Yuji Takihara

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.

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.

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.

The Effect of Photocoagulation in Ischemic Areas to Prevent Recurrence of Diabetic Macular Edema After Intravitreal Bevacizumab Injection

PURPOSE This study aimed to investigate whether targeted retinal photocoagulation (TRP) for nonperfused areas (NPAs) could have a preventive effect on the recurrence of diabetic macular edema (DME) after intravitreal injection of bevacizumab (IVB). METHODS Eyes in the IVB group received 1.25 mg IVB, and eyes in the IVB+TRP group received 1.25 mg IVB combined with TRP of NPAs. Two weeks before IVB administration, grid/focal photocoagulation (PC) had been performed in both groups. After IVB treatment, the best corrected visual acuity (BCVA) and central retinal thickness (CRT), determined by optical coherence tomography, were measured every month for 6 months. RESULTS Fifty-two patients with DME were enrolled and randomized to an IVB group (n = 26) and an IVB+TRP group (n = 26). After IVB, the CRT decreased temporally, and the CRT significantly increased at 2 months and thereafter in the IVB group but did not increase significantly in the IVB+TRP group. Maximum increase in CRT after IVB was significantly correlated with the width of NPAs in the IVB group (P = 0.0368), but not in the IVB+TRP group. Best corrected visual acuity in the IVB+TRP group was significantly better than that in the IVB group 5 and 6 months after treatment (P < 0.05). CONCLUSIONS Targeted retinal photocoagulation for NPAs was effective to maintain the reduced CRT after grid/focal PC and IVB for patients with DME. These results suggest that retinal ischemia is associated with the pathogenesis of recurrence of DME after IVB. ( www.umin.ac.jp/ctr number, UMIN000007566.).

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.