Shiroaki Shirato

Optic disc hemorrhage in low-tension glaucoma.

The prevalence of optic disc hemorrhage (DH) was determined in groups consisting of 192 primary open-angle glaucoma, 113 primary angle-closure glaucoma, 78 low-tension glaucoma, and 473 normal patients. The DH was mot prevalent (20.5%) among low tension glaucoma patients (chi 2; P less than 0.001). The epidemiological features of DH were studied in 58 low-tension glaucoma patients by examining them every one to four weeks from 6 to 32 months. All the DHs but one took place within a seven-month follow-up and the incidence of DH varies from 0 to 10% during the 32-month follow-up period. The overall incidence of DH was 24.8% during that period of time. Recurrences were seen in 64% of the eyes and 92% of these occurred within 28 weeks following the previous hemorrhages. Ninety-two percent of all DHs were present for at least four weeks. Low-tension glaucoma eyes seem to consist of two different groups; one which develops recurrent DH and one which is very unlikely to bleed through its entire course.

Mutations in the TIGR gene in familial primary open-angle glaucoma in Japan.

To the Editor:As described in an editorial by Raymond (1997)xMolecular genetics of the glaucomas: mapping of the first five “GLC” loci. Raymond, V. Am J Hum Genet. 1997; 60: 272–277PubMedSee all ReferencesRaymond (1997), glaucoma is characterized by progressive excavation of the optic disk, with both loss of retinal nerve fiber and visual field defects. This disease is one of the most common causes of bilateral blindness, and it is estimated that by the year 2000 ∼66.8 million people worldwide will be affected by it (Quigley 1996xNumber of people with glaucoma worldwide. Quigley, HA. Br J Ophthalmol. 1996; 80: 389–393Crossref | PubMedSee all ReferencesQuigley 1996). Recently, the glaucoma geneGLC1A was shown to be identical to the trabecular meshwork–inducible glucocorticoid response (TIGR) gene (TIGR) (Stone et al. 1997xIdentification of a gene that causes primary open angle glaucoma. Stone, EM, Fingert, JH, Alward, WLM, Nguyen, TD, Polansky, JR, Sunden, SLF, Nishimura, D et al. Science. 1997; 275: 668–670Crossref | PubMed | Scopus (975)See all ReferencesStone et al. 1997). The TIGR gene was cloned by Polansky and colleagues (Nguyen et al. 1993xGlucocorticoid (GC) effects on HTM cells: molecular biology approaches. Nguyen, TD, Huang, W, Bloom, E, and Polansky, JR. : 331–343See all ReferencesNguyen et al. 1993; Polansky et al. 1997xCellular pharmacology and molecular biology of the trabecular meshwork inducible glucocorticoid response gene product. Polansky, JR, Fauss, DJ, Chen, P, Chen, H, Lutjen-Drecoll, E, Johnson, D, Kurtz, RM et al. Ophthalmologica. 1997; 211: 126–139Crossref | PubMedSee all ReferencesPolansky et al. 1997) and, also, was called “myocilin” (gene MYOC) when it was cloned by Kubota et al. (1997)xA novel myosin-like protein (myocilin) expressed in the connecting cilium of the photoreceptor: molecular cloning, tissue expression, and chromosomal mapping. Kubota, R, Noda, S, Wang, Y, Minoshima, S, Asakawa, S, Kudoh, J, Mashima, Y et al. Genomics. 1997; 41: 360–369Crossref | PubMed | Scopus (250)See all ReferencesKubota et al. (1997). Three different mutations in the gene were shown to be responsible for the development of primary open-angle glaucoma (POAG), the most common form of glaucoma (Stone et al. 1997xIdentification of a gene that causes primary open angle glaucoma. Stone, EM, Fingert, JH, Alward, WLM, Nguyen, TD, Polansky, JR, Sunden, SLF, Nishimura, D et al. Science. 1997; 275: 668–670Crossref | PubMed | Scopus (975)See all ReferencesStone et al. 1997). The prevalence of these mutations was reported to be 4.4% in familial POAG patients and 2.9% in unselected POAG patients (Stone et al. 1997xIdentification of a gene that causes primary open angle glaucoma. Stone, EM, Fingert, JH, Alward, WLM, Nguyen, TD, Polansky, JR, Sunden, SLF, Nishimura, D et al. Science. 1997; 275: 668–670Crossref | PubMed | Scopus (975)See all ReferencesStone et al. 1997). We investigated whether Japanese patients with familial POAG carry identical or other mutants on the same gene. As a result, two new mutations in the TIGR gene were found. The prevalence of mutations in the TIGR gene in Japanese patients with familial POAG was also investigated.Peripheral blood samples were collected, with informed consent, from 52 POAG patients of 50 pedigrees with a family history. The patients were diagnosed with POAG, by ocular and systemic examinations. The family history was obtained by direct interview with the patients. Subjects having at least one relative with POAG within the third degree of relationship were defined as belonging to a pedigree having familial POAG. They all had an elevated intraocular pressure (⩾22 mmHg), open-angle (Shaffer grade III or IV), visual-field loss characteristic of glaucoma, and glaucomatous optic-disk damage. Blood samples from five normal healthy volunteer were also obtained, as controls, with informed consent. Genomic DNA was purified from these blood samples by use of a QIAGEN QIAamp Blood Kit. A DNA fragment encoding a portion of the TIGR protein (amino acid residues 317–476, exon 3; GenBank accession number U85257-AF001620) was amplified, with samples of the purified genomic DNA used as templates, by PCR. The nucleotide sequences of primers used are 5′-ATACTGCCTAGGCCACTGGA (sense strand) and 5′-CATGCTGCTGTACTTATAGCGG (antisense strand). A 150-ng template was mixed with 10 μl of 10 × buffer, 8 μl of the deoxynucleotides mixture, 10 pmol of each primer, and 0.5 μl of Taq polymerase (AmpliTaq Gold; Perkin Elmer), to produce a 100−μl PCR mixture. The nucleotide sequences of both strands of the PCR products were directly determined with the terminator cycle–sequencing method, by use of fluorescent dideoxynucleotides and an automatic DNA sequencer (Applied Biosystems). Mutation was recognized by the approximately equal peak intensity of two fluorescent dyes at the mutation site. When a mutation was detected, the whole procedure of PCR and sequencing was repeated, and the existence of the mutation was confirmed.Of the 52 patients from the 50 pedigrees, 2 patients of one family (a father and a daughter [who was the proband]) carried a heterozygous C→T mutation at the second nucleotide position in the codon corresponding to the 370th amino acid residue of the TIGR protein, resulting in an amino acid change from proline to leucine (Pro370Leu) (figs. 1A1A and 22). The father was diagnosed with POAG at age 26 years old, the daughter at age 16 years. One other patient, from a different pedigree, had a heterozygous G→A mutation at the first nucleotide position in the codon corresponding to the 367th amino acid residue, resulting in an amino acid change from glycine to arginine (Gly367Arg) (fig. 1Bfig. 1B). She was diagnosed with POAG at age 45 years. Both mutations were different from those reported elsewhere (Stone et al. 1997xIdentification of a gene that causes primary open angle glaucoma. Stone, EM, Fingert, JH, Alward, WLM, Nguyen, TD, Polansky, JR, Sunden, SLF, Nishimura, D et al. Science. 1997; 275: 668–670Crossref | PubMed | Scopus (975)See all ReferencesStone et al. 1997). In the pedigree with the Pro370Leu mutation, the mother and a sister of the proband were examined and proved to have neither symptoms of glaucoma nor mutations in the TIGR gene portion examined (fig. 2fig. 2). Therefore, the mutation was inherited in an autosomal dominant manner. The patient with the Gly367Arg mutation had a family history, in that at least her two aunts and five cousins had POAG; but we could not obtain blood samples from her relatives. The prevalence of the mutations in the TIGR gene was 4.0% (2/50 families), which was comparable to that reported in a previous study (Stone et al. 1997xIdentification of a gene that causes primary open angle glaucoma. Stone, EM, Fingert, JH, Alward, WLM, Nguyen, TD, Polansky, JR, Sunden, SLF, Nishimura, D et al. Science. 1997; 275: 668–670Crossref | PubMed | Scopus (975)See all ReferencesStone et al. 1997).Figure 1Chromatograms of nucleotide sequences from patients with mutations (A and B) and from a normal control (C). The double peak of cytosine (blue line) and thymine (red line) (A, red arrow) represents a heterozygous mutation in the codon corresponding to the 370th amino acid residue of the TIGR protein (Pro370Leu). The double peak of guanine (black line) and adenine (green line) (B, green arrow) represents a heterozygous mutation at the codon of 367th amino acid residue (Gly367Arg).View Large Image | View Hi-Res Image | Download PowerPoint SlideFigure 2Pedigree of patients with the Pro370Leu mutation. The proband is indicated by an arrow.View Large Image | View Hi-Res Image | Download PowerPoint SlideThe present study has revealed that mutations in the TIGR gene are also responsible for familial POAG in Japan. The mutations in the third exon of the TIGR gene were found to be associated with ∼4% of Japanese familial POAG patients. The prevalence of the mutations in the gene was comparable in Japanese patients and in the population previously studied. The mutated sites, however, were different from those reported in the previous study, and no common mutations were found. Therefore, the distribution of the mutated sites in the TIGR gene in Japanese POAG may be different from those in other races. Known mutated sites in the TIGR-gene disease alleles are at the 364th, 367th, 368th, 370th, and 437th amino acid residues. The apparent focus of the reported mutations—around the 367th amino acid residue—indicates that the amino acid change around this position may play a critical role in the pathogenesis of POAG. The TIGR-protein product is overexpressed with glucocorticoid stimulation and is thought to contribute to steroid-responsive intraocular-pressure increase, by the obstruction of aqueous outflow (Nguyen et al. 1993xGlucocorticoid (GC) effects on HTM cells: molecular biology approaches. Nguyen, TD, Huang, W, Bloom, E, and Polansky, JR. : 331–343See all ReferencesNguyen et al. 1993; Polansky et al. 1997xCellular pharmacology and molecular biology of the trabecular meshwork inducible glucocorticoid response gene product. Polansky, JR, Fauss, DJ, Chen, P, Chen, H, Lutjen-Drecoll, E, Johnson, D, Kurtz, RM et al. Ophthalmologica. 1997; 211: 126–139Crossref | PubMedSee all ReferencesPolansky et al. 1997). Further investigations of the TIGR gene will reveal more information about the pathogenesis of POAG.

Comparison of diclofenac and fluorometholone in preventing cystoid macular edema after small incision cataract surgery : A multicentered prospective trial

PURPOSE To compare a nonsteroidal topical solution (0.1% diclofenac) to a steroidal topical solution (0.1% fluorometholone) in preventing cystoid macular edema (CME) and disruption of the blood-aqueous barrier. METHODS A multicentered, prospective clinical trial was performed on eyes undergoing phacoemulsification followed by implantation of a foldable acrylic intraocular lens by the envelope technique. The presence and degree of cystoid macula edema (CME) was determined by fluorescein angiography. A breakdown of the blood-aqueous barrier was determined by laser flare-cell photometry. RESULTS Five weeks after surgery, CME was present in 3 of 53 eyes (5.7%) receiving diclofenac and in 29 of 53 eyes (54.7%) receiving fluorometholone. This difference was statistically significant (P < .001). The amount of flare in the anterior chamber at 3 days, 1, 2, 5, and 8 weeks after surgery was also significantly lower (P < .01-P < .001) in the diclofenac group. The degree of flare at 3 days, 1, 2, 5, and 8 weeks after surgery was significantly higher in eyes with CME (P < .001). CONCLUSIONS These findings suggest that diclofenac effectively prevents CME following cataract surgery and that CME is closely related to the breakdown of the blood-aqueous barrier.

A Clinical Evaluation of Uveitis-associated Secondary Glaucoma

PURPOSE To investigate the clinical features of secondary glaucoma associated with uveitis. METHODS The subjects of the study were 1,099 patients with uveitis (1,604 eyes) treated at the Miyata Eye Hospital, Miyakonojo, Miyazaki, between October 1974 and January 2000. The intraocular pressure (IOP) and clinical data were analyzed retrospectively. Secondary glaucoma was diagnosed in the patients when IOP was higher than 21 mm Hg at two consecutive visits and they needed treatment with medication to control the high IOP. RESULTS Secondary glaucoma was found in 293 eyes (18.3%) of 217 patients (19.7%) among the uveitis patients. The clinical entity with the highest incidence of secondary glaucoma was Posner-Schlossman syndrome in 100%, followed by sarcoidosis in 34.1%, herpetic anterior uveitis in 30.4%, Behçets disease in 20.8%, human leukocyte antigen-B27-related acute anterior uveitis in 20.0%, Vogt-Koyanagi-Haradas disease in 16.4%, and human T-lymphotropic virus type 1 uveitis in 16.2%. Among these 293 eyes with secondary glaucoma, the majority (72%) had active anterior uveitis at the time of high IOP. Only 7.5% of the secondary glaucoma eyes had peripheral anterior synechia wider than 180 degrees of the trabecular meshwork. Steroid-induced glaucoma was found in only 8.9% of the secondary glaucoma eyes. Surgical therapy, mainly trabeculectomy with anti-metabolites, was performed in 38 eyes and the post-surgical IOP was controlled under 20 mm Hg in 34 eyes. Despite the medical and surgical therapy for secondary glaucoma, visual field defect was found in 39% of the secondary glaucoma eyes. CONCLUSIONS The incidence of secondary glaucoma in the 1,604 eyes with uveitis was 18.3%, but it differed depending upon the clinical entity of the uveitis. The evaluation and the management of IOP are very important in the treatment of patients with uveitis, in addition to the management of intraocular inflammation.

Long-term follow-up of initial trabeculectomy with mitomycin C for primary open-angle glaucoma in Japanese patients.

PurposeTo determine the long-term intraocular pressure (IOP) control and postoperative complications after initial trabeculectomy with use of mitomycin C (MMC) in patients with primary open-angle glaucoma (POAG). Patients and MethodsA retrospective review was conducted of a consecutive series of 123 eyes (87 patients) with POAG who underwent initial trabeculectomy with MMC and had at least 4 years of follow-up. All patients underwent standard trabeculectomy with 0.04% MMC applied intraoperatively for 3 minutes. The long-term outcomes (IOP control and bleb leak, long-standing hypotony, bleb-related infections) were analyzed with the Kaplan-Meier life-table method on the basis of three definitions of successful IOP control (defined as IOP <18 mmHg (definition 1), IOP <16 mmHg (definition 2), and IOP decrease of by ≥30% and <21 mmHg (definition 3)). ResultsThe mean follow-up time was 6.8±1.4 (mean±SD) years. The cumulative survival rates were 67.0±4.6%, 44.5±5.4%, and 74.1±4.2%, respectively, based on definitions 1, 2, and 3, 8 years postoperatively by life-table analysis. At 8 years, bleb leak occurred in 7.9±2.6% of eyes, long-standing hypotony in 8.3±2.5%, and bleb-related infections in 5.9±2.4%. ConclusionLong-term outcome after initial trabeculectomy with MMC in Japanese POAG patients is comparable with that reported in other populations and with that after trabeculectomy with 5-fluorouracil.

Clinical characteristics and leakage of functioning blebs after trabeculectomy with mitomycin-C in primary glaucoma patients ☆

PURPOSES To describe the clinical characteristics of functioning blebs in Japanese glaucoma patients after primary trabeculectomy with adjunctive mitomycin-C (MMC) and to correlate their associations with postoperative bleb leakage. DESIGN A prospective, observational case series. PARTICIPANTS One hundred sixty-two glaucoma patients who had undergone primary trabeculectomy with MMC at the University of Tokyo Hospital at least 3 months before were examined between December 1997 and February 1998. METHODS A predesigned data form was completed at each visit. Ophthalmologic examinations included Goldmann applanation tonometry, slit-lamp examination, and Seidel tests with and without digital ocular pressure (DOP). MAIN OUTCOME MEASURES Properties of the functioning bleb, including bleb appearance, thickness of bleb wall, dimensions of bleb and avascular area, and leakage status with and without DOP. RESULTS Of 162 Japanese patients, 162 eyes with functioning blebs were included. There were no differences in bleb characteristics among the different types of primary glaucoma. With a long postoperative duration, blebs tended to be thinner (P = 0.024). With DOP, the leaking rate increased from 3.1% to 5.6%, and the oozing rate increased from 11.1% to 35.8% (P < 0.001). Logistic regression analysis indicated that the larger the avascular area, the more likely the bleb leaked without DOP (P = 0.016). When DOP was applied, leakage was more likely to occur in the blebs with a long postoperative duration (P = 0.002) or with a large avascular area (P < 0.001). CONCLUSIONS The clinical characteristics of filtering blebs were similar in Japanese patients with different types of primary glaucoma. Blebs with a large avascular area were associated with a higher risk of bleb leakage. Attention to the increased chance of leakage induced by DOP is important, especially for blebs with a long postoperative duration. Ophthalmologists should be aware of late bleb-related complications in addition to bleb function.

5-Fluorouracil for trabeculectomy in glaucoma.

The effect of 5-fluorouracil (5-FU) subconjunctival injection on the bleb formation and intraocular pressure (IOP) following trabeculectomy was studied in 18 glaucoma patients (20 eyes) with poor surgical prognosis. The results were analyzed by means of life tables and compared with those of 24 glaucoma eyes that had undergone trabeculectomy without postoperative administration of 5-FU after a previous repeat trabeculectomy that had failed. The surgical techniques and postoperative care were virtually identical between the eyes treated with 5-FU and eyes that had undergone repeat trabeculectomy, except that the latter group did not receive 5-FU postoperatively. At the end of 18-month follow-up, the success probability was 68.2% in the 5-FU treated eyes, and it was already as low as 10% in the nontreated eyes at the end of the 14-month follow-up. The difference was statistically highly significant (P < 0.001). Postoperative, subconjunctival injection of 5-FU appears to improve the prognosis following trabeculectomy in patients with a poor surgical prognosis.

Common Variants on Chromosome 9p21 Are Associated with Normal Tension Glaucoma

Although intraocular pressure (IOP) is the most definitive cause of glaucoma, a subtype of open angle glaucoma (OAG) termed normal tension glaucoma (NTG), which occurs in spite of normal IOP, accounts for a large part of glaucoma cases, especially in Japan. To find common genetic variants contributing to NTG in Japanese patients, we conducted a genome-wide association study (GWAS). We performed the first screening for 531,009 autosomal SNPs with a discovery cohort of 286 cases and 557 controls, and then a second screening for the top 30 suggestive loci in an independent cohort of 183 cases and 514 controls. Our findings identified a significantly associated SNP; rs523096 [combined p-value = 7.40× 10−8, odds ratio (OR)  = 2.00 with 95% confidence interval (CI) 1.55–2.58] located 10 kbp upstream of CDKN2B on chromosome 9p21. Moreover, analysis of another independent case-control set successfully replicated the results of the screening studies (combined values of all 3 stages p = 4.96 × 10−11, OR  = 2.13 with 95% CI 1.69–2.68). The SNPs near rs523096 were recently reported to be associated with OAG associated with elevated IOP in primary open-angle glaucoma (POAG), the predominant subtype of glaucoma in Caucasian populations. Our results revealed that the 9p21 locus is also associated with NTG in Japanese. In addition, we identified SNPs more strongly associated with NTG.

Effect of Trabeculectomy on Visual Field Performance in Central 30° Field in Progressive Normal-tension Glaucoma

Abstract Purpose: The authors studied the effects of trabeculectomy on the time course of central 30° visual field performances in progressive normal-tension glaucoma (NTG). Methods: Patients with NTG who had clear ocular media and were adequate performers on the 30-2 program of Humphrey Perimeter were prospectively followed with periodic field testing. Trabeculectomy using an antimetabolite was indicated when the slope of a line fitted to the time course of the mean deviation (MD), MD slope, was significantly negative. The time courses of MD and mean of total deviations (mean TD) in four subfields, superior and inferior arcuate and superior and inferior cecocentral fields, were analyzed using the mixed linear model. Results: In progressive NTG, 21 eyes of 21 cases with postoperative follow-up of 2 years or more, intraocular pressure averaged 16 mmHg, MD averaged −13.5 dB, and MD slope averaged −1.48 dB/year preoperatively; 2 years after surgery, they averaged 9.2 mmHg, −13.6 dB, and +0.13 dB/year, respectively. Trabeculectomy had a significant beneficial effect on the time course of MD and mean TD in the superior and inferior arcuate and superior cecocentral fields, which showed significant preoperative deterioration. The mean TD in the inferior cecocentral field showed no significant time change during the period studied. Conclusion: For patients with NTG in whom the MD slope is significantly negative, trabeculectomy may have beneficial and diffuse effects on further deterioration of the visual field.

Effects of oral brovincamine on visual field damage in patients with normal-tension glaucoma with low-normal intraocular pressure.

PURPOSE To prospectively study the effect of oral brovincamine, a relatively selective cerebral vasodilator, on further deterioration of visual field in patients with normal-tension glaucoma (NTG) with low-normal intraocular pressure (IOP). METHODS Fifty-two patients with NTG (average age 57.7 years) with an IOP that was consistently less than 15 mmHg were randomly assigned to receive oral brovincamine (20 mg three times daily) or to an untreated control group. The groups were prospectively followed for 2 years with visual field examinations every 4 months, using the 30-2 Humphrey perimeter program. Changes in mean deviation (MD), corrected pattern standard deviation (CPSD), and total deviation (TD) at 74 test points were analyzed using regression analysis with linear mixed model. Data from one eye without media opacity of each subject were analyzed. RESULTS There were no differences between groups in age; sex distribution; refraction; blood pressure; baseline IOP; MD, CPSD, or TD at each point. Changes in MD (standard error [SE]) during the study period were -0.778 (0.178) and -0.071 (0.195) dB/year in the control and brovincamine groups, respectively; change in the control group was significantly more negative than in the brovincamine group. Change in CPSD (SE) was 0.032 (0.015) and 0.004 (0.016) dB/year in the control and brovincamine groups, respectively. Change in the control group was significantly positive, but the intergroup difference was not significant. Change in TD was significantly negative at six test points in the control group, whereas no points showed a significant trend in the brovincamine group; the intergroup difference was significant. The average IOP was 13.2 mmHg and 13.1 mmHg in the control and brovincamine groups, respectively, and there was no significant intergroup difference. CONCLUSION Oral brovincamine may retard further visual field deterioration in patients with NTG who have low-normal IOP.