An update on ripasudil for the treatment of glaucoma and ocular hypertension.

Ripasudil (K-115) is a novel Rho-associated protein kinase (ROCK) inhibitor. The Rho-ROCK pathway regulates key downstream effectors involved in many cellular functions, in particular in the actin cytoskeleton activity. The clinical effects of ripasudil expected on the eye include an intraocular pressure-lowering effect and a wound-healing activity on corneal endothelial cells, but many other functions are currently under investigation. To date, ripasudil has been approved in Japan (2014) for the treatment of glaucoma and ocular hypertension, and several clinical trials are currently investigating its role in the treatment of Fuchs' corneal dystrophy. In this review, we will discuss its pharmacokinetics, pharmacodynamics and clinical efficacy, focusing also on its safety and tolerability profile.

Evaluation of Agreement between HRT III and iVue OCT in Glaucoma and Ocular Hypertension Patients.

Purpose. To determine the agreement between Moorfields Regression Analysis (MRA), Glaucoma Probability Score (GPS) of Heidelberg retinal tomograph (HRT III), and peripapillary nerve fibers thickness by iVue Optical Coherence Tomography (OCT). Methods. 72 eyes with ocular hypertension or primary open angle glaucoma (POAG) were included in the study: 54 eyes had normal visual fields (VF) and 18 had VF damage. All subjects performed achromatic 30° VF by Octopus Program G1X dynamic strategy and were imaged with HRT III and iVue OCT. Sectorial and global MRA, GPS, and OCT parameters were used for the analysis. Kappa statistic was used to assess the agreement between methods. Results. A significant agreement between iVue OCT and GPS for the inferotemporal quadrant (κ: 0.555) was found in patients with abnormal VF. A good overall agreement between GPS and MRA was found in all the eyes tested (κ: 0.511). A good agreement between iVue OCT and MRA was shown in the superonasal (κ: 0.656) and nasal (κ: 0.627) quadrants followed by the superotemporal (κ: 0.602) and inferotemporal (κ: 0.586) sectors in all the studied eyes. Conclusion. The highest percentages of agreement were found per quadrant of the MRA and the iVue OCT confirming that in glaucoma damage starts from the temporal hemiretina.

Citicoline oral solution in glaucoma: is there a role in slowing disease progression?

PURPOSE: To assess the effect of citicoline on visual field rates of progression in patients with progressing glaucoma. PATIENTS AND METHODS: Forty-one patients with a diagnosis of progressing glaucoma received citicoline in oral solution for 2 years. Included were patients with a disease progression of at least -1 dB/year (at MD, mean deviation) for at least 3 years before entering the study despite controlled intraocular pressure (IOP). Patients were followed with 4 visual field examinations per year for 2 years. RESULTS: At baseline, the mean rate of progression was -1.1 (±0.7) dB/year despite the fact that the IOP had been below 18 mm Hg for at least 3 years. At study inclusion, the mean IOP was 15.5 (±2.6) mm Hg and the mean MD was -9.2 (±6.7) dB in the worst eye. Starting from the first cycle of treatment with citicoline, the mean rate of progression significantly changed to -0.15 (±0.3) dB/year at the end of the study (p = 0.01). CONCLUSIONS: This study seems to indicate that supplementation with citicoline might significantly slow down glaucomatous rates of progression.

Differences in central corneal thickness between the paired eyes and the severity of the glaucomatous damage.

PURPOSE: To evaluate whether a difference in central corneal thickness (CCT) between the paired eyes could be associated to worse glaucoma in the thinner cornea eye. METHODS: From 16 different glaucoma centres, at least 50 glaucomatous patients were saved on the Italian Glaucoma Register. Eight hundred and sixteen glaucomatous patients were found in the register. CCT, ophthalmoscopic cup/disc ratio, mean deviation (MD), pattern SD (PSD), and intraocular pressure (IOP). The difference (Δ) between the paired eyes was calculated for all the considered parameters and two subgroups were created on the basis of ΔCCT. Because the difference between the two eyes could be positive or negative, the absolute value of Δ was considered for all the measurements. Three different ΔCCT cutoffs were selected: 10, 15, and 20 µm. Student's t-test was used to compare the subgroups. RESULTS: When the entire group was divided in two subgroups using 20 µm as ΔCCT cutoff, no significant difference was found for ΔIOP (-0.38 ± 2.53 (mean ± SD) mm Hg and -0.07 ± 2.35 mm Hg, respectively) between the two subgroups. Significant (P<0.001) difference was found for ΔMD (6.58 ± 7.30 and 3.14 ± 4.22 dB, respectively), ΔPSD (3.92 ± 4.01 and 2.16 ± 2.57, respectively), and ΔC/D (0.11 ± 0.14 and 0.08 ± 0.11, respectively) between the two subgroups. No significant correlation was found between ΔCCT and the other parameters. CONCLUSION: The ΔCCT between the two eyes could be associated to a worse glaucoma in the thinner cornea eye.

Agreement to detect glaucomatous visual field progression by using three different methods: a multicentre study.

AIM: To examine the level of agreement among nine clinicians in assessing progressive deterioration in visual field (VF) overview using three different methods of analysis. METHODS: Each visual field was assessed by Humphrey Field Analyzer (HFA), program 24-2 SITA Standard. Nine expert clinicians assessed the progression status of each series by using HFA 'overview printouts' (HFA OP), the Guided Progression Analysis (GPA) and the Guided Progression Analysis (GPA2). VF series were presented in random order, but each patient's VF remained in chronological order within a given field series. Each clinician adopted his personal methods based on his knowledge to evaluate VF progression. The level of agreement between the clinicians was evaluated by using weighted κ statistics. RESULTS: A total of 303 tests, comprising 38 visual field series of 7.9 ± 3.4 tests (mean ± SD), were assessed by the nine glaucoma specialists. When the intra-observer agreement was evaluated between HFA OP and GPA, the mean κ statistic was 0.58 ± 0.13, between HFA OP and GPA2, κ was 0.55 ± 0.06 and between GPA and GPA2 it was 0.56 ± 0.17. When the inter-observer agreement was analysed κ statistic was 0.65 for HFA OP, 0.54 for GPA and 0.70 for GPA2. CONCLUSIONS: Using any procedure for evaluating the progression of a series of VF, agreement between expert clinicians is moderate. Clinicians had higher agreement when GPA2 was used, followed by HFA OP and GPA printouts, but these differences were not significant.

Test-retest variability of intraocular pressure and ocular pulse amplitude for dynamic contour tonometry: a multicentre study.

AIMS: To assess the test-retest variability of intraocular pressure (IOP) and ocular pulse amplitude (OPA) measurements utilising dynamic contour tonometry (DCT) and to evaluate possible influential factors. METHODS: The study included 350 consecutive subjects (175 glaucoma, 175 control; one eye per subject) from seven European centres. IOP was measured once with a Goldmann applanation tonometer (GAT) and twice by DCT (DCT1, DCT2) in a randomised sequence. OPA was also recorded for both DCT measurements. Differences (DCT1-DCT2; OPA1-OPA2; GAT-DCT1; GAT-DCT2) were assessed using the t test. The intraclass coefficient of correlation (ICC) and coefficient of variation (CoV) for DCT and OPA were calculated. RESULTS: DCT1 was 0.6+/-1.6 mm Hg higher than DCT2 (p<0.001); OPA1 was 0.1+/-0.7 mm Hg higher than OPA2 (p=0.02). Results were not influenced by randomisation test order. In both glaucoma and normal subjects, DCT and OPA showed ICC>0.90 and >0.76, and CoV=4.8-5.0% and 10.3-10.5%, respectively. DCT1 and 2 were 2.4+/-2.6 and 1.8+/-2.6 mm Hg higher respectively than GAT (p<0.001). DISCUSSION: DCT test-retest variability was almost perfect for IOP and good for OPA. Tonometry measurements with DCT tended to be overestimated compared with GAT.

Retinal nerve fibre layer measurements and optic nerve head analysis in multiple sclerosis patients.

PURPOSE: To verify whether scanning laser polarimeter with the new variable corneal compensation algorithm (GDx VCC) and scanning laser ophthalmoscopy (Heidelberg Retina Tomograph (HRT)) allow measuring retinal ganglion cell loss in patients with multiple sclerosis (MS). PATIENTS AND METHODS: We enrolled 23 MS patients with a history of previous demyelinating monocular optic neuritis. Examination included visual evoked potentials (VEPs), scanning laser ophthalmoscopy, and scanning laser polarimeter. HRT was performed to assess optic nerve head (ONH) shape, while GDx VCC was used to evaluate the retinal nerve fibre layer thickness (RNFLt) around the ONH. Statistical analysis was performed comparing results obtained for each eye with the available normative database and with the unaffected fellow eye. RESULTS: When the affected eye group was compared to the fellow-eye group, a significant (P<0.05) difference was found for few GDx VCC parameters. In contrast, no significant correlation was observed between clinical assessment and imaging techniques when the normal database of HRT and GDx VCC was used. A significant association was observed between VEP latency and some GDx VCC parameters. CONCLUSIONS: Our results suggested that scanning laser polarimetry could detect loss of ganglion cells following demyelinating optic neuritis, but further studies are needed.

Rarebit perimetry and frequency doubling technology in patients with ocular hypertension.

PURPOSE: To test the capability of rarebit perimetry (RP), a recent non-conventional perimetric technique, in detecting early functional damage in subjects with ocular hypertension (OHT) and to compare RP findings with those obtained by frequency-doubling technology (FDT) perimetry. METHODS: Thirty patients with OHT were matched with 30 healthy subjects. All were tested with RP and FDT. Frequency-doubling technology mean deviation (MD) and pattern standard deviation (PSD), as well as RP mean hit rate (MHR), of the two groups were analyzed. The agreement between the two techniques was tested by Kappa analysis. RESULTS: In the OHT group the mean (SD) FDT MD was 0.5 (2.1), the mean (SD) FDT PSD was 4.2 (1.6), and the mean (SD) RP MHR was 81.4 (6.7). In the control group, corresponding values were mean (SD) FDT MD 1.1 (1.4), mean (SD) FDT PSD 3.0 (0.3), mean (SD) RP MHR 96.2 (2.0). The differences between the two groups were not significant for the studied indexes. Eleven (36.6%) out of the 30 OHT eyes had abnormal RP results; 12 (40.0%) eyes had abnormal FDT results. Five (16.6%) eyes had abnormal RP and FDT findings. Only 1 eye (3.3%) in the control group had abnormal RP results and 3 eyes (10.0%) had abnormal FDT results. RP and FDT showed a moderate agreement (Kappa=0.43; 95% CI: 0.42 to 0.51). CONCLUSIONS: RP and FDT showed VF defects not shown in standard automated perimetry in the OHT group. This may be indicative of an increased risk in developing glaucoma, even if a gold standard for detecting subtle defects is not currently available. RP has the additional advantage of not requiring any expensive device to be used. The poor agreement between these techniques in identifying eyes with early damage warrants further investigations. Large longitudinal studies are needed before defining the role of RP in early glaucoma diagnosis.

Visual field damage and progression in glaucomatous myopic eyes.

PURPOSE: To make a visual field retrospective analysis on a group of patients with primary open angle glaucoma (POAG) and to evaluate whether different refractive errors could have different progression of the 30 degrees central sensitivity. METHODS: A total of 110 patients with POAG (52 men and 58 women) were included in the study. All the patients were divided into four subgroups based on the refractive error. The visual field of all the included patients was assessed by an Octopus 30 degrees central visual field every 6 months, for a total of 837 visual fields examined. The resulting data were analyzed by PERIDATA for Windows 1.7 TREND function. Mean defect (MD) and loss variance (LV) were considered for the analysis. RESULTS: At the first examination, 82% of eyes showed a global decrease of differential light sensitivity (MD >2 dB) and in 67% the distribution of the defect was nonhomogeneous (LV >6 dB). The analysis of variance for subgroups showed a more significant decrease of MD in highly myopic patients. A linear regression analysis highlighted a statistically significant change in time of MD in 36% and of LV in 34% of the eyes studied. Highly myopic patients had the highest (p<0.01) percentage of change of MD and LV (46% and 42%, respectively). Among the four subgroups, there was no difference in progression of MD decrease in time. CONCLUSIONS: These results showed that after 5 years of glaucoma, the visual field was altered in most of the eyes examined (82%) and that in 67% of cases, its defect was nonhomogeneous and worsened with the increase of myopia. The regression linear analysis of visual field changes in time showed a progressive increase of MD and LV in approximately one third of all the eyes examined.

Sector-based analysis of frequency doubling technology sensitivity and optic nerve head shape parameters.

PURPOSE: To evaluate which Heidelberg Retina Tomograph (HRT) parameter is the best predictor of frequency doubling technology (FDT) sensitivity by using a sector based analysis between FDT and optic nerve head shape parameters such as cup shape measure (CSM) and rim area (RA), which have been shown to have the best correlation with FDT indices among all the HRT parameters. METHODS: One eye was randomly chosen from 100 patients with primary open angle glaucoma (abnormal visual field and/or abnormal optic nerve and untreated intraocular pressure above 21 mm Hg). All the patients were examined with Humphrey field analyzer (HFA), program 24-2, SITA standard, FDT program C 20, and HRT. RA and CSM for the HRT analysis and mean deviation, pattern standard deviation, and the sensitivity of each tested point for the FDT test were considered in this study. All the parameters were calculated as both global and sector measurements. Findings were analyzed using Pearson's correlation coefficient and linear regression model. RESULTS: Significant (p<0.001) correlation was found between FDT indices and HRT RA and CSM. Significant (p<0.001) sector correlation was found between FDT sensitivity and RA and CSM, but when a linear regression model was applied, RA was the most predictive parameter of FDT. Temporal CSM was more strongly correlated to FDT fovea sensitivity than temporal RA. Furthermore, sector HRT parameters were better correlated to HFA than to FDT. CONCLUSIONS: In this glaucomatous group, cup shape measure and RA were significantly correlated to FDT indices. RA was more predictive of FDT abnormality than CSM in all the considered sectors except in the temporal one. However, HFA was a stronger predictor of HRT parameters than FDT.

Corneal thickness and visual field damage in glaucoma patients.

PURPOSE: To verify whether there was a significant correlation between central corneal thickness (CCT) and visual field damage in patients with primary open angle glaucoma (POAG). METHODS: A total of 99 eyes with POAG were consecutively recruited. Patients were classified as glaucomatous based on visual field and optic nerve head damage. All underwent applanation tonometry, Humphrey perimetry, and measurement of CCT with ultrasonic pachymetry. Based on CCT value, the sample was split at the mode in two groups (group 1<535 microm, n=49; group 2>or=535 microm, n=50). RESULTS: Entire cohort: mean CCT 554 microm+/-45.03; mean deviation (MD) -6.68 dB+/-7.32; pattern standard deviation (PSD) 5.33+/-3.75; intraocular pressure (IOP) 17.91+/-4.16 mmHg with treatment. Group 1: CCT was 504.8 microm+/-30.8; MD -9.01 dB+/-8.72; PSD 6.38+/-3.99; IOP 18.02 mmHg+/-4.66. Group 2: mean CCT 574.6 microm+/-35.03; MD -4.39 dB+/-4.70; PSD 4.25+/-3.19; IOP 17.79 mmHg+/-3.57. A significant difference was found between the two groups for both MD and PSD. Linear regression analysis showed a significant correlation between CCT and PSD (P<0.001). CONCLUSIONS: Our data show that patients with a thinner cornea had a worse MD and PSD. As a thinner CCT causes an underestimation of the true IOP, there may be a delay in the diagnosis of POAG or an inadequate estimate of the clinical course despite apparently desirable IOP applanation readings.

Detection of glaucomatous optic nerve head by using Heidelberg topographic maps.

PURPOSE: To evaluate the capacity of a new topographic map analysis to detect abnormal optic discs from healthy ones in a new cohort of subjects. PATIENTS AND METHODS: Only one eye was chosen randomly from each subject included in the study. In total, 20 normal eyes with a normal visual field, an IOP of <22 mmHg and no history of glaucoma in their family, and 20 glaucomatous eyes with an abnormal visual field and an open angle were selected. All the subjects were examined with the Heidelberg Retina Tomograph (HRT, Heidelberg Engineering GMBH, Heidelberg, Germany) and Humphrey Perimeter, program 30-2 (Humphrey Instrument, Inc., San Leandro, CA, USA). Topographic maps analysis was performed to each HRT optic nerve head image. Sensitivity, specificity, and diagnostic precision were calculated. RESULTS: When the topographic map analysis was applied to the group, a sensitivity of 80%, a specificity of 75%, and a diagnostic precision of 77.5% were obtained. CONCLUSION: Using the topographic map analysis, the HRT capacity to differentiate normal optic discs from those with glaucoma was similar to those already published in the literature, but using this technique there is no input from the observer to draw the contourline and reference plane is not necessary.

Observer interpretation variability of peripapillary flow using the Heidelberg Retina Flowmeter.

PURPOSE: To evaluate the intraobserver and interobserver reproducibility of the automatic full field perfusion image analysis (AFFPIA) program on Heidelberg Retina Flowmeter (HRF) derived perfusion images in a multicentre study group. METHODS: A total of 10 subjects were consecutively recruited in the study. One eye was randomly selected for each patient. Blood flow was assessed by HRF and flow measurements were analyzed by using the AFFPIA program. AFFPIA calculates the Doppler frequency shift and the haemodynamic variables: flow for each pixel. Intraobserver and interobserver reproducibility was calculated for AFFPIA program. The retinal blood flow was calculated in the superior and inferior section, furthermore, each section was divided into three parts: the temporal area, the nasal, and the rim area, as for software, but only the temporal and nasal areas were considered in this study. The blood flow and the area considered were evaluated for each part. RESULTS: When the intraobserver and intraimage reproducibility was studied, the coefficient of variation ranged from 0.4 to 1.9%. When the interobserver and intraimage reproducibility was studied, the retinal blood flow coefficient of variation ranged from 0.52 to 3.30% for the supero-temporal area, from 0.13 to 2.67% for the inferotemporal area, from 0.15 to 2.75% for the supero-nasal area, and from 0.04 to 5.65% for the infero-nasal area. CONCLUSION: Our results with AFFPIA showed an interobserver coefficient of variation of retinal blood flow measurements always less than 6% in both temporal and nasal areas. No significant difference was found among the four observers for the flow measurements.

Retinal nerve fiber layer measured by Heidelberg retina tomograph and nerve fiber analyzer.

PURPOSE: To compare retinal nerve fiber layer (RNFL) thickness measured by Heidelberg retina tomograph (HRT) and nerve fiber analyzer (GDx). METHODS: Twenty eyes of 20 consecutive healthy subjects were recruited for this study. Each subject had a normal visual field and a normal optic nerve head, which was assessed by slit-lamp biomicroscopy using a 90 degrees lens. Using the HRT and GDx, RNFL measurement was calculated as for software vs 2.01 and vs 1.0.14, respectively. Retinal nerve fiber layer thickness was evaluated for the entire annulus surface every 5 degrees degrees. RNFL was assessed by HRT and GDx. HRT RNFL measurement was calculated at 0 microm from the edge, while GDx RNFL measurement at 1.75 disc diameter as for software. The difference between the highest points and the deepest points was calculated and compared. Furthermore, because of the possibility of different scales in the two systems, the following ratio was calculated: superior/inferior, superior/temporal, superior/nasal, inferior/temporal, and inferior/nasal. RESULTS: When the entire RNFL thickness was considered, a significant (p<0.001) difference was found between the HRT and GDx measurements. A difference of 200 microm was found between the highest and the deepest HRT points while a difference of 40 microm was found between the highest and the deepest GDx points. CONCLUSIONS: HRT and GDx RNFL measurements were statistically different in each sector. However, ratio parameters showed no difference between the obtained values except for superior/temporal ratio and inferior/temporal ratio.

Quality of life in patients with early, moderate and advanced glaucoma.

PURPOSE: To evaluate the quality of life in glaucomatous patients using two different questionnaires: the medical outcomes study 36-item short-form health survey (MOS SF-36) and Viswanathan et al's questionnaire and to compare these two questionnaires. METHODS: Seventy-seven patients with glaucoma were consecutively selected. Two force-choice questionnaires were administered to each patient. Viswanathan et al's questionnaire was related to visual disability and the second was related to the quality of life from the MOS 36-item short-form health survey. Both questionnaires were evaluated among all the considered patients and the results were compared. Then the questionnaire which did the best evaluation was used to test the quality of life in three different subgroups based on the mean deviation of the worse eye. Mann-Whitney non parametric test and Spearman's r coefficient were used and a P value less than 0.05 was considered to be statistically significant. A linear regression model was used. RESULTS: In the entire group (n = 77) the Mean Deviation (MD) was -6.5 +/- 6.8 dB (mean +/- standard deviation) and Corrected Pattern Standard Deviation (CPSD) was 4.7 +/- 4.1 dB. The score of the Viswanathan et al's questionnaire was 8.3 +/- 2.4, while MOS SF-36 score ranged from 60.5% to 100% (mean score %). A significant (P < 0.0001) correlation was found between the score of the Viswanathan et al's questionnaire and MD (r = 0.79), Pattern Standard Deviation (PSD) (r = -0.68) and CPSD (r = -0.61). CONCLUSION: Viswanathan et al's questionnaire was more useful than MOS SF-36, both for the score and for the velocity to use. Furthermore Viswanathan et al's questionnaire was more significantly correlated to visual field MD.

Clinical ability of Heidelberg retinal tomograph examination to detect glaucomatous visual field changes.

PURPOSE: To determine the agreement between Heidelberg Retinal Tomograph (HRT; Heidelberg Instruments, Heidelberg, Germany) and visual field examinations in differentiating normal from glaucomatous eyes and to evaluate the sensitivity and specificity of HRT optic disc examination in detecting eyes with glaucomatous damage. STUDY DESIGN: Cross-sectional study. PARTICIPANTS: Three hundred fifty-nine patients, for a total of 359 eyes (55 normal, 209 with ocular hypertension [OHT], and 95 with primary open-angle glaucoma). INTERVENTION: Optic disc imaging by HRT, using a 10 degrees angle view; a mean of three repeated images were analyzed using version 2.01 software. The optic disc was classified as "normal/glaucomatous" on the basis of multivariate discriminant analysis and cumulative frequency distribution (ranked-segment distribution curves). The visual field was examined using the DS 30 II program (Humphrey perimeter, Zeiss Humphrey System, Dublin, CA), with a glaucomatous visual field being defined on the basis of an abnormal glaucoma hemifield test and a statistically significant corrected pattern standard deviation less than 4 dB. MAIN OUTCOME MEASURES: Agreement between HRT and visual field examinations calculated by means of the kappa statistic and the sensitivity and specificity of HRT examination. RESULTS: The agreement between the visual field-based and HRT definition of glaucoma was fair to poor, with a kappa statistic of between 0.48 and 0.28. The sensitivity and specificity of the HRT examination were, respectively, 80% and 65%, according to Mikelberg's analysis, and, respectively, 31% to 53% and 90% to 92%, according to the analysis based on cumulative curves of normality. CONCLUSIONS: In a broad clinical setting including normal, OHT, and glaucoma patients, the HRT and visual field tests have fair to poor agreement in detecting glaucoma. The HRT demonstrated a lack of specificity when using Mikelberg's multivariate discriminant analysis and a lack of sensitivity when using cumulative frequency distribution (ranked-segment distribution) curves. These values did not change when normal or OHT patients were excluded from the analysis. In the clinical setting, caution should be used when interpreting HRT results on the basis of multivariate discriminant analysis or cumulative frequency distribution curves.

Three-dimensional optic nerve head algorithm for the detection of glaucomatous damage.

PURPOSE: To determine whether a three-dimensional optic disc algorithm could be useful in differentiating optic nerve heads (ONH) with a normal visual field from those with an abnormal visual field also when using a simultaneous stereoscopic computerised ONH analyser. METHODS: One eye was randomly chosen from 45 normals and 55 patients with glaucoma (mean deviation -7.7 +/- 9.0 dB, corrected pattern standard deviation 3.1 +/- 2.3 dB). All the subjects were examined with the Humphrey Perimeter (program 30-2) and with the Topcon Image-net X Rev-3.51 b. Using the topographic map of the system, the algorithm of the third moment or cup shape measure was applied to the numbers (the number of points ranged from 623 to 1,883 depending on the size of the disc area) that identify the heights of all the points of the optic disc surface. Findings were analysed by means of the Mann-Whitney U test and receiver operator characteristic curves. RESULTS: The sensitivity and specificity of this three-dimensional ONH algorithm applied to Topcon Image-net was 90.6% and 85.1% respectively. No difference was found between the groups for age, disc area and number of the analysed points. CONCLUSIONS: The algorithm of cup shape measure or third moment is a useful parameter to separate eyes with normal from those with abnormal visual field also when using a simultaneous stereoscopic system such as Image-net.