Minako Ogata-Iwao

Long-term outcomes and prognostic factors for trabeculectomy with mitomycin C in eyes with uveitic glaucoma: a retrospective cohort study.

Purpose:To elucidate the long-term outcomes and prognostic factors for trabeculectomy with mitomycin C (MMC) in eyes with uveitic glaucoma (UG). Methods:A retrospective, consecutive, comparative cohort study was conducted with 204 patients who underwent trabeculectomy with MMC between 1999 and 2008 at 2 Japanese clinical centers. The study group included 101 eyes with UG and 103 eyes with primary open-angle glaucoma (POAG). Surgical failure was defined as intraocular pressure levels of ≥21 mm Hg or an additional glaucoma surgery. Kaplan-Meier survival curves for surgical failure were compared between UG and POAG eyes, and prognostic factors for surgical failure of trabeculectomy in UG eyes were analyzed by the Cox proportional hazards model. Secondary outcome measures included comparisons of the frequency of additional cataract surgery and other surgical complications after trabeculectomy between UG and POAG eyes. Results:The mean follow-up periods (±SD) were 34.7±37.9 and 37.7±34.7 months (median, 24.0 and 27.4 mo) for UG and POAG, respectively. The subtypes of uveitis were granulomatous uveitis (n=20) including sarcoidosis (n=12), Vogt-Koyanagi-Harada disease (n=5) and varicella zoster virus uveitis (n=3), Behçet disease (n=10), Posner-Schlossman syndrome (n=5), and other types of UG (n=12). Fifty-four eyes were diagnosed with idiopathic UG. The 3-year probabilities of success after trabeculectomy were 71.3% and 89.7% for UG and POAG, respectively (P=0.0171). A multivariable model showed that UG eyes with previous cataract surgery [relative risk (RR)=2.957, P=0.0344)] and granulomatous uveitis (RR=3.805, P=0.0106) were associated with surgical failure. UG eyes experienced more frequent cataract surgeries after trabeculectomy than POAG eyes: the 3-year probabilities of additional cataract surgery of 62.6% and 10.7% for UG and POAG, respectively (P<0.0001). There was no significant difference in the frequency of surgical complications such as bleb leakage, hypotensive maculopathy, severe anterior-chamber hemorrhage, and infectious endophthalmitis. Conclusions:Trabeculectomy with MMC was less effective in maintaining intraocular pressure reduction in UG eyes than in POAG eyes. The prognostic factors for surgical failure of trabeculectomy in UG eyes were previous cataract surgery and granulomatous uveitis. In addition, UG eyes after trabeculectomy more frequently required additional cataract surgery.

Heparan sulfate deficiency leads to Peters anomaly in mice by disturbing neural crest TGF-β2 signaling

During human embryogenesis, neural crest cells migrate to the anterior chamber of the eye and then differentiate into the inner layers of the cornea, the iridocorneal angle, and the anterior portion of the iris. When proper development does not occur, this causes iridocorneal angle dysgenesis and intraocular pressure (IOP) elevation, which ultimately results in developmental glaucoma. Here, we show that heparan sulfate (HS) deficiency in mouse neural crest cells causes anterior chamber dysgenesis, including corneal endothelium defects, corneal stroma hypoplasia, and iridocorneal angle dysgenesis. These dysfunctions are phenotypes of the human developmental glaucoma, Peters anomaly. In the neural crest cells of mice embryos, disruption of the gene encoding exostosin 1 (Ext1), which is an indispensable enzyme for HS synthesis, resulted in disturbed TGF-beta2 signaling. This led to reduced phosphorylation of Smad2 and downregulated expression of forkhead box C1 (Foxc1) and paired-like homeodomain transcription factor 2 (Pitx2), transcription factors that have been identified as the causative genes for developmental glaucoma. Furthermore, impaired interactions between HS and TGF-beta2 induced developmental glaucoma, which was manifested as an IOP elevation caused by iridocorneal angle dysgenesis. These findings suggest that HS is necessary for neural crest cells to form the anterior chamber via TGF-beta2 signaling. Disturbances of HS synthesis might therefore contribute to the pathology of developmental glaucoma.

Heparan Sulfate Regulates Intraretinal Axon Pathfinding by Retinal Ganglion Cells

PURPOSE. Heparan sulfate (HS) is abundantly expressed in the developing neural retina; however, its role in the intraretinal axon guidance of retinal ganglion cells (RGCs) remains unclear. In this study, the authors examined whether HS was essential for the axon guidance of RGCs toward the optic nerve head. METHODS. The authors conditionally ablated the gene encoding the exostosin-1 (Ext1) enzyme, using the dickkopf homolog 3 (Dkk3)-Cre transgene, which disrupted HS expression in the mouse retina during directed pathfinding by RGC axons toward the optic nerve head. In situ hybridization, immunohistochemistry, DiI tracing, binding assay, and retinal explant assays were performed to evaluate the phenotypes of the mutants and the roles of HS in intraretinal axon guidance. RESULTS. Despite no gross abnormality in RGC distribution, the mutant RGC axons exhibited severe intraretinal guidance errors, including optic nerve hypoplasia, ectopic axon penetration through the full thickness of the neural retina and into the subretinal space, and disturbance of the centrifugal projection of RGC axons toward the optic nerve head. These abnormal phenotypes shared similarities with the RGC axon misguidance caused by mutations of genes encoding Netrin-1 and Slit-1/2. Explant assays revealed that the mutant RGCs exhibited disturbed Netrin-1-dependent axon outgrowth and Slit-2-dependent repulsion. CONCLUSIONS. The present study demonstrated that RGC axon projection toward the optic nerve head requires the expression of HS in the neural retina, suggesting that HS in the retina functions as an essential modulator of Netrin-1 and Slit-mediated intraretinal RGC axon guidance.

Trabeculectomy for open-angle glaucoma in phakic eyes vs in pseudophakic eyes after phacoemulsification: a prospective clinical cohort study.

IMPORTANCE Whether pseudophakic eyes are resistant to trabeculectomy remains unknown. OBJECTIVE To determine the effect of previous phacoemulsification on surgical success of trabeculectomy with mitomycin C for open-angle glaucoma. DESIGN, SETTING, AND PARTICIPANTS Prospective clinical cohort study at Kumamoto University Hospital, Kumamoto, Japan, among patients 55 years or older having open-angle glaucoma with intraocular pressure (IOP) of 22 mm Hg or higher, including 39 phakic eyes (phakic group) and 25 pseudophakic eyes after phacoemulsification (pseudophakic group). INTERVENTION Trabeculectomy with mitomycin C was performed. MAIN OUTCOMES AND MEASURES The primary outcome measure was the probability of success at 1 year after trabeculectomy. Surgical failure was defined as the following 3 IOP levels: 21 mm Hg or higher (criterion A), 18 mm Hg or higher (criterion B), and 15 mm Hg or higher (criterion C). Secondary outcome measures included IOP, the number of postoperative antiglaucoma medications, and the number of laser suture lysis procedures, as well as postoperative complications. RESULTS The probabilities of success at 1 year in the phakic vs pseudophakic groups were 95% vs 74% for criterion A (P = .02), 84% vs 62% for criterion B (P = .04), and 67% vs 53% for criterion C (P = .10). Only pseudophakia was significantly associated with outcome in the multivariable analysis for criterion A (relative risk, 9.37) and for criterion B (relative risk, 5.52) (P = .01 for both). Postoperative IOP in the pseudophakic group was significantly higher than that in the phakic group at 6 months (P = .03) and 9 months (P = .047) after trabeculectomy. No significant difference between groups was noted in postoperative complications or in the number of postoperative antiglaucoma medications or the number of laser suture lysis procedures. CONCLUSIONS AND RELEVANCE Among patients with open-angle glaucoma, trabeculectomy with mitomycin C in pseudophakic eyes after phacoemulsification for target IOP of less than 21 mm Hg or less than 18 mm Hg is less successful compared with that in phakic eyes. No significant difference between phakic and pseudophakic eyes was observed for secondary outcome measures other than IOP. TRIAL REGISTRATION clinicaltrials.gov Identifier: University Hospital Medical Information Network Clinical Trials Registry of Japan UMIN000001196.

A prospective comparison between trabeculectomy with mitomycin C and phacotrabeculectomy with mitomycin C.

Editor, C ombined phacoemulsification with intraocular lens implantation and trabeculectomy (phacotrabeculectomy) is a surgical option for elderly patients with glaucoma and coexisting cataracts (Friedman et al. 2002); however, whether or not phacotrabeculectomy lowers intraocular pressure (IOP) to the same extent as trabeculectomy remains controversial (Stewart et al. 1995; Guggenbach et al. 1999; Kleinmann et al. 2002; Lochhead et al. 2003). Therefore, the current prospective study compared the surgical outcomes of phacotrabeculectomy with mitomycin C (MMC) with those of trabeculectomy with MMC in patients with open-angle glaucoma (OAG) and coexisting cataracts. The protocol was registered with the University Hospital Medical Information Network Clinical Trials Registry of Japan (No. C000000437). Fifty-two patients (26 in the trabeculectomy group and 26 in the phacotrabeculectomy group) were recruited from Kumamoto University Hospital (Kumamoto City, Japan) between 1 July 2006 and 22 December 2009 using the following inclusion criteria: ‡40 years of age, primary OAG or exfoliation glaucoma with coexisting cataracts, IOP >21 mmHg and no history of ocular surgery. Trabeculectomy was performed by creating a fornix-based conjunctival flap and a 4-mm-wide half-layer scleral flap, followed by the application of MMC (0.4 mg ⁄ml) for 4 min for phacoemulsification through a clear corneal temporal incision. The patient chose to receive either trabeculectomy or phacotrabeculectomy. We defined three criteria for IOP decrease at ‡3 months with or without anti-glaucoma medications: IOP ‡21 mmHg (criterion A), ‡18 mmHg (criterion B) and ‡15 mmHg (criterion C) or <20% decrease from baseline. IOP was measured again 1 month later, and surgical success or failure was decided on the basis of those values. However, if IOP was ‡26 mmHg at ‡3 months, despite completion of laser suture lysis and bleb needling, we immediately defined the patient as a surgical failure, irrespective of criteria. One patient from each group did not complete the 1-year follow-up examination. The baseline characteristics of patients who completed the study are shown in Table 1. Results of Kaplan–Meier survival curve analysis for both the groups with criteria A, B and C are shown in Fig. 1. The 1-year success rates were 96.2 versus 72.9% for criterion A (p = 0.024), 96.2 versus 61.1% for criterion B (p = 0.0024) and 80.4 versus 46.2% for criterion C (p = 0.0063) patients in the phakic and pseudophakic groups, respectively. No eye required repeat surgery or exhibited loss of light perception during the follow-up period. The number of anti-glaucoma medications at 12 months after surgery was 0.04 ± 0.20 and 0.44 ± 0.92 (p = 0.041), the number of postoperative laser suture lysis procedures was 1.6 ± 1.2 and 2.3 ± 1.0 (p = 0.032), and changes in the best-corrected visual acuity (LogMAR) at 12 months after surgery were 0.18 ± 0.37 and )0.07 ± 0.46 (p = 0.0045) in the trabeculectomy and phacotrabeculectomy groups, respectively. Cataract progressed in 3 eyes in the trabeculectomy group. Choroidal detachment occurred in 9 and 5 eyes, flat anterior chamber in 3 and 2,

Impact of phacoemulsification on failure of trabeculectomy with mitomycin-C

PURPOSE: To evaluate whether phacoemulsification after trabeculectomy affects postoperative intraocular pressure (IOP). SETTING: Kumamoto University, Kumamoto, Japan. DESIGN: Cohort study. METHODS: The medical records of patients with primary open‐angle glaucoma or exfoliation glaucoma who had trabeculectomy with mitomycin‐C were reviewed. The primary endpoints were condition A (persistent postoperative IOP 21 mm Hg or higher or additional glaucoma procedures with or without medications) and condition B (postoperative IOP 18 mm Hg or higher or additional glaucoma procedures with or without medications). Multivariable analysis was performed using the Cox proportional hazards model. RESULTS: The records of 178 patients (178 eyes) were reviewed. The mean follow‐up was 37.0 months. For condition A, the probability of treatment success at 1 year, 2 years, and 3 years was 97.9%, 95.0%, and 92.7%, respectively. For condition B, the corresponding probabilities of success were 92.3%, 84.1%, and 81.8%. Thirty‐seven patients (37 eyes) had phacoemulsification after trabeculectomy; 10 of those patients had phacoemulsification within 1 year after trabeculectomy. Multivariate analysis showed that a higher IOP before trabeculectomy was a significant risk factor for condition A and condition B (P=.01 and P=.0006, respectively); phacoemulsification within 1 year after trabeculectomy was significantly associated with trabeculectomy failure for condition B (P=.04). CONCLUSION: Postoperative IOP in eyes with previous trabeculectomy may be affected by the IOP before trabeculectomy and phacoemulsification within 1 year after trabeculectomy. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned.

Long-term relationship between intraocular pressure and visual field loss in primary open-angle glaucoma.

PurposeTo investigate the dependence upon intraocular pressure (IOP) of the progression of visual field defects in eyes with primary open-angle glaucoma (POAG), in which the mean IOP was maintained at ≤21 mm Hg. MethodsThis study involved 100 eyes with POAG, which were followed up for ≥5 years. The mean IOP levels were maintained at ≤21 mm Hg during the follow-up period. The relationship between the IOP and the progression of visual field defects, which was scored using the Advanced Glaucoma Intervention Study criteria, was investigated retrospectively. ResultsCompared with the baseline scores, the visual field defect scores had significantly worsened by the end of the follow-up period (P<0.0001, Wilcoxon paired signed rank test). The change in the visual field defect score (2.5±0.5) in eyes with average IOP levels of ≥16 mm Hg (n=36) was significantly greater (P=0.031, Mann-Whitney U test) than the change (1.3±0.3) in eyes with average IOP levels of <16 mm Hg (n=64). Moreover, IOP of ≥18 mm Hg made a major contribution to the aggravation of visual field defects in eyes with POAG. ConclusionsEyes with POAG and with mean IOP levels maintained at ≤21 mm Hg underwent IOP-dependent progression of their visual field defects. Our results suggest that further IOP lowering would be beneficial in such cases.

Restricted post-trabeculectomy bleb formation by conjunctival scarring

PurposeTo evaluate the effects of radial conjunctival incision during fornix-based trabeculectomy, and conjunctival scarring associated with previous ocular surgeries, for the restriction of bleb formation.MethodsDigital photo-slit lamp images of filtering blebs, which had undergone fornix-based trabeculectomy with mitomycin C previously, were analysed. The area and the height of the bleb in the conjunctivae with radial incision (Ain and Hin, respectively) were compared with the area and the height of the bleb in the conjunctivae without radial incision (Ano and Hno, respectively). We compared the parameters of bleb area (total bleb area, Ain and Ano) and bleb height (the bleb height at the centre of the scleral flap; Hc, Hin and Hno) in eyes without previous ocular surgeries, with those in eyes that underwent previous ocular surgeries.ResultsThe study population consisted of 51 eyes. The Ano and the Hno were significantly larger than the Ain (p < 0.001) and the Hin (p < 0.001) respectively. Subgroup analyses in eyes without previous ocular surgeries and eyes with phacoemulsification cataract surgery also showed that the Ano was significantly larger than the Ain. However, there was no significant difference between the Ano and the Ain in eyes with previous trabeculectomy. A comparison of bleb formation between eyes without previous ocular surgeries and eyes with cataract surgery showed no significant differences in each of the bleb area and bleb height parameters. By contrast, the total bleb area (p = 0.021), the Ano (p = 0.017) and the Hc (p = 0.045) were significantly smaller in eyes with previous trabeculectomy than in eyes without previous ocular surgeries.ConclusionsOur data demonstrate that bleb formation depends on radial conjunctival incision during fornix-based trabeculectomy and surgical conjunctival scarring from previous trabeculectomy.

Heparan sulfate deficiency in periocular mesenchyme causes microphthalmia and ciliary body dysgenesis.

The heparan sulfate (HS) is a component of proteoglycans in the extracellular matrix and on cell surfaces, modulating developmental processes. The aim of this study is to investigate whether the defect of HS in the periocular mesenchyme impairs ocular morphogenesis. First, using Protein 0-Cre transgenic mice, we ablated Ext1, which encodes an indispensable enzyme for HS synthesis, in the developing periocular mesenchyme. The expression of Ext1 messenger RNA (mRNA) and HS were observed by RT-PCR and immunohistochemistry, respectively. The phenotypes in the mutant were evaluated by light microscopy and immunohistochemistry for cellular makers. Second, the distribution of the mutant periocular mesenchymal cells was tracked using a Rosa26 Cre-reporter gene. No mutant embryos (Protein 0-Cre;Ext1(flox/flox)) were identified after embryonic day 14.5 (E14.5). RT-PCR showed that an intense band amplified from Ext1 was observed in cDNAs from the control periocular mesenchymal cells at E13.5; however, the band for Ext1 was hardly detectable in cDNA from the mutant embryo, indicating that the mRNA was missing in the mutant periocular mesenchyme at E13.5. The HS expression was disrupted in the periocular mesenchyme of the mutant ocular tissues. The HS deficiency resulted in microphthalmia with reduced axial lengths, lens diameters, and vitreous sizes compared with the littermate eyes. The mutant embryos showed agenesis of the anterior chamber, where cells expressing Cre recombinase were distributed. Moreover, the mutants showed phenotypic alterations in the neural ectoderm including dysgenesis of the presumptive ciliary body and agenesis of the optic nerve head. These findings demonstrate that HS in the periocular mesenchyme plays a critical role in normal ocular morphogenesis, indicating reciprocal interactions between the periocular mesenchyme and the neural ectoderm.