Keiichiro Iwao

Trabeculectomy with Mitomycin C for Neovascular Glaucoma: Prognostic Factors for Surgical Failure

PURPOSE To evaluate the prognostic factors for surgical outcomes of trabeculectomy with mitomycin C (MMC) for neovascular glaucoma (NVG). DESIGN Retrospective cohort study. METHODS We reviewed the medical records of 101 patients (101 eyes) with NVG treated at Kumamoto University Hospital. The primary endpoint was persistent intraocular pressure > or = 22 mm Hg, deterioration of visual acuity to no light perception, and additional glaucoma procedures. Multivariate analysis was performed using the Cox proportional hazards model. RESULTS The mean follow-up period was 29.3 months (range, 0.5 to 142.3 months). The probability of success 1, 2, and 5 years after trabeculectomy was 62.6%, 58.2%, and 51.7%, respectively. The multivariate model showed that younger age (relative risk [RR], 0.96/year; P = .0007) and previous vitrectomy (RR, 1.62; P = .02) were prognostic factors for surgical failure among all NVG patients. Additionally, an eye with unremoved proliferative membrane and/or unrepaired retinal detachment (RD) after vitrectomy (RR, 1.59; P = .05) was a probable prognostic factor in a subgroup of 66 eyes with previous vitrectomy, and having a fellow eye with NVG (RR, 1.73; P = .003) was a significant prognostic factor in 82 eyes with NVG attributable to diabetic retinopathy. CONCLUSIONS The prognostic factors for surgical failure of trabeculectomy with MMC for NVG were younger age and previous vitrectomy in all NVG patients, and having a fellow eye with NVG in patients with disease caused by diabetic retinopathy. Persistent proliferative membrane and/or RD after vitrectomy might contribute to poorer outcomes of trabeculectomy.

In vivo imaging of axonal transport of mitochondria in the diseased and aged mammalian CNS

Significance The lack of intravital imaging of axonal transport of mitochondria in the living mammalian CNS precludes the characterization of transport dynamics in the diseased and aged mammalian CNS. Here we report minimally invasive intravital multiphoton imaging of mouse retinal ganglion cells that offers sequential time-lapse images of mitochondria transported in a single axon with submicrometer resolution. We show highly dynamic axonal transport of mitochondria in the mammalian CNS in vivo under physiological conditions and characterize disturbances of mitochondrial transport in a mouse glaucoma model and age-related changes in mitochondrial transport. Our method is useful for characterizing the dynamics of axonal transport of mitochondria and the dynamics of other submicrometer structures in the diseased and aged mammalian CNS in vivo. The lack of intravital imaging of axonal transport of mitochondria in the mammalian CNS precludes characterization of the dynamics of axonal transport of mitochondria in the diseased and aged mammalian CNS. Glaucoma, the most common neurodegenerative eye disease, is characterized by axon degeneration and the death of retinal ganglion cells (RGCs) and by an age-related increase in incidence. RGC death is hypothesized to result from disturbances in axonal transport and in mitochondrial function. Here we report minimally invasive intravital multiphoton imaging of anesthetized mouse RGCs through the sclera that provides sequential time-lapse images of mitochondria transported in a single axon with submicrometer resolution. Unlike findings from explants, we show that the axonal transport of mitochondria is highly dynamic in the mammalian CNS in vivo under physiological conditions. Furthermore, in the early stage of glaucoma modeled in adult (4-mo-old) mice, the number of transported mitochondria decreases before RGC death, although transport does not shorten. However, with increasing age up to 23–25 mo, mitochondrial transport (duration, distance, and duty cycle) shortens. In axons, mitochondria-free regions increase and lengths of transported mitochondria decrease with aging, although totally organized transport patterns are preserved in old (23- to 25-mo-old) mice. Moreover, axonal transport of mitochondria is more vulnerable to glaucomatous insults in old mice than in adult mice. These mitochondrial changes with aging may underlie the age-related increase in glaucoma incidence. Our method is useful for characterizing the dynamics of axonal transport of mitochondria and may be applied to other submicrometer structures in the diseased and aged mammalian CNS in vivo.

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.

Frequency and risk factors for intraocular pressure elevation after posterior sub-Tenon capsule triamcinolone acetonide injection.

PurposeThis study investigated the effects of posterior sub-Tenon capsule (PST) injection of triamcinolone acetonide (TA) on intraocular pressure (IOP) in the human eye. MethodsThe study included 115 patients who received PST injections of 40-mg TA to treat macular edema with diabetic retinopathy (n=57), branch retinal vein occlusion (n=35), central retinal vein occlusion (n=13), or other disorders (n=10). IOP measurements were performed on the day of injection, and 0.5, 1, 2, 3, 6, 9, and 12 months later. ResultsIn 26 (22.6%) of the 115 eyes, an IOP of 24 mm Hg or higher was observed during the 12-month follow-up period after PST TA injection. IOP elevation significantly correlated with young age, but not with past history of diabetes mellitus or systemic hypertension, sex, or type of retinal disease with macular edema. In total, 23 eyes were treated with antiglaucoma medications to control elevated IOP (24 mm Hg or higher). External trabeculotomy was performed in 1 case where medications failed to correct elevated IOP. ConclusionsPST TA injection is associated with high rates of steroid-induced IOP elevation in eyes with previously normal IOP. However, IOP elevation may be less common after PST injection than after intravitreal injection. Our findings indicate that IOP must be carefully monitored after PST TA injection.

Combined intravitreal bevacizumab and trabeculectomy with mitomycin C versus trabeculectomy with mitomycin C alone for neovascular glaucoma.

PurposeTo evaluate the effects of intravitreal bevacizumab (IVB) before mitomycin C trabeculectomy (MMCT) for neovascular glaucoma (NVG). MethodsThe study is a retrospective, comparative, consecutive case series. The study group consisted of 57 eyes from 50 patients with NVG who underwent a first MMCT: 33 eyes were treated with MMCT alone between June 1, 2005 and May 17, 2007 (Control Group); and, 24 eyes were treated with a combination of IVB and MMCT after May 18, 2007 (IVB Group). Surgical complications, intraocular pressure (IOP), and the probability of success were compared between the 2 groups. Surgical failure was defined as IOP ≥22 mm Hg for 2 consecutive follow-up visits, a deterioration of visual acuity to no light perception, or additional glaucoma surgeries. ResultsThere were no significant differences in preoperative data between the groups. Hyphema associated with MMCT occurred significantly less often in the IVB Group (P=0.006). IOPs at 7 and 10 days after MMCT were significantly lower in the IVB Group (P=0.01 and 0.02, respectively). However, Kaplan-Meier survival-curve analysis showed the probability of success 120, 240, and 360 days after MMCT of 87.5%, 79.2%, and 65.2% in the IVB Group, and 75.0%, 71.9%, and 65.3% in the Control Group. No significant difference in survival times was found between the groups (P=0.76). ConclusionsIVB before MMCT reduced hyphema associated with MMCT for NVG. IVB provided further IOP reduction immediately after MMCT, but did not significantly improve surgical outcomes over longer periods.

Intraocular Pressure Elevation after Injection of Triamcinolone Acetonide : A Multicenter Retrospective Case-Control Study

PURPOSE To determine the risk factors for intraocular pressure (IOP) elevation after the injection of triamcinolone acetonide (TA). DESIGN Retrospective interventional case-control study. METHODS SETTING Multicenter. PATIENT POPULATION Four hundred and twenty-seven patients. OBSERVATION PROCEDURES Intraocular pressure levels after TA treatment by the sub-Tenon capsule injection (STI; 12 mg, 20 mg, or 40 mg), intravitreal injection (IVI; 4 mg or 8 mg), or the combination of STI (20 mg) and IVI (4 mg), and IOP levels after two TA treatments. MAIN OUTCOME MEASURE Risk factors for IOP levels of 24 mm Hg or higher. RESULTS Younger age (hazards ratio [HR], 0.96/year; P < .0001), IVI (HR, 1.89/year; P < .0001), and higher baseline IOP (HR, 1.15/mm Hg; P = .003) were identified as risk factors. Dose dependency was shown in STI-treated eyes (HR, 1.07/mg; P = .0006), as well as after IVI (HR, 1.64/mg; P = .013). The combination of STI and IVI was a significant risk factor (HR, 2.27; P = .003) compared with STI alone. In eyes receiving two TA treatments, IVI (HR, 2.60; P = .010), higher IOP elevation after the first injection (HR, 1.18/mm Hg; P = .011), and increased dosage of STI (HR, 1.07/mm Hg; P = .033) were risk factors. CONCLUSIONS Younger age, higher baseline IOP, IVI, and increased TA dosage were associated with TA-induced IOP elevation. IOP elevation after repeated TA injection was frequently associated with eyes treated with IVI, high IOP elevation after the first injection, and high doses of STI.

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.

Success rates of trabeculotomy for steroid-induced glaucoma: a comparative, multicenter, retrospective cohort study.

PURPOSE To evaluate the surgical outcomes of trabeculotomy for steroid-induced glaucoma. DESIGN Multicenter, retrospective cohort study. METHODS At 17 Japanese clinical centers, 121 steroid-induced glaucoma patients who underwent trabeculotomy between 1997 and 2006 were reviewed. Surgical failure was defined by the need for additional glaucoma surgery, deterioration of visual acuity to no light perception, or intraocular pressure ≥21 mm Hg (criterion A) and ≥18 mm Hg (criterion B). Surgical outcomes were compared with those of 108 primary open-angle glaucoma (POAG) patients who underwent trabeculotomy and 42 steroid-induced glaucoma patients who underwent trabeculectomy. Prognostic factors for failure were evaluated using the Cox proportional hazards model. RESULTS The probabilities of success at 3 years for trabeculotomy for steroid-induced glaucoma vs trabeculotomy for POAG was 78.1% vs 55.8% for criterion A (P = .0008) and 56.4% vs 30.6% for criterion B (P < .0001), respectively. At 3 years, the success of trabeculotomy for steroid-induced glaucoma was comparable to trabeculectomy for steroid-induced glaucoma for criterion A (83.8%; P = .3636), but lower for criterion B (71.6%; P = .0352). Prognostic factors for failure of trabeculotomy for steroid-induced glaucoma were previous vitrectomy (relative risk [RR] = 5.340; P = .0452 on criterion A, RR = 3.898; P = .0360 for criterion B) and corticosteroid administration other than ocular instillation (RR = 2.752; P = .0352 for criterion B). CONCLUSIONS Trabeculotomy is effective for controlling intraocular pressure <21 mm Hg in steroid-induced glaucoma eyes.

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.