Yuichiro Ohtake

Decreased blood flow at neuroretinal rim of optic nerve head corresponds with visual field deficit in eyes with normal tension glaucoma

PurposeTo determine the relationship between the blood flow parameters of the optic disc rim and the glaucomatous visual field changes.DesignObservational cross-sectional study.MethodsTissue blood flow in the neuroretinal rim within the optic disc was determined with the Heidelberg retina flowmeter(HRF) in 54 eyes of 54 patients with normal tension glaucoma (NTG). Patients were selected whose visual field defects were confined to either the superior or inferior hemifield. Blood flow measurements were made in a 10°×2.5° area of the superior and inferior neuroretinal rim within the optic disc. The mean blood flow (MBF) was calculated by the automatic full-field perfusion image analyzer program, and the ratio of the MBF in the superior to the inferior rim areas (the S/I ratio) was calculated from the same HRF image in order to minimize the variation of measurement condition.ResultsInferior rim blood flow is less than superior rim blood flow in patients with superior hemifield defect, and superior rim blood flow is reduced compared to inferior in patients with inferior hemifield defect. The mean S/I ratios of the MBF in the patients with superior hemifield defect (1.46, n=37) was significantly higher than that in the patients with inferior hemifield defect (0.79, n=17; P<0.0001, Mann-Whitney U-test).ConclusionsThe blood flow in the neuroretinal rim was found to correspond to the regional visual field defect in eyes with NTG. Reductions in flow were associated with reductions in function.

Phenotype of cytochrome P4501B1 gene (CYP1B1) mutations in Japanese patients with primary congenital glaucoma

Aim: To investigate the phenotypes associated with cytochrome P4501B1 gene (CYP1B1) mutations in Japanese patients with primary congenital glaucoma (PCG). Methods: 66 Japanese patients with PCG were screened for sequence mutations in the CYP1B1 gene using single strand conformation polymorphism analysis followed by automated DNA sequencing. 11 cases had a CYP1B1 mutation in both alleles (the mutation group) and 21 cases did not have a CYP1B1 mutation (the “no mutation” group). The clinical features, such as age of onset, sex, intraocular pressure, and Descemet‘s membrane rupture, of the two groups were compared. Results: The clinical symptoms and signs did not differ for the two groups. The mean age at onset was 1.7 months in the mutation group and 3.1 months in the no mutation group, and the male:female ratio was 6:5 in the mutation group and 19:2 in the no mutation group. Both of these differences were statistically significant. Conclusions: In clinically diagnosed cases of PCG, a subgroup shows a CYP1B1 gene mutation. Age at onset was earlier in PCG patients with CYP1B1 mutations than in patients without mutations. Women were more prevalent among patients with mutations than those without mutations.

Scanning laser Doppler flowmeter study of retinal blood flow in macular area of healthy volunteers

Aim: To compare the interocular and intraocular differences of capillary perfusion, and the intraocular regional differences of retinal blood flow in the macular area of healthy volunteers. Methods: Tissue blood flow in the macula was examined in both eyes of 20 healthy volunteers with the Heidelberg retinal flowmeter. Blood flow measurements were made in a 10°×2.5° area superior and inferior to the macula. The mean blood flow (MBF) was calculated by an automatic full field perfusion image analyser program. The MBF in the right and left eyes and in the superior and inferior macular areas of the same eye were compared. Results: The ratios of the MBF in the right eye to the left eye in the macular areas were 1.00, and 1.03, respectively. The ratio of the MBF in the superior macular area to the inferior area was 1.01 for the right eyes and 1.04 for the left eyes. Conclusions: Because no significant differences were found in the MBF between the two eyes and between the superior and inferior macular areas in the same eye, interocular (for example, affected eye versus fellow eye) and intraocular (superior versus inferior macular areas) comparisons of MBF can be made to determine if changes in retinal perfusion have occurred.

Novel Mutations in the Myocilin Gene in Japanese Glaucoma Patients

Myocilin is a gene responsible for juvenile onset primary open angle glaucoma (POAG) mapped as the GLC1A locus and, many mutations have been reported worldwide. Some mutations were found not only in patients with juvenile onset POAG, but also in patients with late onset POAG and in patients with normal tension glaucoma. To investigate the mutation prevalence in Japan, we performed a mutation analysis in 140 unrelated Japanese patients. We have identified the 10 sequence variants, of which four were highly probable for disease‐causing mutations (Arg46ter, Arg158Gln, Ile360Asn, and Ala363Thr), and six polymorphisms (Gln19His, Arg76Lys, Asp208Glu, Val439Val, Arg470His, and Ala488Ala). Thus, myocilin mutations were found at the rate of 4/140 (2.9%) probands, similar to previous reports with other ethnic populations. Hum Mutat 16:270, 2000.

Reduced choroidal blood flow can induce visual field defect in open angle glaucoma patients without intraocular pressure elevation following encircling scleral buckling.

Purpose: To determine the cause of the progressive glaucomatous visual field defects in three patients after an encircling scleral buckle for a rhegmatogenous retinal detachment (RRD). Methods: Scanning laser Doppler flowmetry and visual field tests were performed on three cases with unilateral progressive visual field defect after an encircling scleral buckling for a RRD. Similar measurements were made after the buckle was removed. Results: After implanting the scleral buckle, the intraocular pressure was normal and chamber angle was open. The blood flow in the neuroretinal rim of the optic disk was lower than that in the healthy fellow eye. After removing the buckle, the blood flow improved to normal levels and a further worsening of the visual field was not detected. Conclusions: These results suggest that an encircling scleral buckle may impair choroidal circulation and lead to visual field defects similar to eyes with normal tension glaucoma.

Effect of topical unoprostone isopropyl on optic nerve head circulation in controls and in normal-tension glaucoma patients.

PurposeTo evaluate the effect of unoprostone isopropyl on microcirculation in the optic nerve head (ONH) of controls and patients with normal-tension glaucoma (NTG).MethodsThirty healthy volunteers were randomly placed in a placebo group or a control group. For ten NTG patients, one eye was selected to receive the placebo drops and the contralateral eye received the unoprostone in a masked fashion. In both studies, the intraocular pressure (IOP) and the parameters of the blood hemodynamics of the ONH were obtained before and at 1 and 2 h after the instillation. Blood flow measurements were made with a scanning laser Doppler flowmeter.ResultsIn both control subjects and NTG patients, the changes in the IOPs after the instillation of either unoprostone or the placebo were not significant because almost all of the NTG patients had IOPs lower than 15 mmHg. Although the hemodynamic parameters were not significantly changed in the placebo-treated eyes of the controls, the eyes of the controls treated with unoprostone had mean blood velocity and flow values that were significantly higher than the baseline values 1 and 2 h after instillation (P < 0.01). The velocity values of the controls treated with unoprostone were significantly higher than in those controls receiving the placebo at 2 h postinstillation (P = 0.027). The values for the three circulation parameters (volume, velocity, flow) were significantly higher than the baseline values after instillation in the eyes of the NTG patients treated with unoprostone (P < 0.05). In contrast, none of these parameters was significantly different from the baseline in the eyes of NTG patients treated with placebo.ConclusionsThese results showed that unoprostone significantly increased microcirculation in the ONH in control subjects and in NTG patients without reducing the IOP significantly. Jpn J Ophthalmol 2005;49:287–293

Lead Accumulation as Possible Risk Factor for Primary Open-Angle Glaucoma

We evaluated the association between hair lead concentrations and primary open-angle glaucoma. Ninety-eight Japanese patients (40 males, 58 females; average age 57.6±10.8 years) with primary open-angle glaucoma and control subjects (131 males, 114 females; average age 56.0±12.8 years) were recruited in this study. Hair lead levels were measured by inductively coupled plasma mass spectrometry. Hair lead concentrations between primary open-angle glaucoma and control groups were compared using Mann–Whitney U test. As a subgroup analysis, we compared hair lead concentrations between low-tension glaucoma, high-tension glaucoma, and control groups using one-factor analysis of variance. Lead accumulation levels were significantly higher in the female subjects with primary open-angle glaucoma compared to the control group (P=0.03). Lead accumulation levels were significantly higher in female patients with low intraocular pressure compared to control group 2 (P=0.02). A higher hair lead level, which reflects the total body burden of lead, was observed to be associated with primary open-angle glaucoma in females especially with low-tension glaucoma. Accumulation of lead may be an unrecognized risk factor of non-pressure-dependent glaucomatous optic neuropathy.

Variants of the Myocilin Gene in Japanese Patients with Normal-Tension Glaucoma

Myocilin (MYOC) mutations are associated with juvenile- and adult-onset primary open-angle glaucoma (POAG). The purpose of this study was to determine whether MYOC gene mutations are associated with normal-tension glaucoma (NTG). The prevalence of MYOC mutations was determined in 80 Japanese NTG patients and 100 control subjects. In addition, the expression of mutant MYOC was determined by transforming COS-1 cells with five myocilin variants (R158Q, D208E, I360N, A363T, and I477S) and examining whether myocilin was present in the cultured cells and/or the culture medium by western blotting. Six different nucleotide sequence variants, R46Stop, R76K, R158Q, D208E, A488A, and one in the 3′ non-coding region, were identified in 80 NTG patients. Variants in codon 46 (R46Stop), codon 158 (R158Q), and codon 488 (A488A) were not found in the 100 normal controls. The frequency of other sequence changes (R76K, D208E, and 3′ non-coding) in NTG patients did not differ significantly from the frequencies in the control subjects. COS-1 cells transfected with the wild type, R158Q, or D208E variants secreted myocilin into the culture medium. On the other hand, the detected myocilin was significantly reduced in the medium of cells transfected with the I360N, A363T, or I477S variants that were previously identified as mutations for POAG. Definitive evidence of MYOC variants associated with NTG was not found.

Trabeculectomy with or without intraoperative sub-tenon injection of triamcinolone acetonide in treating secondary glaucoma.

PURPOSE To investigate the efficacy of intraoperative sub-Tenon injection of triamcinolone acetonide (TA) in increasing the success rate of trabeculectomy for the treatment of secondary glaucoma. DESIGN Prospective randomized controlled clinical trial. METHODS Fifty-three consecutive eyes scheduled for trabeculectomy were randomly allocated in an institutional setting. In the study group (n = 26), TA was injected in the sub-Tenon at the conclusion of the surgery. In the control group (n = 27) surgery was completed without TA injection. Surgical success was defined as a complete success if the intraocular pressure (IOP) was 21 mm Hg or less with an IOP reduction of greater than or equal to 20% without any antiglaucoma medication. Success rates in both groups were compared using Kaplan-Meier survival curves and the log-rank test. The morphologic characteristics of the filtering blebs were evaluated using the Indiana Bleb Appearance Grading Scale. RESULTS Fifty-three eyes completed the study (26 in the study group and 27 in the control group), with a follow-up of 12 months. Complete success rates were 65.4% for the study group and 63.0% for the control group (P = .77) at 12 months. The morphologic characteristics of the filtering blebs and postoperative complications were similar in the study and the control eyes (P > .40). IOP measurements in both groups were similar at all visits (P > .05). CONCLUSIONS Trabeculectomy with intraoperative sub-Tenon injection of TA for the treatment of secondary glaucoma neither increased the intermediate-term success rate nor decreased postoperative complications.

Novel myoc Gene Mutation, Phe369leu, in Japanese Patients with Primary Open-angle Glaucoma Detected by Denaturing High-performance Liquid Chromatography

Purpose:To screen for mutations in the MYOC gene in Japanese patients with primary open-angle glaucoma (POAG) using denaturing high-performance liquid chromatography (DHPLC). Patients and Methods:Blood samples were collected from 171 patients with POAG and 100 controls from seven institutions in Japan. For high-throughput analysis, seven exonic regions were amplified by polymerase chain reaction using DNA pooled from three patients; each DNA pool was then analyzed chromatographically. For analysis of a small number of samples, 7 exonic regions were amplified separately but simultaneously with annealing at 58°C in each patient and then chromatographed, using 7 wells of the same 96-well plate per sample. When chromatographic patterns were abnormal by either method, the PCR products of the individual samples were sequenced. Results:Four glaucoma-causing mutations were identified in five POAG patients (2.9%). One missense mutation, Phe369Leu, is new; and three others, Ile360Asn, Ala363Thr, and Thr448Pro, have been reported in Japanese patients. Phe369Leu was associated with adult onset POAG. Conclusions:Mutations in the MYOC gene were demonstrated chromatographically in 2.9% of our Japanese POAG patients. The use of pooled DNAs with DHPLC analysis is a time- and labor-saving technique. All mutations detected appear to be specific to Japanese patients.