isopropyl were enrolled. Intraocular pressure (IOP) was compared at baseline and 3, 6, 9, and 12 months after administration. The mean deviation values at baseline and 12 months measured using the Humphrey visual field test (30-2 Swedish Interactive Threshold Algorithm standard) were compared. Adverse reactions and dropouts were observed. Results: IOP significantly decreased from 15.5 ± 2.7 mmHg at baseline to 13.3 ± 2.5 mmHg after 3 months, 13.7 ± 2.3 mmHg after 6 months, 13.9 ± 2.4 mmHg after 9 months, and 13.7 ± 2.3 mmHg after 12 months (P < 0.0001). There was no significant difference in the mean deviation values at baseline (-3.66 ± 3.49 dB) and after 12 months (-3.41 ± 3.80 dB). Adverse reactions occurred in 9 patients (9.0%): conjunctival hyperemia (n = 6), eye pain (n = 1), iritis (n = 1), and blepharitis (n = 1). Twenty-one patients (21.0%) discontinued administration because of changes in medication (n = 7), interruption of visits (n = 5), adverse reactions (n = 4), and others. Conclusions: After administering omidenepag isopropyl, the IOP in patients with NTG decreased within 1 year, visual fields were maintained, and safety was satisfactory. Omidenepag isopropyl can be used as the first-line medication for patients with NTG.

Frequent self-monitoring of intraocular pressure can determine effectiveness of medications in eyes with normal tension glaucoma: A case report.

RATIONALE: It is difficult to follow changes in the intraocular pressure (IOP) in glaucomatous eyes comprehensively because of the limited number of outpatient examinations. We report our findings in a case of normal tension glaucoma (NTG) in which frequent self-measurements of the IOP were used to evaluate the IOP-lowering effect of different medications. PATIENT CONCERNS: A 50-year-old man with NTG had a nasal step visual field defect in his right eye and was being treated with 0.005% latanoprost (LAT) ophthalmic solution (XALATAN®). DIAGNOSIS: The patient was diagnosed with NTG. INTERVENTIONS: The patient had a mean IOP in the right eye of 10.9 ±â€…1.5 mm Hg (68 measurements in 1 month, Period A) during treatment with 0.005% LAT ophthalmic solution. During the second month (Period B), the mean IOP in the same eye was 9.8 ±â€…1.7 mm Hg (59 measurements) with treatment with a LAT and carteolol fixed combination (LCFC). And during the third month (Period C), the mean IOP was 7.4 ±â€…1.1 mm Hg (57 measurements) on the same right eye after the addition of brimonidine and brinzolamide fixed combination ophthalmic solution to the LCFC ophthalmic solution. OUTCOMES: Comparisons of the IOPs between Periods A and B and between B and C showed that the reductions in the IOP were significant. CONCLUSION: We conclude that frequent self-measurements of the IOP can determine that small changes of the IOPs are significant.

Sovesudil (locally acting rho kinase inhibitor) for the treatment of normal-tension glaucoma: the randomized phase II study.

PURPOSE: To evaluate ocular hypotensive efficacy and the safety of sovesudil (formally known as PHP-201), a novel Rho-associated protein kinase (ROCK) inhibitor, in patients with normal-tension glaucoma (NTG). DESIGN: Multicentre, prospective, double-masked, randomized, placebo-controlled, parallel clinical study. METHODS: Patients with NTG (unmedicated baseline IOP ≤ 21 mmHg) were randomized in 3 groups and treated with sovesudil in concentrations of 0.25% and 0.5%, or with a placebo three times daily (TID) for 4 weeks. The primary end-point was the mean diurnal IOP change from the baseline at week 4. Safety was recorded over a 4-week treatment period and the following 2-week observation period. RESULTS: A total of 119 patients were included in the primary efficacy analysis. The mean diurnal IOP change from the baseline at week 4 was -1.56 mmHg for the high-dose group, -1.10 mmHg for the low-dose group and -0.65 mmHg for the placebo group. The difference between the high-dose and the placebo groups was -0.91 mmHg (95% confidence intervals: -1.73, -0.09). 0.5% sovesudil TID met the criteria for superiority to the placebo. The most frequent ocular adverse event among sovesudil-treated patients was conjunctival hyperaemia (24.4% for the high-dose and 17.5% for the low-dose group) and predominately classified as mild. CONCLUSIONS: Sovesudil 0.25% and 0.5% TID showed statistically significant IOP-lowering effects and 0.5% concentration's IOP-lowering effects met the superiority criteria in comparison with the placebo at week 4. Sovesudil was well tolerated with mild adverse events including relatively low incidence of conjunctival hyperaemia in patients with NTG.