Ocular penetration of levofloxacin, ofloxacin and ciprofloxacin in eyes with functioning filtering blebs: investigator masked, randomised clinical trial.

BACKGROUND/AIMS: To compare the penetration of levofloxacin, ofloxacin and ciprofloxacin in the aqueous humour of eyes with functioning filtering blebs. METHODS: In this investigator-masked study, 48 patients with functioning filtering blebs requiring cataract surgery were randomised into six groups of eight patients. Groups 1, 2 and 3 received topical ofloxacin 0.3% (Ocuflox), ciprofloxacin 0.3% (Ciloxan) and levofloxacin (Quixin) respectively; Groups 4, 5 and 6 received the same treatment with the corresponding oral dose of ofloxacin 400 mg (Floxin), ciprofloxacin 400 mg (Cipro) and levofloxacin 250 mg (Levaquin). Aqueous antibiotic levels were determined by mass spectrometry of aqueous samples from each patient. RESULTS: The mean aqueous level for topical levofloxacin was significantly higher than those achieved by topical ofloxacin or ciprofloxacin (p value = 0.02 and 0.01, respectively). The combination of topical and oral levofloxacin was significantly higher than topical levofloxacin alone (p = 0.05) and the ciprofloxacin combination (p = 0.003) but not significantly higher than the ofloxacin combination therapy. CONCLUSIONS: Topical levofloxacin penetrates better than ofloxacin or ciprofloxacin into the aqueous of eyes with functioning filtering blebs. The combination of topical and oral levofloxacin may be preferable in the treatment of bleb-associated infections (NCT 00392275; Clinical trials.gov).

Intraocular pressure-lowering efficacy of bimatoprost 0.03% and travoprost 0.004% in patients with glaucoma or ocular hypertension.

AIM: To evaluate the efficacies of bimatoprost and travoprost for lowering of intraocular pressure (IOP) for the treatment of glaucoma and ocular hypertension. METHODS: Prospective, randomised, investigator-blinded, parallel-group clinical trial. After completing a washout of all glaucoma drugs, patients (n = 157) were randomised to bimatoprost or travoprost for 6 months. Visits were at baseline, 1 week, and 1, 3 and 6 months. IOP was measured at 09:00 h at each visit and also at 13:00 and 16:00 h at baseline and at 3 and 6 months. RESULTS: No significant between-group differences were observed in IOP at baseline, at 09:00, 13:00 or 16:00 h (p> or =0.741). After 6 months, both drugs significantly reduced IOP at every time point (p< or =0.001). After 6 months, mean IOP reduction at 09:00 h was 7.1 mm Hg (27.9%) with bimatoprost (n = 76) and 5.7 mm Hg (23.3%) with travoprost (n = 81; p = 0.014). At 13:00 h, mean IOP reduction was 5.9 mm Hg with bimatoprost (25.3%) and 5.2 mm Hg (22.4%) with travoprost (p = 0.213). At 16:00 h, the mean IOP reduction was 5.3 mm Hg (22.5%) with bimatoprost and 4.5 mm Hg (18.9%; p = 0.207) with travoprost. Both study drugs were well tolerated, with ocular redness the most commonly reported adverse event in both treatment groups. CONCLUSIONS: Bimatoprost provided greater mean IOP reductions than travoprost.

Delayed suprachoroidal hemorrhage after glaucoma filtration procedures.

OBJECTIVES: To determine the incidence of, risk factors for, and outcomes of delayed suprachoroidal hemorrhage (DSCH) after glaucoma filtration surgery. DESIGN: Retrospective case-control study. PARTICIPANTS: All patients undergoing glaucoma filtration procedures between 1986 and 2000 at Indiana University who were diagnosed postoperatively with suprachoroidal hemorrhage. A total of 66 patients with DSCH were identified. These were compared with a randomly selected group of patients who underwent similar procedures but did not have suprachoroidal hemorrhage. METHODS: Total cases of DSCH were initially compared with the total number of glaucoma surgeries to determine the overall incidence and the incidence in the different procedures. Subsequently, a case-control study was performed comparing the group with hemorrhage to the control group to identify risk factors. Finally, outcomes and prognostic factors were determined by comparing vision preoperatively and postoperatively and parameters of patients with good and poor outcomes. MAIN OUTCOME MEASURES: Incidence of DSCH, risk factors associated with its occurrence, visual outcomes, and factors important for prognosis. RESULTS: Of a total of 2285 glaucoma filtration procedures, 66 (2.9%) cases of DSCH were identified. It developed in 9 of 615 (1.5%) trabeculectomies without antimetabolite, 30 of 1248 (2.4%) trabeculectomies with antimetabolite, 2 of 72 (2.8%) valved tube shunt implantations, and 25 of 350 (7.1%) nonvalved tube shunt implantations. The increased incidence of DSCH after tube shunts compared with trabeculectomy-associated DSCH was significant (P < 0.0001) with an odds ratio of 3.2. The risk factors for DSCH after glaucoma surgery include white race (P = 0.012), anticoagulation (P = 0.034), severe postoperative hypotony (P = 0.033), and aphakia/anterior chamber intraocular lens (P = 0.002). The visual outcomes of patients with hemorrhage were poor, with a decrease in logarithm of the minimum angle of resolution visual acuity from 0.72 to 1.36, which was statistically significant compared with the controls (P < 0.009). CONCLUSIONS: Delayed suprachoroidal hemorrhage occurs more frequently after tube shunt implantation than after trabeculectomy. Caution should be exercised when operating on patients with known risk factors, because the visual outcomes after DSCH are poor.

The effect of mechanical strain on matrix metalloproteinase production by bovine trabecular meshwork cells.

PURPOSE: To evaluate the effects of mechanical stretching of trabecular meshwork cells on matrix metalloproteinase activity. METHODS: Cultured bovine trabecular meshwork cells grown on collagen-coated elastomer were subjected to 10% biaxial mechanical stretching. After various time intervals, culture medium was collected from stretched and non-stretched control cells. Matrix metalloproteinase activity was studied by zymography and levels of inhibitors were determined by immunoblotting or immunoassay of the collected medium. RESULTS: Trabecular meshwork cells subjected to mechanical strain showed increased stromelysin and gelatinase A activity at 24 to 72 hours after initial stretching compared to control cells. By 72 hours of strain, stromelysin activity increased to up to 73% (p < 0.01) whereas gelatinase A activity increased by 31% (p < 0.05). The increased metalloproteinase activity was reversible with relaxation of mechanical stretch. Levels of tissue inhibitor of matrix metalloproteinase-1 and -2 remained unchanged during 72 hours of stretch. CONCLUSIONS: Changes in mechanical strain on the trabecular meshwork, which may occur in vivo during changes in intraocular pressure, induce changes in matrix metalloproteinase activity. The resultant alterations in the extracellular matrix may affect outflow resistance through the trabecular meshwork in response to alterations in intraocular pressure.

Autologous blood injection for late-onset filtering bleb leak.

PURPOSE: To report the outcomes of autologous blood injections for late-onset filtering bleb leak. METHODS: Retrospective chart review of all eyes that had autologous blood injection(s) for filtering bleb leak occurring at least 2 months after trabeculectomy at the Indiana University Medical Center. Successful treatment was defined as resolution of the bleb leak and no need for additional glaucoma medications. Failure was defined as a persistent bleb leak, intraocular pressure greater than 21 mm Hg, or the occurrence of a vision-threatening event related to the procedure. RESULTS: Thirty-two eyes of 31 patients had autologous blood injection for filtering bleb leak and were followed for a mean of 4.9 months (SD, 9.2; range, 1 to 37 months). Twenty-three eyes (72%) were outright failures because of persistence of the leak. Nine eyes (28%) had an initially successful outcome, but the success rate decreased over time as bleb leaks recurred in three of the nine eyes at 5, 6, and 37 months. No patient characteristics correlated with outcome. Mean intraocular pressure increased from pretreatment to final examination (4.5 to 6.5 mm Hg, P =.003). Mean logarithm of minimal angle of resolution (logMAR) vision remained unchanged from pretreatment to final examination (P =.55). Blood seepage into the anterior chamber after autologous blood injection was common but transient. CONCLUSIONS: Autologous blood injection is of limited success in treating late-onset filtering bleb leak.

Cataract surgery after tube shunts.

PURPOSE: To determine the effect of cataract surgery on glaucomatous eyes with functioning tube shunts. METHODS: Retrospective analysis of 11 eyes of 11 patients with functioning tube shunts who underwent cataract extraction. RESULTS: The mean follow-up after cataract extraction was 21 +/- 27 months (range, 4-97 months). There was no statistically significant difference between the mean preoperative intraocular pressure and mean postoperative intraocular pressure (17.4 +/- 3.7 mm Hg vs 17.8 +/- 5.9 mmHg; P = 0.85, paired t test). Most patients exhibited a statistically significant rise or drop in pressure, but in none was there a clinically significant change. The mean number of preoperative and postoperative antiglaucoma medications was also not significantly different (1.5 +/- 1.1 vs 1.7 +/- 1.2; P = 0.44, paired t test). Snellen visual acuity improved at least 2 lines in 6 eyes (55%). Complications after cataract extraction included corneal edema in three eyes, one of which had subsequent loss of control of intraocular pressure. CONCLUSIONS: Eyes with a functioning tube shunt undergoing cataract extraction can maintain control of intraocular pressure while achieving visual improvement.

Revision of dysfunctional filtering blebs by conjunctival advancement with bleb preservation.

PURPOSE: To assess the outcome of advancing a conjunctival flap with preservation of the bleb in eyes undergoing filtration bleb revision after trabeculectomy. METHODS: A retrospective review of cases from a university-based referral practice identified 30 eyes of 30 patients that had undergone bleb revision after trabeculectomy by advancement of a conjunctival flap over the de-epithelialized bleb. Success was defined as resolution of the bleb-associated complication necessitating the revision (leak, hypotony, discomfort) with maintenance of intraocular pressure greater than or equal to 6 and less than or equal to 21 mm Hg without glaucoma medications. Qualified success met the above criteria but with the use of glaucoma medications. Summary data including visual acuity were obtained. RESULTS: On the 30 eyes, 30 conjunctival advancement procedures were performed. Seventeen were for bleb leaks, 10 for prolonged hypotony without bleb leak, and three for dysesthetic bleb. Eighteen eyes (60%) were classified as a complete success and 24 eyes (80%) achieved at least a qualified success. Cumulative probability of at least qualified success was 77% at 2 years. Failures included inadequate intraocular pressure control (one eye), recurrent bleb leak (three eyes), and hypotony without bleb leak (two eyes). The mean preoperative intraocular pressure for all eyes increased from 4.4 +/- 3.7 mm Hg to 12.3 +/- 6.2 mm Hg (P <.00001) at the final visit with a mean follow-up of 18.9 +/- 15.5 months. Visual acuity improved or remained within 1 line of preoperative acuity in all but five patients. Complications included two patients with mild ptosis and four patients with hypertropia. CONCLUSION: Advancement of a conjunctival flap with preservation the preexisting bleb often provides successful resolution of bleb-associated complications.

Shunt revision versus additional tube shunt implantation after failed tube shunt surgery in refractory glaucoma.

PURPOSE: To compare tube shunt revision with additional tube shunt after failed tube shunt surgery. METHODS: We identified 281 patients who underwent a primary tube shunt procedure from 1985 to 1998 at Indiana University and reviewed 33 eyes of 33 patients that had failed and required further surgery. Shunt revision was performed in 12, whereas an additional shunt was placed in 21 eyes. Intraocular pressure, antiglaucoma medications, visual acuity, and complications were noted. Success was defined as at least a 25% reduction in intraocular pressure that was deemed clinically adequate. Qualified success was defined as a 25% intraocular pressure reduction but with additional medications or a significant reduction in medications with stable intraocular pressure for preoperative intraocular pressure less than 21 mm Hg. RESULTS: Preoperative intraocular pressures (mean +/- 95% confidence interval) for the revision and additional tube groups were 28.8 +/- 5.8 mm Hg and 29.8 +/- 2.7 mm Hg (P =.73), with an average follow-up period of 25.2 months (range, 3 to 108 months) and 34.8 months (range, 6 to 84 months), respectively. Final mean intraocular pressure was 25.3 +/- 6.7 mm Hg for the revision group and 17.7 +/- 3.4 mm Hg for the additional tube group (P =.037). Forty-two percent in the revision group versus 62% in the additional tube group achieved at least a qualified success (P =.30, Fisher exact test). Corneal edema was a common complication, especially in the additional tube group. Limitations of this study include the small sample sizes and the uneven distribution of neovascular glaucoma between the two groups (six of 12 in the revision group vs two of 21 in the additional tube group; P =.015, Fisher exact test). CONCLUSIONS: Our series showed that after failed tube shunt surgery, an additional tube shunt offers better intraocular pressure control than revision by excision of an encapsulated bleb.

Outcomes of sequential tube shunts in complicated glaucoma.

OBJECTIVE: To evaluate intraocular pressure (IOP) control, change in visual acuity, and complications in eyes that have undergone a second glaucoma tube shunt procedure. DESIGN: Retrospective, noncomparative case series. PARTICIPANTS: Twenty-two eyes of 22 patients that have undergone sequential tube implants for management of glaucoma. METHODS: Parameters analyzed included IOP, visual acuity, and number of hypotensive agent before each shunt procedure and at last follow-up visit. The overall IOP lowering effect attributable to each tube shunt was calculated. Any ocular complications after the second tube shunt were recorded. Success was defined as an IOP between 6 and 21 mm Hg and a 20% reduction in IOP from the second tube shunt procedure. Qualified successes met one of these two requirements at the last follow-up visit. Total failures did not meet any of the above criteria, required additional surgical intervention to lower IOP, or both. MAIN OUTCOME MEASURES: Intraocular pressure control, visual acuity preservation, and complications. RESULTS: At the last follow-up visit, the average percent reduction in IOP from both tube shunt procedures was 42+/-21%. The average percent IOP reduction from the second tube shunt was 33+/-17%. Eleven (50%) patients met the criteria for success, 8 (36.4%) patients were qualified successes, and 3 (13.6%) were failures. The median number of hypotensive agents decreased from two to one. Ten patients experienced new or worse pseudophakic bullous keratopathy after the second tube shunt, six of whom underwent penetrating keratoplasty. Thirteen (59%) patients maintained visual acuity within one line of their second tube shunt pre-operative Snellen visual acuity. Seven (32%) patients lost more than 2 lines, and one patient lost light perception. CONCLUSIONS: Although corneal morbidity is a common complication, a second tube shunt does not cause higher-than-expected rates of other complications associated with tube shunt surgery. Eyes that undergo a second tube shunt procedure can achieve pressure control, require fewer hypotensive agents, and may maintain stable visual acuity.

Combined penetrating keratoplasty and trabeculectomy with mitomycin C.

OBJECTIVE: To evaluate corneal graft survival and intraocular pressure control in eyes that have undergone combined penetrating keratoplasty and trabeculectomy with mitomycin C (MMC). DESIGN: Retrospective noncomparative case series. INTERVENTION: Penetrating keratoplasty combined with trabeculectomy with MMC and other surgical procedures. PARTICIPANTS: Twenty-four eyes of 22 patients undergoing combined penetrating keratoplasty and trabeculectomy with mitomycin C. MAIN OUTCOME MEASURES: Corneal graft clarity and intraocular pressure control. RESULTS: The cumulative probability of corneal graft survival was 85% at 1 year and 60% at 2 years. The cumulative probability of adequate pressure control was 67% at 3 months, 55% at 12 months, and 50% at 24 months. The incidence of bleb failure was higher in cases involving additional concomitant procedures, such as anterior vitrectomy, lens implantation or exchange, and drainage tube implantation. CONCLUSIONS: Combined penetrating keratoplasty and trabeculectomy with mitomycin C is associated with good corneal graft survival but also a risk of early failure of intraocular pressure control. Other concomitant procedures during the combined penetrating keratoplasty/trabeculectomy may increase the risk of early bleb failure.

Intracameral urokinase for dissolution of fibrin or blood clots after glaucoma surgery.

PURPOSE: To report the use of intracameral urokinase for dissolving fibrin or blood clots after glaucoma surgery. METHODS: Four eyes of four patients who had undergone glaucoma surgery developed an anterior chamber fibrin or blood clot and increased intraocular pressure. Urokinase was injected into the anterior chamber in each patient to dissolve the clot. RESULTS: In all cases, urokinase injection resulted in reduction of intraocular pressure. No adverse effects of urokinase injection were detected during the short follow-up period. CONCLUSIONS: Urokinase may be a safe, inexpensive, and convenient alternative to tissue plasminogen activator for dissolving fibrin or blood clots after glaucoma surgery. Additional studies are warranted to evaluate the long-term safety of intracameral injection.

Comparison of visual function in fellow eyes after bilateral nonarteritic anterior ischemic optic neuropathy.

PURPOSE: Although previous studies have examined the risk of bilaterality of nonarteritic ischemic optic neuropathy (NAION), none have compared extensively the extent of visual loss between fellow eyes. The authors examined cases of bilateral NAION to determine the extent of vision loss in the second eye compared with that in the first eye. METHODS: Thirty-one cases of bilateral NAION were reviewed. Variables included age, gender, and the presence of comorbid disease. Visual function was assessed by Snellen visual acuity, color vision, and pattern and mean deviation of the visual fields. RESULTS: No correlation was detected between the extent or pattern of visual loss in fellow eyes. No significant difference in visual function existed between first and second eyes for the patients overall. Patients who retained better visual function in the second eye were significantly older than those who retained better visual function in the first eye (visual acuity, P = 0.0005; color vision, P = 0.07; mean deviation, P = 0.02). In patients older than 50 years of age (25 of 31 cases), the second eye had significantly better visual acuity (P = 0.04) and less Humphrey visual field mean deviation (P = 0.04) than the first eye. CONCLUSION: Visual function in the second eye correlated poorly with that of the first eye. Older patients with bilateral NAION retained better visual function in the second eye than in the first eye. For younger patients, the extent of visual loss in the second eye could not be predicted based on the visual loss in the first eye.

Genetic heterogeneity in Hispanic families with autosomal dominant juvenile glaucoma.

A gene for autosomal dominant, juvenile-onset, primary open angle glaucoma (GLCIA) has been previously mapped to 1q21-31 in several Caucasian pedigrees. We studied two Hispanic families with this disease to determine if their disease genes also map to this region. Individuals were considered as being affected if they had 1OP > 30 mmHg (without treatment) and glaucomatous optic nerve damage or visual field defects. Persons older than 40 years with intraocular pressures < or = 21 mmHg and no evidence of optic nerve damage or visual field loss were scored as unaffected. Individuals not falling into these two categories were considered unknown. Genomic DNA was extracted from blood samples and subjected to PCR-based microsatellite marker analysis. Computer-based linkage analysis was used to determine if the disease gene mapped to chromosome 1q2I-31. In the family from the Canary Islands, the disease gene was linked to the chromosome 1q2I-31 region previously identified by other researchers. Markers D1S212 and D1S218 produced maximum lod scores of 3.38 and 2.99, respectively. In the family from the Balearic Islands, the disease gene was excluded from this region by genetic linkage analysis. Haplotype analysis also excluded the disease gene from chromosome 1q21-31. Our Hispanic families showed genetic heterogeneity with respect to autosomal dominant, juvenile-onset, primary open angle glaucoma.

Cell surface receptors for herpes simplex virus are heparan sulfate proteoglycans.

The role of cell surface heparan sulfate in herpes simplex virus (HSV) infection was investigated using CHO cell mutants defective in various aspects of glycosaminoglycan synthesis. Binding of radiolabeled virus to the cells and infection were assessed in mutant and wild-type cells. Virus bound efficiently to wild-type cells and initiated an abortive infection in which immediate-early or alpha viral genes were expressed, despite limited production of late viral proteins and progeny virus. Binding of virus to heparan sulfate-deficient mutant cells was severely impaired and mutant cells were resistant to HSV infection. Intermediate levels of binding and infection were observed for a CHO cell mutant that produced undersulfated heparan sulfate. These results show that heparan sulfate moieties of cell surface proteoglycans serve as receptors for HSV.

Heparan sulfate glycosaminoglycans as primary cell surface receptors for herpes simplex virus.

Our current incomplete picture of the earliest events in HSV infection may be summarized as follows. The initial interaction of virus with cells is the binding of virion gC to heparan sulfate moieties of cell surface proteoglycans. Stable binding of virus to cells may require the interaction of other virion glycoproteins with other cell surface receptors as well (including the interaction of gB with heparan sulfate). Penetration of virus into the cell is mediated by fusion of the virion envelope with the cell plasma membrane. Events leading up to this fusion require the action of at least three viral glycoproteins (gB, gD and gH), one or more of which may interact with specific cell surface components. It seems likely that binding of gB to cell surface heparan sulfate may occur and may be important in the activation of some event required for virus penetration. Heparan sulfate is present not only as a constituent of cell surface proteoglycans but also as a component of the extracellular matrix and basement membranes in organized tissues. In addition, body fluids contain both heparin and heparin-binding proteins, either of which can prevent the binding of HSV to cells (WuDunn and Spear, 1989). As a consequence, the spread of HSV infection is probably influenced, not only by immune responses to the virus, but also by the probability that virus will be entrapped or inhibited from binding to cells by extracellular forms of heparin or heparan sulfate.

Glycoprotein C of herpes simplex virus type 1 plays a principal role in the adsorption of virus to cells and in infectivity.

The purpose of this study was to identify the herpes simplex virus glycoprotein(s) that mediates the adsorption of virions to cells. Because heparan sulfate moieties of cell surface proteoglycans serve as the receptors for herpes simplex virus adsorption, we tested whether any of the viral glycoproteins could bind to heparin-Sepharose in affinity chromatography experiments. Two glycoproteins, gB and gC, bound to heparin-Sepharose and could be eluted with soluble heparin. In order to determine whether virions devoid of gC or gB were impaired for adsorption, we quantitated the binding of wild-type and mutant virions to cells. We found that at equivalent input concentrations of purified virions, significantly fewer gC-negative virions bound to cells than did wild-type or gB-negative virions. In addition, the gC-negative virions that bound to cells showed a significant delay in penetration compared with wild-type virus. The impairments in adsorption and penetration of the gC-negative virions can account for their reduced PFU/particle ratios, which were found to be about 5 to 10% that of wild-type virions, depending on the host cell. Although gC is dispensable for replication of herpes simplex virus in cell culture, it clearly facilitates virion adsorption and enhances infectivity by about a factor of 10.

Initial interaction of herpes simplex virus with cells is binding to heparan sulfate.

We have shown that cell surface heparan sulfate serves as the initial receptor for both serotypes of herpes simplex virus (HSV). We found that virions could bind to heparin, a related glycosaminoglycan, and that heparin blocked virus adsorption. Agents known to bind to cell surface heparan sulfate blocked viral adsorption and infection. Enzymatic digestion of cell surface heparan sulfate but not of dermatan sulfate or chondroitin sulfate concomitantly reduced the binding of virus to the cells and rendered the cells resistant to infection. Although cell surface heparan sulfate was required for infection by HSV types 1 and 2, the two serotypes may bind to heparan sulfate with different affinities or may recognize different structural features of heparan sulfate. Consistent with their broad host ranges, the two HSV serotypes use as primary receptors ubiquitous cell surface components known to participate in interactions with the extracellular matrix and with other cell surfaces.