Management of blebitis by members of the American Glaucoma Society: a survey.

PURPOSE: To investigate the practice patterns among glaucoma subspecialists in the American Glaucoma Society regarding the management of blebitis. METHODS: An anonymous survey incorporating 14 questions regarding the management of blebitis was mailed to all current active American Glaucoma Society members, including provisional members, in October 1999. RESULTS: A total of 319 physicians received the survey, and 204 members (64%) returned surveys. Sixty-nine percent of respondents do not ask their patients with functioning blebs to use topical antibiotics at home for early symptoms of blebitis. Thirty-four percent never or almost never obtain conjunctival cultures at the onset of isolated blebitis, whereas 44% always or usually do. Fifty-one percent prescribe a topical fluoroquinolone alone as the initial empirical treatment of isolated blebitis. Twenty-three percent use a fluoroquinolone in combination with one or two other antibiotics. Twenty-one percent choose a combination of fortified topical agents, usually including a fortified aminoglycoside, vancomycin, or cephalosporin. Thirty-one percent use fortified agents in some combination with or without a fluoroquinolone. Five percent prescribe some other single agent alone. Only 6% routinely use an oral antibiotic in cases of blebitis. Sixty-two percent use topical corticosteroids in conjunction with antibiotic treatment. Of these, 68% start them after initial antibiotic treatment is established or once improvement of blebitis is noted. Fifty-six percent indicated that a moderate or severe anterior chamber reaction, including fibrin, would prompt treatment as a possible endophthalmitis. In a persistently Seidel-positive bleb, 77% generally attempt surgical bleb revision. CONCLUSIONS: Methods of the management of blebitis differ among members of the American Glaucoma Society. Treatment recommendations generated from randomized clinical trials are needed.

Molecular mechanism of the short-term cardiotoxicity caused by 2',3'-dideoxycytidine (ddC): modulation of reactive oxygen species levels and ADP-ribosylation reactions.

The short-term cardiac side effects of 2',3'-dideoxycytidine (ddC, zalcitabine) were studied in rats in order to understand the biochemical events contributing to the development of ddC-induced cardiomyopathy. In developing animals, ddC treatment provoked a surprisingly rapid appearance of cardiac malfunctions characterized by prolonged RR, PR, and QT intervals and J point depression. The energy metabolism in the heart was compromised, characterized by a decreased creatine phosphate/creatine ratio (from 2.05 normal value to 0.75) and a decreased free ATP/ADP ratio (from 332 normal value to 121). The activity of respiratory complexes (NADH: cytochrome c oxidoreductase and cytochrome oxidase) also decreased significantly. Southern blot and polymerase chain reaction analysis did not show deletions or a decrease in the quantity of mitochondrial DNA (mtDNA) deriving from ddC-treated rat hearts, indicating that under our experimental conditions, ddC-induced heart abnormalities were not the direct consequence of mtDNA-related damage. The ddC treatment of rats significantly increased the formation of reactive oxygen species (ROS) in heart and skeletal muscle as determined by the oxidation of non-fluorescent dihydrorhodamine123 to fluorescent rhodamine123 and the oxidation of cellular proteins determined from protein carbonyl content. An activation of the nuclear poly-(ADP-ribose) polymerase (EC 2.4.2.30) and an increase in the mono-ADP-ribosylation of glucose-regulated protein and desmin were observed in the cardiac tissue from ddC-treated animals. A decrease in the quantity of heat shock protein (HSP)70s was also detected, while the level of HSP25 and HSP60 remained unchanged. Surprisingly, ddC treatment induced a skeletal muscle-specific decrease in the quantity of three proteins, one of which was identified by N-terminal sequencing as myoglobin, and another by tandem mass spectrometer sequencing as triosephosphate isomerase (EC 5.3.1.1). These data show that the short term cardiotoxicity of ddC is partially based on ROS-mediated signalling through poly- and mono-ADP-ribosylation reactions and depression of HSP70 levels, whose processes represent a new mtDNA independent mechanism for ddC-induced cell damage.

Increased myosin light chain phosphorylation is not required for growth factor stimulation of collagen matrix contraction.

Previous research suggested the possibility that contraction of floating collagen matrices by human fibroblasts required increased myosin light chain (MLC) phosphorylation. In the current studies, we show that increased MLC phosphorylation was neither necessary for platelet-derived growth factor (PDGF)-dependent matrix contraction nor sufficient for lysophosphatidic acid (LPA)-dependent contraction. In contrast, increased MLC phosphorylation did appear to be coupled to the formation of stress fibers by cells spreading in monolayer culture. Signal transduction pathways required for PDGF- and LPA-dependent matrix contraction involved phosphatidylinositol 3-kinase and the G(i) class of heterotrimeric G proteins, respectively. Our results indicate that PDGF- and LPA-dependent contraction of floating collagen matrices can be uncoupled from an increase in MLC phosphorylation.

Differences in the regulation of fibroblast contraction of floating versus stressed collagen matrices.

To learn more about the regulation of contraction of collagen matrices by fibroblasts, we compared the ability of lysophosphatidic acid (LPA) and platelet-derived growth factor (PDGF) to stimulate contraction of floating and stressed collagen matrices. In floating collagen matrices, PDGF and LPA stimulated contraction with similar kinetics, but appeared to utilize complementary signaling pathways since contraction obtained by the combination of growth factors exceeded that observed with saturating concentrations of either alone. The PDGF-simulated pathway was selectively inhibited by the protein kinase inhibitor KT5926. In stressed collagen matrices, PDGF and LPA stimulated contraction with different kinetics, with LPA acting rapidly and PDGF acting only after an approximately 1-h lag period. Pertussis toxin, known to block signaling through the Gi class of heterotrimeric G-proteins, inhibited LPA-stimulated contraction of floating but not stressed matrices, suggesting that LPA-stimulated contraction depends on receptors coupled to different G-proteins in floating and stressed matrices. On the other hand, the Rho inhibitor C3 exotransferase blocked contraction of both floating and stressed collagen matrices. These results suggest the possibility that distinct signaling mechanisms regulate contraction of floating and stressed collagen matrices.

Autosomal dominant nanophthalmos (NNO1) with high hyperopia and angle-closure glaucoma maps to chromosome 11.

Nanophthalmos is an uncommon developmental ocular disorder characterized by a small eye, as indicated by short axial length, high hyperopia (severe farsightedness), high lens/eye volume ratio, and a high incidence of angle-closure glaucoma. We performed clinical and genetic evaluations of members of a large family in which nanophthalmos is transmitted in an autosomal dominant manner. Ocular examinations of 22 affected family members revealed high hyperopia (range +7.25-+13.00 diopters; mean +9.88 diopters) and short axial length (range 17.55-19.28 mm; mean 18.13 mm). Twelve affected family members had angle-closure glaucoma or occludable anterior-chamber angles. Linkage analysis of a genome scan demonstrated highly significant evidence that nanophthalmos in this family is the result of a defect in a previously unidentified locus (NNO1) on chromosome 11. The gene was localized to a 14.7-cM interval between D11S905 and D11S987, with a maximum LOD score of 5. 92 at a recombination fraction of .00 for marker D11S903 and a multipoint maximum LOD score of 6.31 for marker D11S1313. NNO1 is the first human locus associated with nanophthalmos or with an angle-closure glaucoma phenotype, and the identification of the NNO1 locus is the first step toward the cloning of the gene. A cloned copy of the gene will enable examination of the relationship, if any, between nanophthalmos and less severe forms of hyperopia and between nanophthalmos and other conditions in which angle-closure glaucoma is a feature.

Autoantibodies against subunits of pyruvate dehydrogenase and citrate synthase in a case of paediatric biliary cirrhosis.

In a newborn girl with a history of connatal liver damage, histological examination of a liver biopsy sample taken during the seventh week of life revealed incipient destruction of bile ducts. Very high titres of antimitochondrial antibodies were later detected in the plasma. As the hepatic injury tended towards fibrosis, the histological diagnosis became primary biliary cirrhosis. Autoantibodies against E1 alpha, E2, and E3 subunits and protein X component of pyruvate dehydrogenase complex, and against citrate synthase were detected on western immunoblotting in a 1 in 1000 dilution of the patient's serum. The patient died of her illness at 11 years of age. In liver specimens obtained at autopsy human immunoglobulin deposition was detected on the surface of almost all hepatic cells by immunohistology. As there is a physical and functional interaction between pyruvate dehydrogenase and citrate synthase within the mitochondria, the presence of autoantibodies against certain proteins in the patient suggests that in this form of the disease the molecular recognition and then the autoimmunisation process could be directed against a mitochondrial enzyme cluster containing both pyruvate dehydrogenase and citrate synthase.

A long-term dose-response study of mitomycin in glaucoma filtration surgery.

OBJECTIVE: To establish the long-term, dose-response relationship between the concentration of and duration of exposure to mitomycin to a decrease in intraocular pressure (IOP) and fewer complications. METHODS: We performed a prospective double-masked, placebo-controlled, 1-year study evaluating the decrease in IOP and fewer complications of fornix-based trabeculectomy surgery in 300 eyes equally divided among therapy with placebo; mitomycin, 0.2 mg/ mL, applied for 2 minutes; mitomycin, 0.4 mg/mL, applied for 4 minutes; or mitomycin, 0.4 mg/mL, applied for 2 minutes. All of the eyes had vertical and horizontal cup-disc ratios greater than 0.7. RESULTS: We observed significant treatment-related differences in IOP, with a decrease in IOP in all 3 mitomycin-treated groups for all of the times beyond 1 month. The number of eyes achieving strict IOP control and the development of cataract suggest a possible dose-response effect for concentration and time of exposure. Progressive lens opacification was the most frequent complication in 54 eyes (18.1%). The incidence of progressive lens changes markedly increased in subjects receiving 4 minutes of mitomycin therapy. Cataract formation was unrelated to IOP. Other complications were rare. Macular folds developed in 6 patients, with visual acuity returning to better than 20/40 in all but 1 patient. CONCLUSIONS: A possible dose-response relationship seemed to exist between the concentration of and duration of exposure to mitomycin. Length of exposure seems to be more important than concentration. The benefits of additional decreases in IOP must be weighed against the potential for increases in the risk of complications.

Bleb-related endophthalmitis after trabeculectomy with mitomycin C.

PURPOSE: To determine whether filtering blebs resulting from adjunctive use of mitomycin C (MMC) leads to an increased risk of endophthalmitis. METHODS: The authors retrospectively reviewed the records of 232 consecutive trabeculectomies performed at the W. K. Kellogg Eye Center with adjunctive use of MMC from May 1990 through June 1993. Data obtained from the records included patient age, sex, race, type of glaucoma, site of filtration surgery, concentration and duration of exposure to MMC, presence of early or late bleb leakage, and the occurrence of endophthalmitis. RESULTS: Three patients were lost to follow-up less than 1 month after surgery. A total of 229 eyes of 192 patients (11 women and 82 men) were included in the study. Mean follow-up of patients remaining free of infection was 18.5 +/- 10.8 months (range, 1-44 months). The overall incidence of bleb-related endophthalmitis was 2.6%. Endophthalmitis developed in 8% of patients (4 or 50) in whom an inferior approach was used and in 1.1% (2 or 179) in whom a superior approach was used (P = 0.02, Fisher's exact test). The estimated odds ratio for the development of endophthalmitis after trabeculectomy with adjunctive MMC for inferior versus superior filtration sites was 7.7. CONCLUSION: Short-term follow-up of trabeculectomies performed with adjunctive use of MMC demonstrates an overall incidence of endophthalmitis comparable to filtrationprocedures performed with 5-fluorouracil or without antifibrotic agents. However, inferior trabeculectomy performed with adjunctive MMC carries a significantly increased risk of bleb-related endophthalmitis compared with filters performed superiorly.

Mitomycin C versus 5-fluorouracil in high-risk glaucoma filtering surgery. Extended follow-up.

PURPOSE: To compare the outcome of filtering surgery in high-risk patients using intraoperative mitomycin C (MMC) versus postoperative 5-fluorouracil (5-FU). METHODS: In a randomized clinical trial, the use of postoperative subconjunctival injections of 5-FU in 19 eyes of 19 patients was compared with a single intraoperative application of MMC in 20 eyes of 20 patients. All eyes were at high risk for failure of glaucoma filtering surgery. RESULTS: Follow-up ranged from 26 to 38 months (mean, 32.0 months). Three eyes in the MMC-treated group and two eyes in the 5-FU-treated group required subsequent surgery to control the IOP. Excluding these patients, intraocular pressure (IOP) averaged 9.0 +/- 4.9 mmHg in the MMC-treated eyes versus 16.3 +/- 4.6 mmHg in the 5-FU-treated eyes at the patient's last visit (P = 0.0003). Of the MMC-treated eyes, 81.3% had IOPs less than or equal to 12 mmHg compared with 26.7% of eyes in the 5-FU group (P = 0.0023). In the MMC-treated group, the average number of medications for IOP control at last visit was 0.5 +/- 0.8 compared with 1.6 +/- 1.3 in the 5-FU-treated group (P = 0.01). Late postoperative complications (those occurring more than 3 months after surgery) were similar for the two groups, with the exception of formation of a Tenon cyst in three of the eyes treated with MMC compared with none of the 5-FU-treated eyes. CONCLUSIONS: Eyes treated with MMC have lower IOP on fewer medications than eyes treated with 5-FU. Late postoperative complications are similar with the exception of an increased incidence of Tenon cyst formation in the MMC-treated eyes.

Viscoelastic-related glaucomas.

The routine surgical use of viscoelastic substances has revolutionized many anterior segment procedures. All of the currently available agents may be responsible for causing or exacerbating a transient, but occasionally significant, postoperative IOP elevation. In spite of differences in physical properties such as molecular weight, concentration, and viscosity, none of the various viscoelastics has consistently shown a decreased likelihood of producing ocular hypertension. Moreover, any newly introduced product must be evaluated carefully for this potential complication. Lavage of viscomaterial from the anterior chamber and administration of ocular antihypertensives may be helpful in averting or controlling the increased IOP. The surgeon should be cognizant of any pre-existing optic nerve damage and adjust the aggressiveness of postoperative glaucoma therapy accordingly. In the future, the development of new substances or simultaneous use of degrading enzymes may reduce or eliminate the incidence of viscoelastic-induced ocular hypertension.

Intraoperative mitomycin versus postoperative 5-fluorouracil in high-risk glaucoma filtering surgery.

In a randomized clinical trial, the authors compared the use of postoperative subconjunctival injections of 5-fluorouracil (5-FU) in 19 eyes with a single intraoperative application of subconjunctival mitomycin (MMC) at the filtering site in 20 eyes at high risk for failure of glaucoma filtering surgery. Six months after surgery, intraocular pressures averaged 10.9 +/- 5.3 mmHg (mean +/- standard deviation) in the MMC-treated eyes versus 14.2 +/- 5.5 mmHg in the 5-FU-treated eyes (P = 0.08) and were less than or equal to 12 mmHg in 60.0% of MMC-treated eyes and 21.1% of 5-FU-treated eyes (P = 0.03). Mitomycin-treated eyes were receiving an average of 0.3 +/- 0.5 medications for intraocular pressure control, and 5-FU-treated eyes were receiving an average of 1.1 +/- 1.1 medications (P = 0.01). Drug-induced corneal epithelial defects were seen in nine 5-FU-treated eyes and in no MMC-treated eyes (P = 0.0004). These results suggest that intraoperative MMC may be a viable alternative to postoperative 5-FU, with lower overall intraocular pressures, decreased dependence on postoperative ocular antihypertensive medications, and decreased corneal toxicity.

The effects of subconjunctival mitomycin-C on glaucoma filtration surgery in rabbits.

A prospective, randomized, masked, placebo-controlled study was performed to determine whether a single, intraoperative subconjunctival application of a 0.5-mg/mL solution of mitomycin-C enhances the success of full-thickness filtration surgery in rabbits. Compared with control eyes, mitomycin-C-treated eyes showed significant increases in bleb duration from 8.1 +/- 2.4 to 68.0 +/- 20.8 days and in intraocular pressure reduction from 6.0 +/- 3.0 to 63.6 +/- 21.5 days. Histopathologic evaluation confirmed the inhibitory effects of mitomycin-C on fibrovascular, fibrocellular, and collagenous organization of the filtering blebs that resulted in their preservation. Transient, superficial, corneal vascularization anterior to the bleb occurred in all mitomycin-C-treated eyes. No other clinical or pathologic signs of undesirable side effects were noted. We studied the effectiveness and safety of a single intraoperative application of mitomycin-C in prolonging the success of filtration surgery in rabbits and its potential for similar use in humans.

The effects of glaucoma medications on Tenon's capsule and conjunctiva in the rabbit.

Glaucoma filtering surgery fails most frequently due to fibrosis at the episcleral-conjunctival/Tenon's capsule interface. Sherwood et al have suggested that chronic topical antiglaucoma medications increase conjunctival inflammatory cells, which could increase the likelihood of fibrosis and subsequent bleb failure. In a pilot study in a rabbit model, we placed timolol, pilocarpine, and epinephrine, or a combination of all three, in one eye of 24 animals twice daily for 7 months. The fellow eye received distilled water. Microscopic examination revealed no statistically significant change in the number of acute or chronic inflammatory cells, fibroblasts, or goblet cells in the treated as compared with the control eyes. A longer duration of drug administration, or drug administration followed by surgical intervention, may be required to produce an effect on the conjunctiva and Tenon's capsule, if such an effect exists.

The effect of glaucoma filtering surgery on corneal endothelial cell density.

Corneal endothelial cell counts were obtained preoperatively and 3 months postoperatively in 46 eyes undergoing glaucoma filtering surgery. Average central endothelial cell loss in eyes without postoperative iridocorneal touch was 1.6%. In eyes with iridocorneal touch (Spaeth's grades 1 and 2), the average cell counts decreased by 7.1% and 9.3%, respectively. The average loss for combined grades 1 and 2 (8.1%) approached statistical significance (P +/- .06). The average loss in two patients with corneolenticular touch (Spaeth's grade 3) was greater than 50%. These findings suggest that early postoperative iridocorneal touch is unlikely to lead to corneal compromise in most eyes, but that corneolenticular touch can result in severe endothelial cell loss.

MK-507 versus sezolamide. Comparative efficacy of two topically active carbonic anhydrase inhibitors.

Topical carbonic anhydrase inhibitors MK-507 and sezolamide hydrochloride (previously known as MK-417) were compared in a double-masked, randomized, placebo-controlled study in 82 patients with bilateral primary open-angle glaucoma or ocular hypertension. MK-507 was given every 8 or 12 hours, sezolamide every 8 hours, or placebo every 8 or 12 hours for 4 days. Both drugs lowered intraocular pressure (IOP) substantially. MK-507 was somewhat more active than sezolamide, with a peak mean IOP reduction of 26.2% for MK-507 versus 22.5% for sezolamide, although the difference between the treatments was not statistically significant. These drugs may have potential in the treatment of glaucoma.

Time course of thymoxamine reversal of phenylephrine-induced mydriasis.

We conducted a randomized, double-masked, paired comparison of 0.1% thymoxamine vs placebo for the reversal of phenylephrine-induced mydriasis. Mydriasis was induced with 2.5% phenylephrine in each eye of 74 subjects (148 eyes). Each subject then received 0.1% thymoxamine in one eye and placebo in the other eye. Pupillary measurements were obtained at regular intervals during the ensuing 8 hours. At all intervals, a greater percentage of thymoxamine-treated eyes returned to baseline pupillary diameters compared with placebo-treated eyes (P less than or equal to .01). For subjects in whom both pupils returned to baseline, thymoxamine-treated eyes returned to baseline in a mean of 2.2 hours, vs 5.2 hours for placebo (P less than .0001). Among thymoxamine-treated eyes, those with light irides responded more rapidly than those with dark irides, returning to baseline in 1.6 vs 2.8 hours, respectively (P = .0046). After constriction to baseline pupillary diameter had been achieved, no patients experienced a rebound dilation.

Angle-closure glaucoma as initial presentation of myelodysplastic syndrome.

A 57-year-old man presented with proptosis of the right eye and findings consistent with bilateral angle-closure glaucoma. Subsequent evaluation revealed severe bilateral uveal effusions and associated nonrhegmatogenous retinal detachments, which were felt to be related to orbital pseudotumour and associated scleritis. Hematologic studies were consistent with a diagnosis of myelodysplastic syndrome. Although myelodysplastic syndrome has been reported in one patient with orbital inflammation and myositis, to our knowledge ciliochoroidal effusion and secondary angle closure have not previously been reported in myelodysplastic syndrome.