Experimental scleral cross-linking increases glaucoma damage in a mouse model.

The purpose of this study was to assess the effect of a scleral cross-linking agent on susceptibility to glaucoma damage in a mouse model.CD1 mice underwent 3 subconjunctival injections of 0.5 M glyceraldehyde (GA) in 1 week, then had elevated intraocular pressure (IOP) induced by bead injection. Degree of cross-linking was measured by enzyme-linked immunosorbent assay (ELISA), scleral permeability was measured by fluorescence recovery after photobleaching (FRAP), and the mechanical effects of GA exposure were measured by inflation testing. Control mice had buffer injection or no injection in 2 separate glaucoma experiments. IOP was monitored by Tonolab and retinal ganglion cell (RGC) loss was measured by histological axon counting. To rule out undesirable effects of GA, we performed electroretinography and detailed histology of the retina. GA exposure had no detectable effects on RGC number, retinal structure or function either histologically or electrophysiologically. GA increased cross-linking of sclera by 37% in an ELISA assay, decreased scleral permeability (FRAP, p = 0.001), and produced a steeper pressure-strain behavior by in vitro inflation testing. In two experimental glaucoma experiments, GA-treated eyes had greater RGC axon loss from elevated IOP than either buffer-injected or control eyes, controlling for level of IOP exposure over time (p = 0.01, and 0.049, multivariable regression analyses). This is the first report that experimental alteration of the sclera, by cross-linking, increases susceptibility to RGC damage in mice.

Clear corneal vitrectomy combined with phacoemulsification and foldable intraocular lens implantation.

BACKGROUND: We have developed a technique for the treatment of cataract and epiretinal membrane using a 25-gauge vitrectomy system through corneal ports. DESIGN: Randomized, prospective study, Toyama Prefectural Central Hospital, Toyama, Japan. PARTICIPANTS: Twenty eyes of equal patients scheduled for cataract surgery combined with vitrectomy. METHODS: Twenty eyes with cataract and epiretinal membrane were received treatment with our newly developed system (clear corneal vitrectomy) or the standard 25-gauge pars plana vitrectomy with corneal incision cataract surgery. The newly developed system uses 0.5-mm wide corneal side ports located at the superonasal, superotemporal and inferotemporal positions. After phacoemulsification using corneal incision, an infusion cannula was inserted from the inferotemporal port. Then core 25-gauge vitrectomy was performed using the corneal three port. After the epiretinal membrane was removed using forceps, an intraocular lens was implanted into the capsular bag. Finally, all corneal incision wounds were hydrated. MAIN OUTCOME MEASUREMENT: Visual acuity, intraocular pressure, corneal thickness, corneal endothelial cell and ocular inflammation were examined. RESULTS: All procedures were uncomplicated in both groups. There was no leakage of aqueous humour from the corneal wounds in the developed system. There were no significant differences in visual acuity, corneal thickness and endothelial cell density loss. CONCLUSIONS: Clear corneal vitrectomy would be a good option for selected cases with cataract and vitreoretinal diseases.

Effect of prophylactic 360° laser treatment for prevention of retinal detachment after phacovitrectomy: (Prophylactic 360° laser treatment for prevention of retinal detachment).

BACKGROUND: To investigate the effect of intraoperative 360° laser retinopexy anterior to the equator for the prevention of retinal detachment after phacovitrectomy. METHODS: The patients were part of two consecutive case series cohorts in macular hole (MH) and rhegmatogenous retinal detachment (RRD), one which did not receive intraoperative prophylactic 360° laser, and one which received intraoperative prophylactic 360° laser. For the 360° laser treatment group, three rows of medium-white burns were positioned anterior to the equator. The baseline characteristics and the risk of retinal detachment over time were analyzed and compared between the groups. RESULTS: Prophylactic intraoperative 360° laser treatment was performed on 77 MH cases (67.3 years) and compared to a control group of 35 MH cases (65.8 years). Additionally, prophylactic intraoperative 360° laser treatment was performed on 108 RRD cases (64.0 years) and compared to 270 RRD cases (64.4 years). The 360° laser group showed a significant reduction (0%, 0/77 eyes) in the rate of the incidence of retinal detachment after vitrectomy at 12 months after surgery in MH cases, compared with the control group (5.7%, 2/35 eyes) (p = 0.034). Kaplan-Meier survival analysis demonstrated that the rate of retinal detachment in the control group was significantly higher than that in the 360° laser group (p = 0.035). There was no significant difference between the groups in RRD cases (p = 0.092). CONCLUSIONS: Intraoperative 360° laser retinopexy following phacovitrectomy resulted in a significant reduction in the rate of postoperative retinal detachment in MH cases.

N-Acetylcysteine promotes long-term survival of cones in a model of retinitis pigmentosa.

Retinitis pigmentosa (RP) is a major source of blindness caused by a large variety of mutations that lead to the death of rod photoreceptors. After rods die, cones gradually die from progressive oxidative damage. Several types of antioxidant formulations have been shown to reduce cone cell death over a relatively short-time frame, but in order for this strategy to be translated into a new treatment for patients with RP, prolonged effects will be needed. In this study, we determined that orally administered N-acetylcysteine (NAC) reduced cone cell death and preserved cone function by reducing oxidative damage in two models of RP, rd1(+/+) and rd10(+/+) mice. In rd10(+/+) mice, supplementation of drinking water with NAC promoted partial maintenance of cone structure and function for at least 6 months. Topical application of NAC to the cornea also reduced superoxide radicals in the retina and promoted survival and functioning of cones. Since oral and/or topical administration of NAC is feasible for long-term treatment in humans, and NAC has a good safety profile, it is reasonable to consider clinical trials to evaluate the effects of prolonged treatment with NAC in patients with RP.

Constituents of bile, bilirubin and TUDCA, protect against oxidative stress-induced retinal degeneration.

Two constituents of bile, bilirubin and tauroursodeoxycholic acid (TUDCA), have antioxidant activity. However, bilirubin can also cause damage to some neurons and glial cells, particularly immature neurons. In this study, we tested the effects of bilirubin and TUDCA in two models in which oxidative stress contributes to photoreceptor cell death, prolonged light exposure and rd10+/+ mice. In albino BALB/c mice, intraperitoneal injection of 5 mg/kg of bilirubin or 500 mg/kg of TUDCA prior to exposure to 5000 lux of white light for 8 h significantly reduced loss of rod and cone function assessed by electroretinograms. Both treatments also reduced light-induced accumulation of superoxide radicals in the outer retina, rod cell death assessed by outer nuclear layer thickness, and disruption of cone inner and outer segments. In rd10+/+ mice, intraperitoneal injections of 5 or 50 mg/kg of bilirubin or 500 mg/kg of TUDCA every 3 days starting at postnatal day (P) 6, caused significant preservation of cone cell number and cone function at P50. Rods were not protected at P50, but both bilirubin and TUDCA provided modest preservation of outer nuclear layer thickness and rod function at P30. These data suggest that correlation of serum bilirubin levels with rate of vision loss in patients with retinitis pigmentosa could provide a useful strategy to test the hypothesis that cones die from oxidative damage in patients with retinitis pigmentosa. If proof-of-concept is established, manipulation of bilirubin levels and administration of TUDCA could be tested in interventional trials.

Increased expression of catalase and superoxide dismutase 2 reduces cone cell death in retinitis pigmentosa.

Oxidative and nitrosative damage are major contributors to cone cell death in retinitis pigmentosa (RP). In this study, we explored the effects of augmenting components of the endogenous antioxidant defense system in models of RP, rd1, and rd10 mice. Unexpectedly, overexpression of superoxide dismutase 1 (SOD1) in rd1 mice increased oxidative damage and accelerated cone cell death. With an elaborate mating scheme, genetically engineered rd10 mice with either inducible expression of SOD2, Catalase, or both in photoreceptor mitochondria were generated. Littermates with the same genetic background that did not have increased expression of SOD2 nor Catalase provided ideal controls. Coexpression of SOD2 and Catalase, but not either alone, significantly reduced oxidative damage in the retinas of postnatal day (P) 50 rd10 mice as measured by protein carbonyl content. Cone density was significantly greater in P50 rd10 mice with coexpression of SOD2 and Catalase together than rd10 mice that expressed SOD2 or Catalase alone, or expressed neither. Coexpression of SOD2 and Catalase in rd10 mice did not slow rod cell death. These data support the concept of bolstering the endogenous antioxidant defense system as a gene-based treatment strategy for RP, and also indicate that coexpression of multiple components may be needed.

NADPH oxidase plays a central role in cone cell death in retinitis pigmentosa.

Retinitis pigmentosa (RP) is a collection of diseases in which rod photoreceptors die from a variety of mutations. After rods die, the level of tissue oxygen in the outer retina becomes elevated and there is progressive oxidative damage to cones that ultimately triggers apoptosis. In this study, we investigated the hypothesis that NADPH oxidase (Nox) and/or xanthine oxidase serve as critical intermediaries between increased tissue oxygen and the generation of excessive reactive oxygen species that cause oxidative damage to cones. Apocynin, a blocker of Nox, but not allopurinol, a blocker of xanthine oxidase, markedly reduced the superoxide radicals visualized by hydroethidine in the outer retina in the retinal degeneration-1 (rd1(+/+)) model of RP. Compared to rd1(+/+) mice treated with vehicle, those treated with apocynin, but not those treated with allopurinol, had significantly less oxidative damage in the retina measured by ELISA for carbonyl adducts. Apocynin-treated, but not allopurinol-treated, rd1(+/+) mice had preservation of cone cell density, increased mRNA levels for m- and s-cone opsin, and increased mean photopic b-wave amplitude. In Q344ter mice, a model of dominant RP in which mutant rhodopsin is expressed, apocynin treatment preserved photopic electroretinogram b-wave amplitude compared to vehicle-treated controls. These data indicate that Nox, but not xanthine oxidase, plays a critical role in generation of the oxidative stress that leads to cone cell death in RP and inhibition of Nox provides a new treatment strategy.

Long-term outcome after vitrectomy for macular edema with retinal vein occlusion dividing into the occlusion site.

Purpose. To investigate the efficacy of treatment for macular edema secondary to retinal vein occlusion (RVO) with vitrectomy. Methods. This retrospective study identified patients with macular edema associated with RVO between January 2004 and April 2006. Inclusion criteria were eyes with (1) preoperative visual acuity (VA) of 20/40 or worse, (2) a central foveal thickness (CFT) greater than 250 µm, and (3) vitrectomy with internal limiting membrane and intravitreal triamcinolone acetonide. Each patient had their RVO classified as a major or macular BRVO or hemispheric RVO (HSRVO). Results. Forty-six eyes with major BRVO, 18 eyes with macular BRVO, and 17 eyes with HSRVO were investigated. VA was significantly improved at 24 months after surgery for each group (P < 0.05). Vision in the macular BRVO group 24 months after surgery was significantly better than that in other groups (P < 0.05). For each group, a concomitant reduction of CFT was noted at every time point when compared to preoperative values (P < 0.001). Conclusions. In macular BRVO, the postoperative vision 24 months after surgery was significantly better than the other groups. These findings suggest that additional and earlier treatments might be more important for patients with major BRVO and HSRVO than for those with macular BRVO.

Optical coherence tomography findings in optic nerve pit maculopathy after vitrectomy.

PURPOSE: The purpose of this study was to present a case of optic nerve pit maculopathy and reappraise the previous concepts regarding the pathways of the fluid and the development. METHODS: A 24-year-old man had an optic nerve pit maculopathy. The visual acuity was 20/50 in the affected eye. Optical coherence tomography showed a multilayered separation of the neurosensory retina, serous retinal detachment, and the optic nerve pit with no membrane on the optic nerve. After 2 months of observations, surgery was performed. RESULTS: Surgery included vitrectomy, the separation of the posterior hyaloid, the internal limiting membrane peeling, and gas tamponade. No laser was performed. The vision improved to 20/20, and optical coherence tomography demonstrated that the inner retinal layer separation was resolved except for the ganglion cell layer connected to the optic nerve pit, and subretinal fluid was increased 1 month after surgery. Eventually, the retinal layer separation and the subretinal fluid were resolved completely. CONCLUSIONS: Vitrectomy with internal limiting membrane peeling and gas tamponade without any additional laser photocoagulation seems to be sufficient for the treatment. Our observations suggest that the fluid can move directly from the optic pit into multiple layers, and fluid emanating from the optic nerve pit still extended even after surgery.

Topical pazopanib blocks VEGF-induced vascular leakage and neovascularization in the mouse retina but is ineffective in the rabbit.

PURPOSE: To test the effect of pazopanib, a tyrosine kinase inhibitor that blocks VEGF and platelet-derived growth factor (PDGF) receptors and c-Kit, on vascular leakage and neovascularization (NV) in the retina. METHODS: Pazopanib was tested to determine its effect on VEGF-induced vascular permeability via measurement of [(3)H]mannitol retina to lung (RLLR) and retina to renal leakage ratios (RRLR) and in rho/VEGF mice with subretinal NV. In rabbits, the effect of intravitreal, topical, and systemic pazopanib on VEGF-induced leakage was tested by vitreous fluorophotometry. RESULTS: In mice, oral pazopanib (40 mg/kg twice a day [bid]) reduced RLLR (0.84 to 0.58, P = 0.0014) and RRLR (0.55 to 0.30, P = 0.0018) in VEGF-injected eyes. After intraocular injection of VEGF into both eyes, topical pazopanib (10 mg/mL three times a day [tid] for 14 days) reduced RLLR (0.85 vs. 0.56, P = 0.001), RRLR (0.44 vs. 0.28, P = 0.0075), and immunoreactive albumin in the retina compared to values in fellow eye controls. Treatment of one eye of rho/VEGF mice with 10 mg/mL, but not 5 mg/mL, pazopanib tid reduced the mean area of subretinal NV compared to that in fellow eyes (0.0055 vs. 0.0025 mm(2), P = 0.020). In rabbits, intravitreal pazopanib suppressed VEGF-induced fluorescein leakage, but topical (10 mg/mL four times a day [qid] or 12 mg/mL bid) had no significant effect. Systemic administration of pazopanib by osmotic pump with or without 10 mg/mL drops tid also failed to suppress VEGF-induced leakage. CONCLUSIONS: Administration of pazopanib topically or systemically suppressed retinal vascular leakage in mice, but not rabbits. These data suggest differences in the blood-retinal barrier (BRB) of mice and rabbits and indicate that penetration through the outer BRB may be needed for topically administered drugs to exert effects in the retina.

Retinal detachment in morning glory syndrome with large hole in the excavated disc.

PURPOSE: To present a case of morning glory syndrome (MGS) associated with retinal detachment and to discuss the pathogenesis of retinal tear. METHODS: A 2-year-old-girl had a MGS with a large hole in the excavated disc and retinal detachment. The visual acuity was 4/200 in the affected eye. The excavated disc and retinal detachment were confirmed by echogram. Optical coherence tomography demonstrated that the large hole was connected to the subretinal space. The excavated lesion did not show contractions. The detachment area and the volume of subretinal fluid rose and fell between initial examinations, but ultimately increased. After 2 years of observations, surgery was performed as the retinal detachment had enlarged to include the macula. RESULTS: Surgery included triamcinolone-assisted vitrectomy, subretinal fluid drainage through the large hole in the excavated disc, retinal photocoagulation along the excavated disc, and long-acting gas tamponade. One month later, the retina was redetached due to incomplete closure of the hole. A second operation was performed using silicone oil tamponade. Ultimately, the retina was reattached after silicone oil-fluid exchange surgery. CONCLUSIONS: One possible reason for a large hole in an excavated disc is origination of the tear from a congenital defect, such as an optic pit. The retinal detachment in patients with MGS with a large hole in the disc can be treated with triamcinolone-assisted pars plana vitrectomy and retinal photocoagulation along the excavated disc. This case has shown that one critical component for a high success rate is the tamponade agent used in the vitreous.

Hydrophobic versus double-square-edged hydrophilic foldable acrylic intraocular lens: effect on posterior capsule opacification.

PURPOSE: To evaluate posterior capsule opacification (PCO) 2 years after cataract surgery with implantation of a hydrophobic acrylic or single-piece sharp-edged hydrophilic acrylic intraocular lens (IOL). SETTING: Toyama Prefectural Central Hospital, Toyama, Japan. DESIGN: Case-control study. METHODS: Patients with bilateral senile cataract were prospectively randomized to receive a hydrophobic IOL (Acrysof SA60AT) in 1 eye and a hydrophilic IOL (Meridian HP60M) in the other eye. The PCO density value, degree of IOL decentration and tilt, and anterior chamber depth (ACD) were measured using Scheimpflug videophotography 1, 6, 12, 18, and 24 months after surgery. Visual acuity and the number of eyes requiring neodymium:YAG laser capsulotomy were also assessed. RESULTS: The study evaluated 16 eyes (63 patients). The PCO value in the hydrophilic group increased significantly with time and was statistically significantly greater than in the hydrophobic group 18 and 24 months postoperatively (both P < .001). The capsulotomy rate was statistically significantly higher in the hydrophilic group than in the hydrophobic group (P < .01). Visual acuity in the hydrophilic group worsened significantly with time and was statistically significantly worse than in the hydrophobic group at 18 and 24 months (both P < .001). Intraocular lens decentration, IOL tilt, and the ACD did not change significantly during the follow-up in either group (P > .05), and there were no statistically significant postoperative differences in these parameters between the 2 IOL groups (P > .05). CONCLUSION: Two years after surgery, the hydrophobic IOL group had less PCO, a lower capsulotomy rate, and better visual acuity than the hydrophilic IOL group. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

Overexpression of SOD in retina: need for increase in H2O2-detoxifying enzyme in same cellular compartment.

In retinitis pigmentosa (RP), various mutations cause rod photoreceptor cell death leading to increased oxygen levels in the outer retina, progressive oxidative damage to cones, and gradual loss of cone cell function. We have been exploring the potential of overexpressing components of the endogenous antioxidant defense system to preserve cone cell function in rd10(+/+) mice, a model of RP. rd10(+/+) mice deficient in superoxide dismutase 1 (SOD1) showed increased levels of superoxide radicals and carbonyl adducts (a marker of oxidative damage) in the retina and more rapid loss of cone function than rd10(+/+) mice with normal levels of SOD1. This suggests that SOD1 is an important component of the antioxidant defense system of cones, but increased expression of SOD1 in rd10(+/+) mice increased oxidative damage and accelerated the loss of cone function. Coexpression of SOD1 with glutathione peroxidase 4 (Gpx4), which like SOD1 is localized in the cytoplasm, but not with catalase targeted to the mitochondria, reduced oxidative damage in the retina and significantly slowed the loss of cone cell function in rd10(+/+) mice. Gene transfer resulting in increased expression of SOD2, but not coexpression of SOD2 and mitochondrial Gpx4, resulted in high levels of H(2)O(2) in the retina. These data suggest that to provide benefit in RP, overexpression of an SOD must be combined with expression of a peroxide-detoxifying enzyme in the same cellular compartment.