Publications by authors named "Tomomi Higashide"

102 Publications

Association of the CYP39A1 G204E genetic variant with increased risk of glaucoma and blindness in patients with exfoliation syndrome.

Ophthalmology 2021 Nov 8. Epub 2021 Nov 8.

Singapore Eye Research Institute and Singapore National Eye Center, Singapore; Duke-NUS Medical School, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address:

Purpose: Carriers of functionally deficient mutations in the CYP39A1 gene have been recently reported to have a 2-fold increased risk of exfoliation syndrome (XFS). The aim of this study was to evaluate the risk of blindness and related clinical phenotypes of XFS patients carrying the loss-of-function CYP39A1 G204E mutation in comparison to XFS patients without any CYP39A1 mutation.

Design: Retrospective case study PARTICIPANTS: 35 patients diagnosed with XFS carrying the CYP39A1 G204E mutation and 150 XFS patients without any CYP39A1 mutation, who were randomly selected from the Japanese XFS cohort.

Methods: Two-sided Fisher's Exact Test with an α-level <0.05 was used to estimate the significance of the calculated Odds Ratio (OR) for all categorical measures. Comparisons between groups of subjects were performed using linear mixed effect models with group as random effect and taking possible dependence between eyes within a subject into account.

Main Outcome Measures: Primary analysis compared the incidence of blindness (defined as visual acuity [VA]<0.05 decimal), prevalence of exfoliation glaucoma (XFG), history of glaucoma surgery, and indices of glaucoma severity such as visual field mean deviation (MD), intraocular pressure (IOP) and vertical cup-disc ratio (CDR), between CYP39A1 G204E carriers and those without any CYP39A1 mutation.

Results: The overall risk for blindness was significantly higher in XFS patients carrying the CYP39A1 G204E variant (10/35 [28.6%]) compared to XFS patients without any CYP39A1 mutations (8/150 [5.3%]; OR7.1 [95%CI:2.7-20.2]; p<0.001). A higher proportion of XFS patients with the CYP39A1 G204E mutation (23/35 [65.7%]) had evidence of XFG in at least one eye compared to the comparison group (41/150 [27.3%]; OR5.1 [95%CI:2.4-11.4]; p<0.0001). Significantly higher peak IOP, larger vertical CDR and worse visual field MD were also found in CYP39A1 G204E variant carriers (p<0.001). Additionally, patients with the CYP39A1 G204E mutation (18/35 [51.4%]) required more laser or glaucoma surgical interventions compared to those without any CYP39A1 mutation (32/150 [21.3%], p<0.001).

Conclusions: Patients with XFS carrying the CYP39A1 G204E mutation had significantly increased risk of blindness, higher occurrence of XFG and more severe glaucoma compared to patients with XFS without any CYP39A1 mutation.
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http://dx.doi.org/10.1016/j.ophtha.2021.11.001DOI Listing
November 2021

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

JAMA 2021 02;325(8):753-764

Department of Ophthalmology, Asahikawa Medical University, Asahikawa, Japan.

Importance: Exfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness.

Objective: To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function.

Design, Setting, And Participants: A 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome.

Exposures: Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function.

Main Outcomes And Measures: The primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 × 10-6. The secondary outcomes included biochemical enzymatic assays and gene expression analyses.

Results: The discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 × 10-7). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4% [interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < .001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome.

Conclusions And Relevance: In this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants. Further research is needed to understand the clinical implications of these findings.
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http://dx.doi.org/10.1001/jama.2021.0507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903258PMC
February 2021

Effect of inhalation anesthesia with isoflurane on circadian rhythm of murine intraocular pressure.

Exp Eye Res 2021 02 24;203:108420. Epub 2020 Dec 24.

Department of Ophthalmology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Purpose: For research on circadian intraocular pressure (IOP), rebound tonometers are widely used with or without general anesthesia as a non-invasive approach to obtain IOP values. However, whether general anesthesia such as inhalation anesthesia with isoflurane affects the circadian rhythm of IOP and in turn IOP measurements is currently unclear. As such, data reporting IOP values obtained under general anesthesia should be interpreted with caution. The purpose of this study was to evaluate how general anesthesia with isoflurane inhalation affects the circadian rhythm of IOP.

Methods: C57Bl/6J strain mice maintained using a 12h:12h light/dark cycle (lights on and off at ZT0 and ZT12, respectively) were used. IOPs were measured using a rebound tonometer (Icare TonoLab) before and 3, 5, 10, 15, and 30 min after initiating anesthesia in both light and dark phases (ZT 2-6 and ZT 14-18, respectively). Awake IOPs and IOPs at 3 and 5 min after anesthesia initiation were also obtained at ZT5, 8, 11, 14, 17, and 20 to assess IOP diurnal curves under gas anesthesia.

Results: IOP values gradually decreased after anesthesia initiation in both light and dark phases (P < 0.001) and there was no interaction between light/dark phase and anesthesia time (P = 0.88). There was a slight, but not significant, reduction in IOP 3 min after initiating anesthesia (P = 0.23), and significant decreases in IOP occurred at subsequent timepoints (P ≤ 0.001). Both awake and anesthetized mice showed a robust IOP rhythm that reached a peak and trough in the dark and light phase, respectively. Awake IOP levels did not significantly differ from those for anesthetized mice at 3 min after anesthesia initiation at all time points (P ≥ 0.07).

Conclusions: Both awake and anesthetized mice demonstrated a robust circadian rhythm for IOP. Murine IOP showed similar gradual decreases under inhalation anesthesia with isoflurane in both the light and dark phases. IOPs measured using a rebound tonometer within 3 min of initiating isoflurane anesthesia were comparable to awake IOPs, and thus may be useful to monitor the circadian rhythm of IOP in mice.
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http://dx.doi.org/10.1016/j.exer.2020.108420DOI Listing
February 2021

Efficacy and Safety of Intravitreal Aflibercept Injection in Japanese Patients with Neovascular Glaucoma: Outcomes from the VENERA Study.

Adv Ther 2021 02 16;38(2):1106-1115. Epub 2020 Dec 16.

Bayer Consumer Care AG, Basel, Switzerland.

Introduction: Neovascular glaucoma is characterized by neovascularization of the iris and anterior angle chamber. Intravitreal anti-vascular endothelial growth factor agents may decrease intraocular pressure (IOP) and improve neovascularization. The VENERA study assessed the efficacy and safety of intravitreal aflibercept (IVT-AFL) in patients with neovascular glaucoma.

Methods: This was a 5-week, single-arm, nonrandomized, open-label, phase 3 study performed at 7 study sites in Japan that enrolled Japanese patients with anterior segment neovascularization and IOP > 25 mmHg who had not undergone (within 30 days prior), nor were imminently scheduled to undergo (within 8 days following) intraocular surgeries, including panretinal photocoagulation (PRP). Patients received background therapy plus 2 mg IVT-AFL at baseline. Background therapy with systemic IOP-lowering drugs was prohibited for 3 days before day 1 and until IOP evaluation at week 1. The primary endpoint was the change in IOP from baseline to week 1 and the secondary endpoint was the proportion of patients with an improvement of ≥ 1 grade of neovascularization of the angle (NVA) from baseline to week 1.

Results: Sixteen patients received treatment (full analysis set); the per-protocol set comprised 15 patients. The mean IOP decreased from 34.1 mmHg at baseline to 25.8 mmHg at week 1 (mean change, -8.3 mmHg [95% confidence interval; CI -12.2 to -4.4; P = 0.0004]). At week 1, 81.3% of patients had an improvement in the grade of neovascularization of the iris (NVI) and 50.0% of patients had an improvement in NVA grade. The proportion of patients with controlled IOP (≤ 21 mmHg) was 43.8% (95% CI 19.8-70.1) at week 1, and increased to 56.3% at week 2 and 86.7% at week 5. The most common ocular treatment-emergent adverse event was eye pain, which occurred in 4 patients (25.0%).

Conclusions: IVT-AFL was associated with statistically significant and clinically meaningful IOP reductions, without concomitant use of systemic IOP-lowering drugs or PRP. The safety profile was consistent with the known safety profile of IVT-AFL. These findings supplement those from the previous VEGA study, and suggest that IVT-AFL may be a potential treatment option for patients with neovascular glaucoma.

Trial Registration: Clinicaltrials.gov identifier NCT03639675.
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http://dx.doi.org/10.1007/s12325-020-01580-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889553PMC
February 2021

Intravitreal Aflibercept in Japanese Patients with Neovascular Glaucoma: The VEGA Randomized Clinical Trial.

Adv Ther 2021 02 16;38(2):1116-1129. Epub 2020 Dec 16.

Bayer Consumer Care AG, Basel, Switzerland.

Introduction: Neovascular glaucoma is characterized by neovascularization of the iris and the anterior angle chamber. Intravitreal anti-vascular endothelial growth factor agents may improve intraocular pressure (IOP) and neovascularization.

Methods: The VEGA trial assessed the efficacy and safety of intravitreal aflibercept (IVT-AFL) in patients with neovascular glaucoma in a 13-week, randomized, double-masked, sham-controlled, phase 3 study performed at multiple sites in Japan that enrolled patients with anterior segment neovascularization and IOP > 25 mmHg. Patients received background therapy plus IVT-AFL (2 mg) or sham injection at baseline. Patients were re-treated if presenting with IOP > 21 mmHg and incomplete regression of iris neovascularization, receiving additional sham or IVT-AFL injections at week 1 and IVT-AFL injections at weeks 5 and/or 9. Double-masking was maintained throughout. The primary endpoint was change in IOP from baseline to week 1.

Results: Fifty-four patients were randomly assigned (full analysis set); the per-protocol set comprised 52 patients. At week 1, the least squares mean change in IOP was -9.9 mmHg for IVT-AFL versus -5.0 mmHg for sham [full analysis set: difference -4.9 mmHg (95% confidence interval -10.2 to 0.3; P = 0.06); per-protocol set: -5.5 mmHg (95% CI -10.8 to -0.2; P = 0.04)]. At week 1, a greater proportion of patients administered IVT-AFL versus sham achieved IOP ≤ 21 mmHg and had improved neovascularization grades. Patients in the sham group who met re-treatment criteria and received IVT-AFL at week 1 [n = 22 (81.5%)] had an additional mean IOP decrease of 9.2 mmHg by week 2, and the proportion with improvement in neovascularization grades increased from 11.5% to 69.2%. Increases in the proportion of patients with improved neovascularization grades and the proportion who achieved IOP control (≤ 21 mmHg) were also observed by week 2 in this group. Overall, 77.8% and 74.1% of patients treated with IVT-AFL and sham/IVT-AFL, respectively, received a single IVT-AFL injection. The most common ocular treatment-emergent adverse event was punctate keratitis (9.3%: 7.4% and 11.1% in the IVT-AFL and sham/IVT-AFL groups, respectively).

Conclusions: IVT-AFL was associated with clinically meaningful improvements in IOP control, indicating that IVT-AFL may be a potential treatment option for patients with neovascular glaucoma.

Trial Registration: Clinicaltrials.gov identifier, NCT02396316.
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http://dx.doi.org/10.1007/s12325-020-01579-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889669PMC
February 2021

The association of primary aldosteronism with glaucoma-related fundus abnormalities.

PLoS One 2020 6;15(11):e0242090. Epub 2020 Nov 6.

Department of Ophthalmology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Purpose: To elucidate glaucoma-related fundus abnormalities in patients with primary aldosteronism (PA).

Methods: The study compared 272 eyes from 137 PA patients and 352 eyes from 177 control subjects selected randomly from 1173 participants of a public glaucoma screening. The presence of glaucomatous optic disc appearance (rim thinning and cup enlargement) and retinal nerve fiber layer defects (RNFLDs) was determined independently from fundus photographs. The results were compared between the PA and control groups.

Results: There were 9 patients (6.6%) with glaucomatous optic disc abnormalities in the PA group and 10 cases (5.6%) identified in the control group (p = 0.92). RNFLDs were detected more frequently in the PA group (55 eyes, 20.2%) than in the control group (26 eyes, 7.4%; p<0.001). The two types of RNFLDs were classified as either having their central ends at the disc margin (D) or away from the disc margin and around the retinal vessels (V). Type D and V RNFLDs were detected in 35 (12.9%) and 26 (9.6%) eyes in the PA group and in 25 (7.1%) and 4 (1.1%) eyes in the control group, respectively. Both types of RNFLDs were more frequent in the PA group than in the control group (Type D and V, p = 0.03, <0.001, respectively).

Conclusion: Although the prevalence of glaucomatous optic disc appearance did not differ between the two groups, RNFLDs were more frequent in PA patients than in the control group. Moreover, RNFLDs with their central ends located around retinal vessels were characteristic of PA patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242090PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7647098PMC
January 2021

Spatial and Temporal Relationship between Structural Progression and Disc Hemorrhage in Glaucoma in a 3-Year Prospective Study.

Ophthalmol Glaucoma 2020 Aug 21. Epub 2020 Aug 21.

Clinical Development Center, R&D Division, Santen Pharmaceutical Co, Ltd, Osaka, Japan.

Purpose: To investigate the spatial and temporal relationship between disc hemorrhage (DH) and structural progression in patients with primary open-angle glaucoma (POAG) in a 3-year prospective study.

Design: Prospective cohort study.

Participants: Patients with POAG and intraocular pressure of ≤18 mmHg on monotherapy with prostaglandin analogs.

Methods: Fundus photographs were taken at baseline and every 3 months for 3 years. Disc hemorrhage and structural progression were detected independently by flicker chronoscopy. If present, clock-hour disc locations in the right eye format and colocalization were determined. Statistical comparisons were based on mixed-effects models accounting for the correlation between different disc sites within the same eye and between fellow eyes in the same patient.

Main Outcome Measures: Relationship between DH and structural progression at the same site.

Results: Among 195 eyes of 115 patients, DH appeared in 85 sites in 65 eyes (33.3%) and was most frequently at the 7 o'clock disc location (29.4%, P < 0.0001). Structural progression occurred at 63 sites of 52 eyes (26.7%) comparably in both superior and inferior hemidiscs, which was mostly detected as widening of the retinal nerve fiber layer defects (RNFLDs). Temporal RNFLD widening was common, whereas nasal widening occurred exclusively in the vertical quadrants (P = 0.035). Of 41 progression sites in eyes with DH, 28 sites (68.2%) had both DH and progression. Progression sites with DH were less common in the superior quadrant than in the inferior and temporal quadrants (P = 0.011). Eyes with DH had a significantly higher risk of progression than eyes without DH (hazard ratio, 3.72; P < 0.0001). For 63 progression sites, DH recurrence and more visits with DH at the progression site were significantly associated with shorter time to progression from baseline (P = 0.021, P = 0.017, respectively), whereas colocalization of DH and progression were not.

Conclusions: In a 3-year prospective study with a Japanese POAG cohort, the relationship between DH and RNFLD and the pattern of RNFLD progression differed by disc location. The association between more frequent DH at the progression site and shorter time to progression indicates that DH may reflect vulnerability to same-site structural deterioration.
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http://dx.doi.org/10.1016/j.ogla.2020.08.008DOI Listing
August 2020

Ability of Macular Inner Retinal Layer Thickness Asymmetry Evaluated by Optical Coherence Tomography to Detect Preperimetric Glaucoma.

Transl Vis Sci Technol 2020 04 15;9(5). Epub 2020 Apr 15.

Department of Ophthalmology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Purpose: We assessed the ability to detect preperimetric glaucoma (PPG) based on asymmetry in the thickness of the macular inner retinal layers measured by spectral-domain optical coherence tomography.

Methods: We studied 45 normal eyes and 50 PPG eyes retrospectively. Three-dimensional optical coherence tomography macular area scans were used to obtain the thickness of the retinal nerve fiber layer (RNFL), ganglion cell layer/inner plexiform layer (GCL/IPL), and ganglion cell complex (GCC). We calculated the thickness differences between the upper and lower macular hemispheres for the corresponding superpixels, then evaluated the mean absolute value of the thickness differences and the number of superpixels in which the thickness difference was greater than µm, where is an integer number from 1 to 10. Areas under the receiver operating characteristic curves (AUCs) for their PPG diagnostic performances were compared to the average thickness measurements of the total and hemiretinal sectors. was determined at the maximum AUC value.

Results: The AUC for the mean absolute value of the difference in GCL/IPL thickness (0.923) was higher than the difference in RNFL and GCC thickness (0.710 and 0.905, respectively). The AUC for the number of superpixels in which the GCL/IPL thickness difference was greater than 8 µm ( = 8) was 0.914. The ability to diagnose PPG using these GCL/IPL parameters was statistically higher than for total or superior and inferior hemiretinal GCL/IPL thicknesses.

Conclusions: Asymmetry in the thickness of the GCL/IPL shows good PPG diagnostic performance.

Translational Relevance: This approach would be useful in the early detection of glaucoma.
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http://dx.doi.org/10.1167/tvst.9.5.8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401966PMC
April 2020

Visualization of the Retina in Intact Eyes of Mice and Ferrets Using a Tissue Clearing Method.

Transl Vis Sci Technol 2020 02 7;9(3). Epub 2020 Feb 7.

Department of Medical Neuroscience, Graduate School of Medical Sciences, Kanazawa University, Ishikawa, Japan.

Purpose: Visualization of specific cells and structures in intact organs would greatly facilitate our knowledge about pathological changes; therefore, a tissue clearing method applicable to the intact eye may be valuable. Here we report a novel imaging method for the retina using the hyperhydration-based tissue clearing technique CUBIC (Clear, Unobstructed Brain/Body Imaging Cocktails and Computational Analysis).

Methods: Eyes of Institute of Cancer Research (ICR) mice, C57BL/6 mice, and normally pigmented sable ferrets () were used. Intact eyes were subjected to CUBIC, melanin bleaching with HO, and immunostaining. Images of the retina in intact eyes were taken using epifluorescence microscopes and confocal microscopes.

Results: The combination of melanin bleaching and CUBIC efficiently made the eyes of C57BL/6 mice transparent. By combining melanin bleaching, CUBIC, and immunostaining, we succeeded in visualization of retinal structures from the outside of the intact eyes of mice. Furthermore, we found that our methods were applicable not only to mouse eyes but also to ferret eyes, which are much larger than those of mice.

Conclusions: Our method was useful for visualizing specific cells and structures in the retina of intact eyes with single-cell resolution without making tissue sections.

Translational Relevance: This simple and efficient method can be applicable to various rodent models, including those associated with glaucoma or myopia, and will facilitate evaluating the effects of novel therapy for relevant eye diseases by visualizing changes from the retina to the sclera at both molecular and macroscopic levels simultaneously in a whole-eye preparation.
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http://dx.doi.org/10.1167/tvst.9.3.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347279PMC
February 2020

Glaucoma-related central visual field deterioration after vitrectomy for epiretinal membrane: topographic characteristics and risk factors.

Eye (Lond) 2021 Mar 28;35(3):919-928. Epub 2020 May 28.

Department of Ophthalmology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Background/objectives: To identify risk factors for glaucoma-related central visual field (VF) deterioration after vitrectomy with internal limiting membrane (ILM) peeling for epiretinal membrane (ERM).

Subjects/methods: A prospective cohort study consisting of cases with or without glaucoma (33 eyes of 33 patients in each group) who underwent vitrectomy with ILM peeling for ERM. Humphrey 10-2 VFs and ganglion cell complex (GCC) thickness were measured at baseline and about 3, 6, and 12 months postoperatively. Longitudinal changes in VF indices and factors associated with their postoperative changes were investigated using mixed-effects models, as was sectorwise total deviation (TD) analysis using six sectors consisting of outer/inner arcuate and cecocentral sectors in each hemifield.

Results: VF mean deviation significantly deteriorated postoperatively only in the glaucoma group (P < 0.001). Older age, longer axial length, preoperative worse mean deviation, and thinner GCC were significant risk factors for postoperative deterioration (coefficient ± standard errors: -0.139 ± 0.067, -0.740 ± 0.241, 0.16 ± 0.07, 0.050 ± 0.020; P = 0.038, P = 0.002, P = 0.024, P = 0.012, respectively). Sectorwise analysis revealed that TD in the superior/inferior outer arcuate sectors significantly deteriorated only in the glaucoma group. Preoperative worse TD and thinner GCC were significant risk factors for deterioration in the superior outer arcuate sector (0.65 ± 0.11, 0.08 ± 0.03; P < 0.001, P = 0.042, respectively).

Conclusions: Central VF deterioration, especially in the outer arcuate sectors, found to be glaucoma-related changes after vitrectomy with ILM peeling for ERM. Preoperative worse VF and thinner GCC were identified as risk factors for postoperative VF deterioration.
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http://dx.doi.org/10.1038/s41433-020-0996-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027793PMC
March 2021

Using 24-hr ocular dimensional profile recorded with a sensing contact lens to identify primary open-angle glaucoma patients with intraocular pressure constantly below the diagnostic threshold.

Acta Ophthalmol 2020 Dec 27;98(8):e1017-e1023. Epub 2020 Apr 27.

Department of Ophthalmology and Visual Science, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Purpose: To evaluate the use of a 24-hr ocular dimensional profile recorded with a contact lens sensor (CLS) combined with a single tonometric intraocular pressure (IOP) reading to indicate the potential for exceeding the diagnostic threshold for normal tension glaucoma (NTG) in Japanese patients.

Methods: Intraocular pressure (IOP) of untreated Japanese NTG patients was measured with tonometry every 3 hr from 9:00 to 24:00. The subsequent day a 24-hr CLS (SENSIMED Triggerfish, Sensimed AG, Lausanne, Switzerland) profile was recorded on the same eye. Patients initially diagnosed as NTG were reclassified as NTG when the measured IOP values were consistently <20 mmHg or as primary open-angle glaucoma (POAG) when IOP was ≥20 mmHg in at least 1 measurement. For each patient and each IOP time-point, IOP values were combined with information provided by the CLS profile ('classifier') to indicate the potential for exceeding the diagnostic threshold value. Statistical analyses were performed for each classifier.

Results: A total of 65 patients, 28 males and 37 females (mean ages: 50.8 ± 14.6 years and 52.6 ± 10.2 years, respectively), were analysed. Following IOP diurnal measurement, five patients (7.7%) were reclassified as POAG. Two classifiers (15:00 CLS and 18:00 CLS) showed high sensitivity and negative predictive value (100%), identifying all the POAG patients.

Conclusion: Contact lens sensor information can be used in conjunction with a single tonometric reading to determine patients' potential of having IOP levels exceeding the diagnostic threshold within a 24-hr period, without the need to perform a 24-hr tonometric curve. This would allow clinicians to identify POAG patients who may otherwise be eventually misclassified as NTG.
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http://dx.doi.org/10.1111/aos.14453DOI Listing
December 2020

Effectiveness of trabeculectomy with mitomycin C for glaucomatous eyes with low intraocular pressure on treatment eye drops.

Acta Ophthalmol 2020 Feb 25;98(1):e81-e87. Epub 2019 Jul 25.

Department of Ophthalmology and Visual Science, Hiroshima University Graduate School of Biomedical Sciences, Minami-ku Hiroshima, Japan.

Purpose: To examine the efficacy and safety of current trabeculectomy with mitomycin C in Japan for glaucomatous eyes with low intraocular pressure (IOP).

Methods: Two hundred ninety-four eyes of 294 patients with IOP ≤21 mmHg before surgery were studied; all patients were participants in the Collaborative Bleb-related Infection Incidence and Treatment Study (CBIITS), a multicentre, prospective, cohort study conducted at 34 ophthalmological institutions throughout Japan. All eyes had an intraocular pressure ≤ 21 mmHg and had undergone trabeculectomy alone or phacotrabeculectomy. Two success criteria were used: Criterion A comprised 20% reduction of baseline IOP and Criterion B comprised 30% reduction of baseline IOP. The primary outcome was the success rate for each of these criteria.

Results: The qualified success rates were 87.3% for Criterion A and 42.0% for Criterion B at 5 years. Mean IOP was significantly reduced, from 16.7 ± 2.7 to 11.6 ± 4.0 mmHg at 5 years after trabeculectomy (p < 0.0001); the number of anti-glaucoma medications significantly decreased from 2.7 ± 1.1 to 1.0 ± 1.2 (p < 0.0001) at 5 years after the surgery. Three or more trabeculectomies, and needling were related to increased risk of failure. Incidences of postoperative hyphema, infection, shallow anterior chamber and bleb leakage were 2.4%, 2.4%, 2.0% and 3.4%, respectively.

Conclusions: This study showed that trabeculectomy with mitomycin C is an effective procedure with few surgical complications for reducing IOP in patients, even if preoperative IOP was within the normal range.
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http://dx.doi.org/10.1111/aos.14195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003922PMC
February 2020

Effects of Trabeculectomy on Waveform Changes of Laser Speckle Flowgraphy in Open Angle Glaucoma.

Invest Ophthalmol Vis Sci 2019 02;60(2):677-684

Department of Ophthalmology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Purpose: To investigate the effect of trabeculectomy on the waveform changes of laser speckle flowgraphy (LSFG) in the optic nerve head (ONH) in patients with glaucoma.

Methods: Forty-eight eyes of 48 patients with open angle glaucoma were included in this prospective study. LSFG was performed before and 1, 3, and 6 months after trabeculectomy. Longitudinal changes in average mean blur rate (MBR), blow out score (BOS), resistivity index (RI), falling rate, skew, acceleration time index, and blow out time in the tissue area of the ONH were analyzed by using mixed-effects models.

Results: Intraocular pressure (IOP) decreased and ocular perfusion pressure increased significantly at each postoperative time point (P < 0.001, each). BOS increased (P < 0.001, each) and RI decreased (P < 0.001, each) significantly at each postoperative time point, although average MBR and other waveform parameters did not change significantly. Multivariate analyses revealed that younger age (coefficients = -0.13 and 0.0014, P = 0.006 and 0.03 for BOS change and RI change, respectively), worse baseline mean deviation of visual fields (coefficients = -0.18 and 0.0026, P = 0.009 and 0.005), larger IOP reduction (coefficients = -0.29 and 0.0037, P < 0.001, each), and larger pulse rate increase (coefficients = 0.17 and -0.0024, P < 0.001, each) are significantly associated with postoperative BOS increase and RI decrease.

Conclusions: Given that postoperative BOS increased and RI decreased with the average MBR remaining unchanged, IOP reduction by trabeculectomy may contribute to stable blood flow throughout the duration of the heartbeat in the tissue area of the ONH.
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http://dx.doi.org/10.1167/iovs.18-25694DOI Listing
February 2019

The Relationship Between Interocular Asymmetry of Visual Field Defects and Optic Nerve Head Blood Flow in Patients With Glaucoma.

J Glaucoma 2019 03;28(3):231-237

Department of Ophthalmology, Kanazawa University Graduate School of Medical Science, Kanazawa.

Purpose: To investigate the association between asymmetry of visual field (VF) defects and optic nerve head (ONH) blood flow in patients with glaucoma using laser speckle flowgraphy.

Methods: In total, 170 eyes of 85 patients with primary open-angle glaucoma were included. Intraocular pressure, VF (Humphrey 24-2, SITA program), mean blur rate in the tissue area (MBR-T) of the ONH measured by laser speckle flowgraphy, axial length, circumpapillary retinal nerve fiber layer thickness (cpRNFLT), disc area, cup/disc area ratio, and parapapillary atrophy (PPA) area was measured in each eye. The paired eyes were divided into better and worse eyes according to the mean deviation (MD) of VF, and intereye differences of various parameters (better MD eye minus worse MD eye) were examined. Factors associated with MD difference, MBR-T difference, or cpRNFLT difference were investigated.

Results: MD of the VF in better and worse eyes were -10.2±7.3 dB and -16.8±7.4 dB, respectively. In stepwise multiple regression analysis, MBR-T differences, cpRNFLT differences and sex (male) were significantly correlated with MD differences (β, 0.26, 0.21, 0.20; P=0.01, 0.04, 0.047, respectively). MD differences were significantly associated with MBR-T differences (β, 0.28; P=0.01). For cpRNFLT differences, differences in β-PPA area and MD differences were identified as significant factors (β, -0.26, 0.22; P=0.02, 0.04, respectively).

Conclusions: Asymmetry of ONH blood flow is significantly associated with asymmetry of visual field defects in patients with glaucoma independently of cpRNFLT.
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http://dx.doi.org/10.1097/IJG.0000000000001181DOI Listing
March 2019

Factors Associated with Progression of Japanese Open-Angle Glaucoma with Lower Normal Intraocular Pressure.

Ophthalmology 2019 08 31;126(8):1107-1116. Epub 2018 Dec 31.

Department of Ophthalmology, Graduate of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan; Department of Ophthalmology, Kanto Central Hospital of the Mutual Aid Association of Public School Teachers, Tokyo, Japan.

Purpose: To characterize the natural history and define the risk factors associated with the progression of normal-tension glaucoma (NTG) in Japanese patients who were followed up closely without treatment.

Design: Prospective 5-year study.

Participants: Patients with NTG with intraocular pressure (IOP) consistently ≤15 mmHg without treatment at baseline.

Methods: Visual field (VF) examinations were performed every 3 months, and disc/peripapillary retina photographs were taken every 6 months. Patients were followed up without treatment.

Main Outcome Measures: Deterioration in VF was defined by reference to Guided Progression Analysis Software of the Humphrey VF Swedish Interactive Thresholding Algorithm 24-2 (Carl Zeiss Meditec, Jena, Germany) and disc/peripapillary retina deterioration as adjudged by 3 independent observers. Life table analysis was used for evaluating the time to disease progression, as defined by VF or deterioration of the optic nerve head structure. The Cox proportional hazards model was used to identify risk factors for glaucoma progression.

Results: We enrolled 90 patients (mean age, 53.9 years; baseline IOP, 12.3 mmHg; mean deviation [MD], -2.8 decibels [dB]). The MD slope averaged -0.33 dB/year (median, -0.23; 95% confidence interval [CI], -0.44 to -0.22). Glaucoma progression probability at 5 years was 66% (95% CI, 55-78), as defined by VF deterioration or disc/peripapillary retina deterioration (criterion 1): 52% (95% CI, 37-60), as defined by VF deterioration (criterion 2), and 50% (95% CI, 38-71), as defined by disc/peripapillary retina deterioration (criterion 3). Presence or history of disc hemorrhage (DH) (P < 0.001), long-term IOP fluctuation (P = 0.020), and a greater vertical cup-to-disc ratio (v-C/D) (P = 0.018) were significant predictors for progression defined by criterion 1. Long-term IOP fluctuation (P = 0.011) and a greater v-C/D (P = 0.036) were significant predictors for progression by criterion 2. Presence or history of DH (P = 0.0018) and long-term IOP fluctuation (P = 0.022) were significant predictors for progression by criterion 3.

Conclusions: In Japanese patients with NTG with mean baseline IOP of 12.3 mmHg without treatment, estimated mean MD slope for 5 years was -0.33 dB/year; probability of glaucoma progression based on VF or disc/peripapillary end points at 5 years was 66%. Presence or history of DH, long-term IOP fluctuation, and greater v-C/D significantly contributed to progression.
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http://dx.doi.org/10.1016/j.ophtha.2018.12.029DOI Listing
August 2019

Effects of ripasudil, a rho kinase inhibitor, on blood flow in the optic nerve head of normal rats.

Graefes Arch Clin Exp Ophthalmol 2019 Feb 24;257(2):303-311. Epub 2018 Nov 24.

Department of Ophthalmology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, 920-8641, Japan.

Purpose: To evaluate the effect of topically administrated ripasudil, a rho kinase inhibitor, on blood flow in the optic nerve head (ONH) of normal rats.

Methods: Ripasudil (0.4%) or placebo was administered in the right eye of normal Brown Norway rats in a double-blind manner. Laser speckle flowgraphy was measured in the ONH of the right eye 20 or 40 min after a single instillation and before and after 7 or 14 days of twice daily instillation. Mean blur rate was evaluated in the total area (MA), the vessel region (MV), and the tissue region (MT). Intraocular pressure (IOP), blood pressure, ocular perfusion pressure (OPP), and heart rate were also recorded at each time point.

Results: After a single instillation, MV was significantly larger at 40 min than 20 min in the ripasudil group (P = 0.044) and was significantly lower in the placebo group (P = 0.023). MA and MV 40 min after instillation were significantly larger in the ripasudil group than in the placebo group (P = 0.022 and P = 0.006, respectively). After continuous instillation, MA and MV in the ripasudil group significantly increased from baseline after 7 and 14 days of treatment (both P < 0.05) and MA, MV, and MT were significantly higher than in the placebo group (MA: 7 and 14 days, P < 0.01; MV: 7 days, P = 0.003, and 14 days, P = 0.012; MT: 7 days, P = 0.046). There were no significant changes in IOP, blood pressure, or OPP after single or continuous instillation.

Conclusions: Topical instillation of ripasudil increased blood flow around the ONH in the eyes of normal rats.
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http://dx.doi.org/10.1007/s00417-018-4191-6DOI Listing
February 2019

Determinants of Corneal Endothelial Cell Loss After Trabeculectomy With Mitomycin C.

J Glaucoma 2019 01;28(1):61-67

Department of Ophthalmology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Purpose: To investigate factors associated with decreased corneal endothelial cell density (ECD) after trabeculectomy with mitomycin C (MMC).

Methods: Retrospective review of consecutive glaucoma cases who underwent trabeculectomy with MMC. The types of glaucoma included were primary open-angle glaucoma, exfoliation glaucoma (XFG), neovascular glaucoma, and uveitic glaucoma (UG). The postoperative ECD changes compared with the preoperative ECD and risk factors for ECD decrease were analyzed using mixed-effects models.

Results: In total, 162 eyes of 136 patients were included in this study. Postoperative ECD measurements were performed 3.7±1.8 times (mean±SD) during a median follow-up period of 34 months. The mean intraocular pressure decreased from 25.3±9.6 to 9.2±2.3 mm Hg postoperatively. The marginal mean (SE) ECD decrease at 24 months was 9.3% (1.3%) in all cases. The marginal mean ECD decrease at 24 months was 18.2% (3.1%) and 20.6% (4.7%) in eyes with XFG and UG, respectively, which was significantly greater than 4.8% (1.8%) in eyes with primary open-angle glaucoma (P<0.001, each), after accounting for the variability in the number and timepoint of ECD measurements. Multivariate mixed-effects model analyses showed that type of glaucoma (XFG and UG) and older age were significantly associated with larger ECD decrease, and preoperative factors (oral carbonic anhydrase inhibitor and vitrectomy) and postoperative choroidal detachment were significantly associated with a declining trend of ECD over time.

Conclusions: The type of glaucoma (XFG, UG) and older age were risk factors for larger ECD decrease after trabeculectomy with MMC.
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http://dx.doi.org/10.1097/IJG.0000000000001108DOI Listing
January 2019

The Management of Glaucoma: Structure and Function.

J Ophthalmol 2018 22;2018:4682586. Epub 2018 Apr 22.

Department of Ophthalmology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.

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http://dx.doi.org/10.1155/2018/4682586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5937419PMC
April 2018

Comparison of Sectoral Structure-Function Relationships in Glaucoma: Vessel Density Versus Thickness in the Peripapillary Retinal Nerve Fiber Layer.

Invest Ophthalmol Vis Sci 2017 10;58(12):5251-5262

Department of Ophthalmology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Purpose: To compare the sectoral structure-function relationships in glaucoma between two structural parameters, vessel density (VD) and thickness, in the peripapillary retinal nerve fiber layer (RNFL).

Methods: Optical coherence tomography (OCT) angiography (AngioVue/RTVue-XR) for VD and OCT (RS-3000) for peripapillary RNFL thickness were performed in 129 eyes from 129 subjects (94 glaucoma, 17 glaucoma suspects, and 18 normal eyes). Humphrey visual field (VF) tests were performed using a SITA standard 24-2 program. Sectoral structure-function relationships based on the Garway-Heath map were compared between VD and thickness using a semipartial correlation coefficient (sr) and partial residual plots determined by multiple linear regression models controlling for the effects of sex, age, axial length, disc area, beta- and gamma- parapapillary atrophy (PPA) zones, and signal strength index (SSI).

Results: For all VF sectors, the sr2 of VD was largest when the VD sector corresponded to the VF sector (sr2: 0.17-0.39). In contrast, in only three sectors was the sr2 of thickness largest when the thickness sector corresponded to the VF sector (sr2: 0.02-0.34): the inferior temporal, temporal, and superior temporal sectors. The partial residual plots against VD showed more linear relationships with VF sensitivity than those against thickness in the qualitative evaluation of fitting by locally weighted scatterplot smoothing. Eyes with larger SSI had higher VD, whereas eyes with a larger extension of the PPA zone into the VD measurement area had lower VD.

Conclusions: Peripapillary RNFL VD and thickness have different characteristic sectoral structure-function relationships in glaucoma.
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http://dx.doi.org/10.1167/iovs.17-21955DOI Listing
October 2017

Rebamipide protects against glaucoma eyedrop-induced ocular surface disorders in rabbits.

PLoS One 2017 19;12(10):e0186714. Epub 2017 Oct 19.

Department of Ophthalmology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan.

Purpose: This study aimed to determine if rebamipide eyedrops can improve ocular surface damage caused by the use of glaucoma eyedrops.

Methods: Female Kbl:Dutch rabbits were used to evaluate glaucoma eyedrop-induced ocular surface damage; one eye of each rabbit was untreated and the other was administered glaucoma eyedrops for 30 days. To evaluate the effects of rebamipide on ocular surface damage, one eye of each rabbit was administered vehicle-treated glaucoma eyedrops and the other was administered rebamipide-treated glaucoma eyedrops for 30 days. Corneal and conjunctival epithelial damage was evaluated using fluorescein and rose bengal staining, respectively. Conjunctival inflammation was observed by light microscopy with hematoxylin-eosin staining. Dark cells (in which the corneal microvilli were damaged) were analyzed by scanning electron microscopy.

Results: There were no significant differences in fluorescein staining between the untreated and glaucoma eyedrop-treated groups; however, rose bengal staining and the number of inflammatory cells in the conjunctiva significantly increased after glaucoma eyedrop treatment. There was a four-fold increase in the number of dark cells in the glaucoma eyedrop-treated group compared to untreated. In contrast, in the conjunctiva of the rebamipide-treated glaucoma eyedrop group, rose bengal staining scores, the number of inflammatory cells, and the number of dark cells were decreased compared to the vehicle-treated glaucoma eyedrop group.

Conclusions: Results from our in vivo rabbit study demonstrated that short-term use of glaucoma eyedrops induces corneal epithelium disorders at the cellular level, but that simultaneous use of rebamipide has the potential to protect and repair the ocular surface.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0186714PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5648230PMC
November 2017

Intraocular pressure and visual field changes in normal-tension glaucoma patients treated using either unoprostone or latanoprost: a prospective comparative study.

Clin Ophthalmol 2017 1;11:1617-1624. Epub 2017 Sep 1.

Department of Ophthalmology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Purpose: We conducted a prospective study in patients with normal-tension glaucoma (NTG) who received either isopropyl unoprostone or latanoprost. We compared the drugs in terms of their effects on intraocular pressure (IOP) and visual field loss progression over a 3-year period.

Study Design: Prospective, randomized controlled study.

Methods: We enrolled 48 patients with newly diagnosed NTG at Kanazawa University Hospital. Eligible patients were randomly allocated (1:1) to receive either unoprostone or latanoprost ophthalmic solutions. The primary outcomes were IOP changes and visual field deterioration within 36 months. Visual field changes were analyzed: the cumulative survival rates were calculated in terms of mean deviation, pattern standard deviation, and total deviation of the upper or lower hemi-visual field, each visual field sector, and guided progression analysis. In addition, we evaluated the progression of glaucomatous optic disc changes using fundus photography and confocal scanning laser ophthalmoscopy.

Results: The mean pretreatment IOP was 15.0±2.4 mmHg in the Unoprostone group and 15.2±1.9 mmHg in the Latanoprost group. The mean IOP during the treatment period was 13.7±2.3 mmHg in the Unoprostone group and 13.0±1.8 mmHg in the Latanoprost group. In both groups, the IOP decreased significantly (<0.001) from baseline after treatment. The posttreatment IOP values were significantly lower in the Latanoprost group than in the Unoprostone group (=0.023). Regarding the 3-year cumulative survival rate of visual field loss progression, there were no significant differences between groups in any parameters of the visual field or guided progression analysis. There were no significant differences between groups in disc changes.

Conclusions: No significant differences were found between groups with regard to the visual field and structural progression in patients with NTG, although unoprostone was less effective than latanoprost in lowering the IOP.
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http://dx.doi.org/10.2147/OPTH.S144344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589109PMC
September 2017

Light entrainment of the murine intraocular pressure circadian rhythm utilizes non-local mechanisms.

PLoS One 2017 21;12(9):e0184790. Epub 2017 Sep 21.

Department of Ophthalmology, University of Washington School of Medicine, Seattle, Washington, United States of America.

Purpose: Intraocular pressure (IOP) is known to have a strong circadian rhythm, yet how light/dark cycles entrain this rhythm is unknown. The purpose of this study was to assess whether, like the retina, the mammalian ciliary body and IOP clocks have an intrinsic ability to entrain to light/dark cycles.

Methods: Iris-ciliary body complexes were obtained from period2:luciferase (PER2::LUC) mice and cultured to measure bioluminescence rhythmicity. Pairs of the iris-ciliary body complex were exposed to antiphasic 9:15 h light/dark cycle in vitro. After 4 days of exposure to light/dark cycles, bioluminescence was recorded to establish their circadian phases. In addition, pairs of the iris-ciliary body complex co-cultured with the retinas or corneas of wild-type mice were also investigated. The IOP circadian changes of free-running Opn4-/-;rd1/rd1 mice whose behavior was antiphasic to wild-type were measured by a rebound tonometry, and compared with wild-type mice. Opn3, Opn4, and Opn5 mRNA expression in the iris-ciliary body were analyzed using RT-PCR.

Results: The iris/ciliary body complex expressed Opn3, Opn4, and Opn5 mRNA; however, unlike in retina and cornea, neither the iris-CB complex nor the co-cultured complex was directly entrained by light-dark cycle in vitro. The diurnal IOP change of Opn4-/-;rd1/rd1 mice showed an antiphasic pattern to wild-type mice and their rhythms followed the whole-animal behavioral rhythm.

Conclusions: Despite expressing mRNA for several non-visual opsins, circadian rhythms of the iris-ciliary body complex of mice do not entrain directly to light-dark cycles ex vivo. Unlike retina, the iris/ciliary body clocks of blind mice remain synchronized to the organismal behavioral rhythm rather than local light-dark cycles. These results suggest that IOP rhythm entrainment is mediated by a systemic rather than local signal in mice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0184790PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5608236PMC
October 2017

POSTOPERATIVE CHANGES AND PROGNOSTIC FACTORS OF VISUAL ACUITY, METAMORPHOPSIA, AND ANISEIKONIA AFTER VITRECTOMY FOR EPIRETINAL MEMBRANE.

Retina 2018 Nov;38(11):2118-2127

Department of Ophthalmology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Purpose: To investigate postoperative changes and prognostic factors of visual impairment after vitrectomy for unilateral epiretinal membrane.

Methods: A prospective observational study on 45 eyes from 45 patients with unilateral idiopathic epiretinal membrane who underwent vitrectomy. Visual parameters (best-corrected visual acuity, metamorphopsia using M-CHARTS, and aniseikonia using the New Aniseikonia Test) and spectral domain optical coherence tomography parameters (macular retinal layer thickness and microstructure of the outer retina) were measured preoperatively and 6 and 12 months postoperatively. Statistical analyses included linear mixed-effects models for the longitudinal changes and prognostic factors of visual parameters.

Results: Best-corrected visual acuity and horizontal metamorphopsia improved significantly from 6 months after surgery (P < 0.001), whereas aniseikonia decreased significantly only at 12 months (P = 0.015). Vertical metamorphopsia remained unchanged. Preoperative inner nuclear layer thickness was significantly correlated with preoperative metamorphopsia. Besides baseline values, best-corrected visual acuity had no significant prognostic factors, but preoperative ellipsoid zone disruption had a negative direction of association with postoperative metamorphopsia (coefficients: -0.37 and -0.62, P = 0.015 and 0.006 for horizontal and vertical metamorphopsia, respectively), and preoperative horizontal metamorphopsia had a positive direction of association with postoperative aniseikonia (coefficient: 1.77, P = 0.002).

Conclusion: After vitrectomy, postoperative changes and prognostic factors for unilateral epiretinal membrane differed for best-corrected visual acuity, metamorphopsia, and aniseikonia.
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http://dx.doi.org/10.1097/IAE.0000000000001831DOI Listing
November 2018

Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci.

Nat Genet 2017 07 29;49(7):993-1004. Epub 2017 May 29.

Department of Ophthalmology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 × 10) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 × 10). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.
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http://dx.doi.org/10.1038/ng.3875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685441PMC
July 2017

Visual field changes after vitrectomy with internal limiting membrane peeling for epiretinal membrane or macular hole in glaucomatous eyes.

PLoS One 2017 18;12(5):e0177526. Epub 2017 May 18.

Department of Ophthalmology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Purpose: To investigate visual field changes after vitrectomy for macular diseases in glaucomatous eyes.

Methods: A retrospective review of 54 eyes from 54 patients with glaucoma, who underwent vitrectomy for epiretinal membrane (ERM; 42 eyes) or macular hole (MH; 12 eyes). Standard automated perimetry (Humphrey visual field 24-2 program) was performed and analyzed preoperatively and twice postoperatively (1st and 2nd sessions; 4.7 ± 2.5, 10.3 ± 3.7 months after surgery, respectively). Postoperative visual field sensitivity at each test point was compared with the preoperative value. Longitudinal changes in mean visual field sensitivity (MVFS) of the 12 test points within 10° eccentricity (center) and the remaining test points (periphery), best-corrected visual acuity (BCVA), intraocular pressure (IOP), and ganglion cell complex (GCC) thickness, and the association of factors with changes in central or peripheral MVFS over time were analyzed using linear mixed-effects models. In addition, 45 eyes from 45 patients without glaucoma who underwent vitrectomy for epiretinal membrane (ERM; 34 eyes) or macular hole (MH; 11 eyes) were similarly examined and statistically analyzed (control group).

Results: In glaucomatous eyes, visual field test points changed significantly and reproducibly; two points deteriorated only at the center and twelve points improved only at the periphery. Central MVFS decreased (p = 0.03), whereas peripheral MVFS increased postoperatively (p = 0.010). In the control group, no visual field test points showed deterioration, and central MVFS did not change significantly after vitrectomy. BCVA improved, GCC thickness decreased, and IOP did not change postoperatively in both groups. The linear mixed-effects models identified older age, systemic hypertension, longer axial length, and preoperative medication scores of ≥2 as risk factors for central MVFS deterioration in glaucomatous eyes.

Conclusions: Visual field sensitivity within 10° eccentricity may deteriorate after vitrectomy for ERM or MH in glaucomatous eyes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0177526PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5436669PMC
September 2017

METAMORPHOPSIA AND OUTER RETINAL MORPHOLOGIC CHANGES AFTER SUCCESSFUL VITRECTOMY SURGERY FOR MACULA-OFF RHEGMATOGENOUS RETINAL DETACHMENT.

Retina 2018 Jan;38(1):148-154

Department of Ophthalmology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Purpose: To evaluate the correlation between metamorphopsia and outer retinal morphologic changes after successful vitrectomy for rhegmatogenous retinal detachment (RRD).

Methods: Forty eyes from 40 patients with macula-off (26 eyes) or macula-on (14 eyes) RRDs that underwent pars plana vitrectomy were included. Metamorphopsia was quantified with M-CHARTS. The relationship between the integrity of the outer retinal layers examined by spectral domain optical coherence tomography and metamorphopsia at 6 and 12 months postoperatively was evaluated.

Results: Metamorphopsia was significantly more frequent in eyes with macula-off RRD (88%) than in eyes with macula-on RRD (21%) at 6 months postoperatively (P < 0.001) and became significantly less frequent in macula-off RRD eyes from 6 months to 12 months (64%) postoperatively (P = 0.041). Horizontal metamorphopsia scores in eyes with continuous interdigitation zone and ellipsoid zone bands were significantly smaller than in eyes with a disrupted interdigitation zone band and a continuous ellipsoid zone band or in eyes with disrupted ellipsoid zone and interdigitation zone bands (P = 0.003 and P <0.001, respectively), which was consistent with the results of vertical metamorphopsia scores.

Conclusion: Restoration of both the ellipsoid zone and interdigitation zone bands seems to be an important factor for the reduction of metamorphopsia after successful vitrectomy for macula-off RRD.
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http://dx.doi.org/10.1097/IAE.0000000000001510DOI Listing
January 2018

The Role of Beta-Adrenergic Receptors in the Regulation of Circadian Intraocular Pressure Rhythm in Mice.

Curr Eye Res 2017 07 25;42(7):1013-1017. Epub 2017 Jan 25.

a Department of Ophthalmology and Visual Science , Kanazawa University Graduate School of Medical Science , Kanazawa , Japan.

Purpose: To investigate whether the elimination of β1- and β2-adrenergic receptors alters the diurnal intraocular pressure (IOP) rhythm in mice.

Materials And Methods: β1-/β2-adrenergic receptor double-knockout and C57BL/6J mice were anesthetized intraperitoneally, with their IOPs measured via microneedle method. After entrainment to a 12-h light-dark (LD) cycle (light phase 6:00-18:00), IOPs were measured every 3 h from 9:00 to 24:00 (group 1, β1-/β2-adrenergic receptor double-knockout mice, n = 11; C57BL/6J, n = 15). The IOP measurements at 15:00 and 24:00 under a 12-h LD cycle and in the constant darkness (1 day and 8 days after exposure to darkness, respectively) were performed in another group of β1-/β2-adrenergic receptor double-knockout mice (group 2, n = 12). IOP variance throughout the day and mean IOP differences among time points were evaluated using a linear mixed model.

Results: β1-/β2-adrenergic receptor double-knockout and C57BL/6J mice showed biphasic IOP curves, low during the light phase and high during the dark phase; the fluctuation was significant (P < 0.001). The peak IOP (18.7 ± 1.4 mmHg) occurred at 24:00 and the trough IOP (13.5 ± 1.5 mmHg) occurred at 15:00 in β1-/β2-adrenergic receptor double-knockout mice group. IOP curves of β1-/β2-adrenergic receptor double-knockout and C57BL/6J were nearly parallel, and the IOPs of β1-/β2-adrenergic receptor double-knockout mice were significantly higher than those of C57BL/6J mice (P < 0.001). Under constant dark (DD) conditions, IOP at 24:00 (18.1 ± 1.5 mmHg) was significantly higher than that at 15:00 (13.3 ± 1.2 mmHg) (P < 0.001). The transition from the LD cycle to DD environment produced no significant change in IOP (P = 0.728).

Conclusions: Elimination of both β1- and β2-adrenergic receptors did not disturb the biphasic diurnal IOP rhythm in mice.
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http://dx.doi.org/10.1080/02713683.2016.1264605DOI Listing
July 2017

Longitudinal Changes in Optic Nerve Head Blood Flow in Normal Rats Evaluated by Laser Speckle Flowgraphy.

Invest Ophthalmol Vis Sci 2016 Oct;57(13):5568-5575

Ophthalmology and Visual Science, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Purpose: To investigate longitudinal changes in mean blur rate (MBR) measured by laser speckle flowgraphy (LSFG) in the rat optic nerve head (ONH), and the reproducibility of MBR.

Methods: Rats were dilated under general anesthesia. Intraocular pressure (IOP), blood pressure, ocular perfusion pressure (OPP), heart rate, and LSFG were measured 30 minutes later. Mean blur rate in the ONH was determined using LSFG-Micro and was subdivided into MBR of the total area (MA), vessel region (MV), and tissue region (MT). Mean blur rate measurements were repeated at 10, 11, 13, 19, and 20 weeks, then every 5 weeks until 60 weeks of age. Intrasession repeatability, intrasession reproducibility, and intersession reproducibility were evaluated.

Results: Coefficient of variation of MBR was 0.3 to 6.2%, 1.3 to 5.2%, and 5.8 to 30.4% for intrasession repeatability, intrasession reproducibility, and intersession reproducibility, respectively. Mean blur rate of the total area, MV, and MT increased similarly until 19 weeks of age, but stabilized thereafter until 60 weeks. Mean blur rate of the total area in the inferior quadrant was significantly higher than in the temporal quadrant from 19 to 55 weeks. These changes exceeded a range of corresponding coefficient of reproducibility. There were no significant changes in IOP, blood pressure, or OPP during the experimental period.

Conclusions: Mean blur rate in the rat ONH changed over time, increased from 10 to 19 weeks of age, then stabilized until 60 weeks. Mean blur rate of the total area exhibited regional differences: higher in the inferior quadrant than in the temporal quadrant. Laser speckle flowgraphy-Micro may provide reliable information for evaluating longitudinal changes of rat ONH blood flow.
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http://dx.doi.org/10.1167/iovs.16-19945DOI Listing
October 2016

Persistent hypotony after trabeculectomy: incidence and associated factors in the Collaborative Bleb-Related Infection Incidence and Treatment Study.

Jpn J Ophthalmol 2016 Jul 13;60(4):309-18. Epub 2016 May 13.

Department of Ophthalmology and Visual Science, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, 920-8641, Japan.

Purpose: To investigate the incidence of and factors associated with persistent hypotony after trabeculectomy with mitomycin C in the Collaborative Bleb-Related Infection Incidence and Treatment Study (CBIITS), a 5-year prospective multicenter study.

Methods: A total of 955 eyes of 955 patients who underwent trabeculectomy with mitomycin C were studied. Surgical failure was defined as insufficient intraocular pressure (IOP) reduction (IOP > 21 mmHg or <20 % IOP reduction, or further glaucoma surgeries), loss of light perception, or persistent hypotony (IOP ≤ 5 mmHg persisting for >6 months). Factors associated with persistent hypotony in eyes with sufficient IOP reduction were determined by survival analysis and logistic regression analysis.

Results: The cumulative probabilities of surgical success and persistent hypotony at 5 years were 62.0 ± 1.7 % (±standard error) and 7.7 ± 0.9 %, respectively. In 685 eyes with sufficient IOP reduction, preoperative IOP (mmHg), limbus-based conjunctival flap, or choroidal detachment that occurred within 6 months of the surgery were significant risk factors for persistent hypotony [Cox proportional hazards regression model: hazard ratio, 0.95, 2.27, 3.24; 95 % confidence interval (CI), 0.91-0.98, 1.21-4.23, 1.51-6.95; P = 0.005, 0.01, 0.003, respectively]. Bleb infection and final visual acuity (logarithm of the minimal angle of resolution) were significantly associated with persistent hypotony (logistic regression: odds ratio, 8.74, 1.37; 95 % CI, 1.89-40.4, 1.03-1.82; P = 0.006, 0.029, respectively).

Conclusions: In the CBIITS, eyes with successful IOP reduction, a limbus-based conjunctival flap, lower preoperative IOP, and choroidal detachment that occurred within 6 months of the surgery were identified as risk factors for persistent hypotony.
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http://dx.doi.org/10.1007/s10384-016-0450-4DOI Listing
July 2016

Influence of Clinical Factors and Magnification Correction on Normal Thickness Profiles of Macular Retinal Layers Using Optical Coherence Tomography.

PLoS One 2016 27;11(1):e0147782. Epub 2016 Jan 27.

Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Purpose: To identify the factors which significantly contribute to the thickness variabilities in macular retinal layers measured by optical coherence tomography with or without magnification correction of analytical areas in normal subjects.

Methods: The thickness of retinal layers {retinal nerve fiber layer (RNFL), ganglion cell layer plus inner plexiform layer (GCLIPL), RNFL plus GCLIPL (ganglion cell complex, GCC), total retina, total retina minus GCC (outer retina)} were measured by macular scans (RS-3000, NIDEK) in 202 eyes of 202 normal Asian subjects aged 20 to 60 years. The analytical areas were defined by three concentric circles (1-, 3- and 6-mm nominal diameters) with or without magnification correction. For each layer thickness, a semipartial correlation (sr) was calculated for explanatory variables including age, gender, axial length, corneal curvature, and signal strength index.

Results: Outer retinal thickness was significantly thinner in females than in males (sr2, 0.07 to 0.13) regardless of analytical areas or magnification correction. Without magnification correction, axial length had a significant positive sr with RNFL (sr2, 0.12 to 0.33) and a negative sr with GCLIPL (sr2, 0.22 to 0.31), GCC (sr2, 0.03 to 0.17), total retina (sr2, 0.07 to 0.17) and outer retina (sr2, 0.16 to 0.29) in multiple analytical areas. The significant sr in RNFL, GCLIPL and GCC became mostly insignificant following magnification correction.

Conclusions: The strong correlation between the thickness of inner retinal layers and axial length appeared to result from magnification effects. Outer retinal thickness may differ by gender and axial length independently of magnification correction.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0147782PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729678PMC
July 2016
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