The Association Between Regional Macula Vessel Density and Central Visual Field Damage in Advanced Glaucoma Eyes.

PRCIS: Both macular superficial vessel density and ganglion cell complex (GCC) thickness measurement are significantly associated with regional and global 10-degree central visual field (VF) sensitivity in advanced glaucoma. PURPOSE: The purpose of this study was to evaluate the regional and global structure-function relationships between macular vessel density (MVD) assessed by optical coherence tomography angiography (OCTA) and 10-2 VF sensitivity in advanced open angle glaucoma eyes. METHODS: Macular OCTA and 10-2 VF sensitivity of 44 patients [mean deviation (MD) <-10 dB] were evaluated. Regional and global VF mean sensitivity (MS) was calculated from total deviation plots. Superficial and deep MVD were obtained from 3 × 3 and 6×6 mm 2 OCTA scans using 2 sectoral definitions. Spectral-domain optical coherence tomography macular GCC thickness was obtained simultaneously from the same scan as the MVD measurements. Linear regression models were used to assess the associations ( R2 ). RESULTS: Lower MS was significantly associated with a reduction in superficial MVD and GCC in each region of both scan sizes for both maps. Associations were weaker in the individual sectors of the whole image grid than the Early Treatment Diabetic Retinopathy Study map. Deep-layer MVD was not associated with central MS. Although 6×6 mm 2 and perifoveal vessel density had better associations with central 10-degree MS compared with GCC thickness (eg, R2 from 25.7 to 48.1 µm and 7.8% to 32.5%, respectively), GCC associations were stronger than MVD associations in the central 5-degree MS. CONCLUSIONS: Given a stronger MVD-central 10-degree VF association compared with GCC, as well as stronger GCC-central 5-degree VF association compared with MVD, MVD and GCC are complementary measurements in eyes with advanced glaucoma. A longitudinal analysis is needed to determine the relative utility of the GCC and MVD measurements.

Efficacy and safety of newly developed preservative-free latanoprost 0.005% eye drops versus preserved latanoprost 0.005% in open angle glaucoma and ocular hypertension: 12-week results of a randomized, multicenter, controlled phase III trial.

AIM: To evaluate the therapeutic efficacy, safety and tolerability of newly developed preservative-free (PF) latanoprost generic [TJO-002] and compare it with benzalkonium chloride (BAK)-preserved latanoprost [Xalatan®] in patients with primary open angle glaucoma (POAG) and ocular hypertension (OHT). METHODS: Included patients were aged ≥19y with POAG/OHT. After a washout period, patients with IOP 21-35 mm Hg at 9 a.m. were enrolled. After a full ophthalmic and glaucoma examination, 144 patients with POAG and OHT participated in this study. Subjects were randomly assigned either PF latanoprost (74 eyes) or BAK-preserved latanoprost (70 eyes). All subjects were examined at 4, 8, and 12wk after first administration. At each follow-up visit, IOP was measured at 9 a.m. and 5 p.m. and compliance was assessed. Throughout the study, all adverse events were recorded and monitored by the masked investigators who measured IOP. RESULTS: Both groups showed a statistically significant decrease of average diurnal IOP at 12wk compared to baseline (-7.21±3.10 mm Hg in the PF latanoprost group and -7.02±3.17 mm Hg in the BAK latanoprost group, both P<0.0001). There was no statistically significant diurnal IOP variation between the groups. In terms of tolerability, pruritus, burning/stinging, and sticky eye sensation, severity was significantly lower in the PF latanoprost group than in the BAK latanoprost group (P<0.05). CONCLUSION: PF latanoprost has at least similar efficacy in terms of IOP reduction and better tolerability compared with BAK latanoprost.

Primary Angle-Closure Glaucoma With Normal Intraocular Pressure at the First Visit: Its Prevalence and Ocular Characteristics.

PURPOSE: To investigate the prevalence of normal intraocular pressure (IOP) at first visit among patients with primary angle-closure glaucoma (PACG) and their ocular characteristics. PATIENTS AND METHODS: We retrospectively reviewed patients with PACG in a referral center. According to untreated IOP, we divided PACG eyes into 2 groups: those with normal IOP and those with high IOP (>21 mm Hg) at the first visit. RESULTS: One hundred sixty eyes of 160 Korean PACG patients were included. Sixty percent (97/160) of the patients had normal IOP at their first visit. The PACG patients with initially normal IOP had significantly longer axial length (mean±SD, 22.99±0.76 vs. 22.74±0.61) and deeper "true" anterior chamber depth (ACD) (2.09±0.27 vs. 1.82±0.33) than those with initially high IOP (both P<0.05). Multiple logistic regression revealed that deeper "true" ACD (per 0.1 mm; odds ratio, 1.38) and more hyperopic refractive errors (odds ratio, 1.48) were independent predictors of initially normal IOP in PACG eyes (P<0.05). The prevalence of disc hemorrhage was higher in PACG patients with initially normal IOP than in those with initially high IOP (29.9% vs. 14.3%, P=0.029). CONCLUSIONS: Sixty percent of patients with PACG had normal IOP at their first visit. This suggests that without gonioscopy clinicians may misdiagnose PACG as normal tension glaucoma. ACD measurement can aid the diagnosis of PACG because even PACG eyes with initially normal IOP have shallow ACD.

Celastrol supports survival of retinal ganglion cells injured by optic nerve crush.

The present study evaluates the effect of celastrol on the survival of retinal ganglion cells (RGCs) injured by optic nerve crush (ONC). Celastrol, a quinine methide triterpene extracted from the perennial vine Tripterygium wilfordii (Celastraceae), has been identified as a potential neuroprotective candidate in a comprehensive drug screen against various neurodegenerative diseases. Two weeks after ONC, the average density of remaining RGCs in retinas of animals treated with daily intraperitoneal (i.p.) injections of celastrol (1mg/kg) was approximately 1332 cells/mm(2), or 40.8% of the Celastrol/Control group. In retinas of the Vehicle/ONC group about 381 RGCs/mm(2) were counted, which is 9.6% of the total number of RGCs in the DMSO/Control group. This corresponds to approximately a 250% increase in RGC survival mediated by celastrol treatment compared to Vehicle/ONC group. Furthermore, the average RGC number in retinas of ONC animals treated with a single intravitreal injection of 1mg/kg or 5mg/kg of celastrol was increased by approximately 80% (760 RGCs/mm(2)) and 78% (753 RGCs/mm(2)), respectively, compared to Vehicle/ONC controls (422 cells/mm(2)). Injection of 0.2mg/kg of celastrol had no significant effect on cell survival, with the average number of RGCs being 514 cells/mm(2) in celastrol-treated animals versus 422 cells/mm(2) in controls. The expression levels of Hsp70, Hsf1, Hsf2, HO-1 and TNF-alpha in the retina were analyzed to evaluate the roles of these proteins in the celastrol-mediated protection of injured RGCs. No statistically significant change in HO-1, Hsf1 and Hsp70 levels was seen in animals with ONC. An approximately 2 fold increase in Hsf2 level was observed in celastrol-treated animals with or without injury. Hsf2 level was also increased 1.8 fold in DMSO-treated animals with ONC injury compared to DMSO-treated animals with no injury suggesting that Hsf2 induction has an injury-induced component. Expression of TNF-alpha in retinas of celastrol-treated uninjured and ONC animals was reduced by approximately 2 and 1.5 fold compared to vehicle treated animals, respectively. The observed results suggest that mechanisms underlying celastrol׳s RGC protective effect are associated with inhibition of TNF-alpha-mediated cell death.

Location of Initial Visual Field Defects in Glaucoma and Their Modes of Deterioration.

PURPOSE: To describe the location of initial visual field defects (VFD) in glaucoma, their modes of deterioration, and those factors associated with different modes of deterioration. METHODS: Patients with POAG were categorized into four groups based on three consecutive initial VFD: (1) superior paracentral defects (PD), (2) inferior PD, (3) superior nasal defects (ND), and (4) inferior ND. According to the worsening of the VF, four further subgroups were identified: (1) superior central worsening (CW), (2) inferior CW, (3) superior peripheral or nasal worsening (NW), and (4) inferior NW. Systemic and ocular factors were analyzed for each of the subgroups to identify possible associations. RESULTS: One hundred sixty-two eyes of 162 subjects were analyzed. Superior PD (n = 40) were more frequent in females and associated with disc hemorrhage (DH), and were less frequent in patients with systemic hypertension (HT). Inferior PD (n = 35) showed a significant association with cup shape measure and axial length. Superior ND (n = 37) were more highly associated with HT and diabetes. Inferior ND (n = 50) showed a lower incidence of DH. With binary logistic regression analysis, superior PD showed a significant association with both HT and DH. With respect to VF worsening, superior CW showed a significant association with HT and diabetes, whereas superior NW was associated with a high minimum IOP during follow-up, and inferior NW was associated with a high maximum IOP during follow-up. CONCLUSIONS: The initial location and subsequent direction of worsening of VFD were associated with different systemic and ocular factors.

Disc haemorrhage is associated with the fast component, but not the slow component, of visual field decay rate in glaucoma.

BACKGROUND/AIMS: To investigate the association of disc haemorrhage (DH) with regional visual field (VF) decay in glaucoma. METHODS: Retrospective longitudinal study was performed. Patients from the University of California, Los Angeles, glaucoma database were assigned to two groups based on the presence or absence of a DH. Pointwise exponential regression was used to identify the fast and slow rate components of VF decay. Associations between patient demographics, ocular and systemic factors, and visual field rates were analysed. RESULTS: A total of 185 patients were included, 54 of whom were documented to have a DH at some point during their course. DH group had a higher female preponderance (p=0.017, OR 2.23), a higher incidence of peripapillary atrophy (p=0.002, OR 4.46), more advanced disease (p=0.016) and a higher fast rate component of VF decay (p<0.001) than non-DH group. With multivariate logistic regression analysis, only the fast rate component showed a statistically significant relationship with DH. CONCLUSIONS: The presence of DH is associated with a greater fast component rate of VF decay. The identification and monitoring of the fast component of VF decay may prove useful in the identification and management of glaucoma patients at high risk of progression.

The dark phase intraocular pressure elevation and retinal ganglion cell degeneration in a rat model of experimental glaucoma.

Intraocular pressure (IOP) elevation is considered as a major risk factor causing the progression of vision deterioration in glaucoma. Although it is known that the IOP level changes widely throughout the day and night, how the dark or light phase IOP elevation contributes to retinal ganglion cell (RGC) degeneration is still largely unclear. To examine the profile of IOP, modified laser photocoagulation was applied to the trabecular meshwork of Brown Norway rats and both light and dark phase IOPs were monitored approximately 1-2 times a week. The relationship between IOP elevation and RGC degeneration was investigated while RGC body loss was analyzed with Rbpms immunolabeling on retinal wholemount and axonal injury in the optic nerve was semi-quantified. The baseline awake dark and light IOPs were 30.4 ± 2.7 and 20.2 ± 2.1 mmHg respectively. The average dark IOP was increased to 38.2 ± 3.2 mmHg for five weeks after the laser treatment on 270° trabecular meshwork. However, there was no significant loss of RGC body and axonal injury. After laser treatment on 330° trabecular meshwork, the dark and light IOPs were significantly increased to 43.8 ± 4.6 and 23 ± 3.7 mmHg respectively for 5 weeks. The cumulative dark and light IOP elevations were 277 ± 86 and 113 ± 50 mmHg days respectively while the cumulative total (light and dark) IOP elevation was 213 ± 114 mmHg days. After 5 weeks, regional RGC body loss of 29.5 ± 15.5% and moderate axonal injury were observed. Axonal injury and loss of RGC body had a high correlation with the cumulative total IOP elevation (R(2) = 0.60 and 0.65 respectively). There was an association between the cumulative dark IOP elevation and RGC body loss (R(2) = 0.37) and axonal injury (R(2) = 0.51) whereas the associations between neuronal damages and the cumulative light IOP elevation were weak (for RGC body loss, R(2) = 0.01; for axonal injury, R(2) = 0.26). Simple linear regression model analysis showed statistical significance for the relationships between the total cumulative IOP elevation and RGC body loss (P = 0.009), and axonal injury (P = 0.016). To examine the role of light and dark IOP elevation in RGC body loss and axonal injury, analyses for the association between different light/dark IOP factors and percentage of RGC body loss/axonal injury grading were performed and only the association between the cumulative dark IOP elevation and axonal injury showed statistical significance (P = 0.033). The findings demonstrated that the cumulative total (light and dark) IOP elevation is a risk factor to RGC degeneration in a rat model of experimental glaucoma using modified partial laser photocoagulation at 330° trabecular meshwork. Further investigations are required to understand the role of longer term light and dark phase IOP elevation contributing to the progression of degeneration in different compartments of RGCs.

The neuronal EGF-related gene Nell2 interacts with Macf1 and supports survival of retinal ganglion cells after optic nerve injury.

Nell2 is a neuron-specific protein containing six epidermal growth factor-like domains. We have identified Nell2 as a retinal ganglion cell (RGC)-expressed gene by comparing mRNA profiles of control and RGC-deficient rat retinas. The aim of this study was to analyze Nell2 expression in wild-type and optic nerve axotomized retinas and evaluate its potential role in RGCs. Nell2-positive in situ and immunohistochemical signals were localized to irregularly shaped cells in the ganglion cell layer (GCL) and colocalized with retrogradely-labeled RGCs. No Nell2-positive cells were detected in 2 weeks optic nerve transected (ONT) retinas characterized with approximately 90% RGC loss. RT-PCR analysis showed a dramatic decrease in the Nell2 mRNA level after ONT compared to the controls. Immunoblot analysis of the Nell2 expression in the retina revealed the presence of two proteins with approximate MW of 140 and 90 kDa representing glycosylated and non-glycosylated Nell2, respectively. Both products were almost undetectable in retinal protein extracts two weeks after ONT. Proteome analysis of Nell2-interacting proteins carried out with MALDI-TOF MS (MS) identified microtubule-actin crosslinking factor 1 (Macf1), known to be critical in CNS development. Strong Macf1 expression was observed in the inner plexiform layer and GCL where it was colocalizied with Thy-1 staining. Since Nell2 has been reported to increase neuronal survival of the hippocampus and cerebral cortex, we evaluated the effect of Nell2 overexpression on RGC survival. RGCs in the nasal retina were consistently more efficiently transfected than in other areas (49% vs. 13%; n = 5, p<0.05). In non-transfected or pEGFP-transfected ONT retinas, the loss of RGCs was approximately 90% compared to the untreated control. In the nasal region, Nell2 transfection led to the preservation of approximately 58% more cells damaged by axotomy compared to non-transfected (n = 5, p<0.01) or pEGFP-transfected controls (n = 5, p<0.01).

Quantitative analysis of retinal ganglion cell survival with Rbpms immunolabeling in animal models of optic neuropathies.

PURPOSE: To investigate whether a recently described retinal ganglion cell (RGC) marker Rbpms (RNA binding protein with multiple splicing) could be used for RGC quantification in various models of RGC degeneration. METHODS: Optic nerve crush, excitotoxicity, and elevated intraocular pressure (IOP) rat models were used. Topographic analysis of Rbpms immunolabeling was performed on retinal wholemounts. Retrograde labelings with Fluorogold (FG) and III ß-tubulin immunohistochemistry were compared. RESULTS: In the optic nerve crush model, 37%, 87%, and 93% of Rbpms-positive cells were lost 1, 2, and 4 weeks, respectively. Significant loss of Rbpms-positive cells was noted 1 week after intravitreal injection of 12, 30, and 120 nmol N-methyl-d-aspartate (NMDA), whereas coinjection of 120 nmol of NMDA along with MK-801 increased the cell number from 10% to 59%. Over 95% of Rbpms-positive cells were FG- and III ß-tubulin-positive after injury caused by optic nerve crush and NMDA injection. In rats with elevated IOP, induced by trabecular laser photocoagulation, there was a significant loss of Rbpms-positive cells compared with that of contralateral controls (P = 0.0004), and cumulative IOP elevation showed a strong linear relationship with the quantification of RGCs by Rbpms immunolabeling and retrograde labeling with FG. More than 99% of the remaining Rbpms-positive cells were double-labeled with FG. CONCLUSIONS: Rbpms can reliably be used as an RGC marker for quantitative evaluation in rat models of RGC degeneration, regardless of the nature and the location of the primary site of the injury and the extent of neurodegeneration.