Risk factors for optic disc hemorrhage in the low-pressure glaucoma treatment study.

PURPOSE: To investigate risk factors for disc hemorrhage detection in the Low-Pressure Glaucoma Treatment Study. DESIGN: Cohort of a randomized, double-masked, multicenter clinical trial. METHODS: Low-Pressure Glaucoma Treatment Study patients with at least 16 months of follow-up were included. Exclusion criteria included untreated intraocular pressure (IOP) of more than 21 mm Hg, visual field mean deviation worse than -16 dB, or contraindications to study medications. Patients were randomized to topical treatment with timolol 0.5% or brimonidine 0.2%. Stereophotographs were reviewed independently by 2 masked graders searching for disc hemorrhages. The main outcomes investigated were the detection of disc hemorrhage at any time during follow-up and their recurrence. Ocular and systemic risk factors for disc hemorrhage detection were analyzed using the Cox proportional hazards model and were tested further for independence in a multivariate model. RESULTS: Two hundred fifty-three eyes of 127 subjects (mean age, 64.7 ± 10.9 years; women, 58%; European ancestry, 71%) followed up for an average ± standard deviation of 40.6 ± 12 months were included. In the multivariate analysis, history of migraine (hazard ratio [HR], 5.737; P = .012), narrower neuroretinal rim width at baseline (HR, 2.91; P = .048), use of systemic ß-blockers (HR, 5.585; P = .036), low mean systolic blood pressure (HR, 1.06; P = .02), and low mean arterial ocular perfusion pressure during follow-up (HR, 1.172; P = .007) were significant and independent risk factors for disc hemorrhage detection. Treatment randomization was not associated with either the occurrence or recurrence of disc hemorrhages. CONCLUSIONS: In this cohort of Low-Pressure Glaucoma Treatment Study patients, migraine, baseline narrower neuroretinal rim width, low systolic blood pressure and mean arterial ocular perfusion pressure, and use of systemic ß-blockers were risk factors for disc hemorrhage detection. Randomization assignment did not influence the frequency of disc hemorrhage detection.

Correlation between intereye difference in visual field mean deviation values and relative afferent pupillary response as measured by an automated pupillometer in subjects with glaucoma.

PURPOSE: To evaluate the effectiveness of a new binocular infrared computerized pupillometer in the quantitative measurement of the relative afferent pupillary response in patients with glaucoma by assessing the correlation of the intereye difference in visual function as measured by standard automated perimetry (SAP) with the intereye difference in the afferent pupillary response. METHODS: Twenty-three patients with glaucoma underwent examination with a prototype, automated, binocular pupillometer. Correlation between the intereye difference in the afferent pupillary response and the intereye difference in mean deviation (MD) was explored. RESULTS: Within 7 months of pupillography, all patients underwent SAP using the Humphrey Field Analyzer IIi, 24-2, Swedish Interactive Threshold Algorithm. The intereye differential pupillary response was 0.69±0.59 (log units, mean±SD). The intereye difference in MD was 5.67±5.29 dB (mean±SD). There was a strong correlation between the intereye difference in the afferent pupillary response and the intereye difference in MD (Spearman correlation coefficient, r = -0.77; P<0.001). CONCLUSIONS: A new, binocular computerized pupillometer provides an automated method for the quantitative assessment of the afferent pupillary response. The intereye asymmetry in the pupil response correlates strongly with asymmetry in visual function, as measured by SAP, in patients with glaucoma.

Risk factors for visual field progression in the low-pressure glaucoma treatment study.

PURPOSE: To investigate risk factors associated with visual field progression in the Low-pressure Glaucoma Treatment Study, a prospective trial designed to compare the effects of the alpha2-adrenergic agonist brimonidine tartrate 0.2% to the beta-adrenergic antagonist timolol maleate 0.5% on visual function in low-pressure glaucoma. DESIGN: Prospective cohort study. METHODS: Low-pressure Glaucoma Treatment Study patients with ≥5 visual field tests during follow-up were included. Progression was determined using pointwise linear regression analysis, defined as the same 3 or more visual field locations with a slope more negative than -1.0 dB/year at P < 5%, on 3 consecutive tests. Ocular and systemic risk factors were analyzed using Cox proportional hazards model and further tested for independence in a multivariate model. RESULTS: A total of 253 eyes of 127 subjects (mean age, 64.7 ± 10.9 years; mean follow-up, 40.6 ± 12 months) were analyzed. Eyes randomized to timolol progressed faster than those randomized to brimonidine (mean rates of progression, -0.38 ± 0.9 vs 0.02 ± 0.7 dB/y, P < .01). In the final multivariate model adjusting for all tested covariates, older age (hazard ratio [HR] = 1.41/decade older, 95% confidence interval [CI] = 1.05 to 1.90, P = .022), use of systemic antihypertensives (HR = 2.53, 95% CI = 1.32 to 4.87, P = .005), and mean ocular perfusion pressure (HR = 1.21/mm Hg lower, 95% CI = 1.12 to 1.31, P < .001) were associated with progression whereas randomization to brimonidine revealed a protective effect (HR = 0.26, 95% CI = 0.12 to 0.55, P < .001). CONCLUSIONS: While randomization to brimonidine 0.2% was protective compared to timolol 0.5%, lower mean ocular perfusion pressure increased the risk for reaching a progression outcome in the Low-pressure Glaucoma Treatment Study. This suggests that the beneficial effect of randomization to the brimonidine arm was independent of possible differences in ocular perfusion pressures between the 2 treatment arms. The current results and large number of drop-outs in the brimonidine 0.2% arm suggest that more research is necessary before altering clinical practice paradigms.

A randomized trial of brimonidine versus timolol in preserving visual function: results from the Low-Pressure Glaucoma Treatment Study.

PURPOSE: To compare the alpha2-adrenergic agonist brimonidine tartrate 0.2% to the beta-adrenergic antagonist timolol maleate 0.5% in preserving visual function in low-pressure glaucoma. DESIGN: Randomized, double-masked, multicenter clinical trial. METHODS: Exclusion criteria included untreated intraocular pressure (IOP) >21 mm Hg, visual field mean deviation worse than -16 decibels, or contraindications to study medications. Both eyes received twice-daily monotherapy randomized in blocks of 7 (4 brimonidine to 3 timolol). Standard automated perimetry and tonometry were performed at 4-month intervals. Main outcome measure was field progression in either eye, defined as the same 3 or more points with a negative slope ≥-1 dB/year at P<5%, on 3 consecutive tests, assessed by pointwise linear regression. Secondary outcome measures were progression based on glaucoma change probability maps (GCPM) of pattern deviation and the 3-omitting method for pointwise linear regression. RESULTS: Ninety-nine patients were randomized to brimonidine and 79 to timolol. Mean (± SE) months of follow-up for all patients was 30.0 ± 2. Statistically fewer brimonidine-treated patients (9, 9.1%) had visual field progression by pointwise linear regression than timolol-treated patients (31, 39.2%, log-rank 12.4, P=.001). Mean treated IOP was similar for brimonidine- and timolol-treated patients at all time points. More brimonidine-treated (28, 28.3%) than timolol-treated (9, 11.4%) patients discontinued study participation because of drug-related adverse events (P=.008). Similar differences in progression were observed when analyzed by GCPM and the 3-omitting method. CONCLUSION: Low-pressure glaucoma patients treated with brimonidine 0.2% who do not develop ocular allergy are less likely to have field progression than patients treated with timolol 0.5%.

Comparison of stereo disc photographs and alternation flicker using a novel matching technology for detecting glaucoma progression.

BACKGROUND AND OBJECTIVE: To compare agreement of automated alternation flicker and serial stereophotograph inspection for detection of progressive glaucoma. PATIENTS AND METHODS: Serial photographs of patients with glaucoma with at least 36 months of follow-up and perimetry every 4 months were assessed by four graders using predefined criteria with both flicker and stereophotography. The main outcome measure was progressive neuroretinal rim deterioration as identified by each technique. RESULTS: Forty eyes (20 patients) were included and 12 eyes progressed with perimetry. Using stereophotography, the overall agreement (kappa ± standard error) was 0.19 ± 0.06 for rim change, 0.78 ± 0.06 for disc hemorrhage, and -0.04 ± 0.06 for vessel movement. Using flicker, the overall agreement was similar for rim change (0.28 ± 0.06; P = .29), worse for disc hemorrhage (0.43 ± 0.06; P < .001), and better for vessel movement (0.22 ± 0.06; P = .002). The agreement between perimetric and disc progression was similar using stereophotography (0.10 ± 0.05) and flicker (0.19 ± 0.05; P = .20). CONCLUSION: Agreement between flicker and stereophotography was similar.

Tissue bioengineering for surgical bleb defects: an animal study.

BACKGROUND: To assess the effectiveness of OloGen (also named iGen), a porous, bioengineered, biodegradable, collagen-glycoaminoglycan matrix implant, in preventing poor bleb formation and early failure after trabeculectomy in eyes with a surgical wound defect. METHODS: The right eyes of 30 female New Zealand albino rabbits underwent trabeculectomy with OloGen implanted subconjunctivally on top of the scleral flap, while six right eyes received trabeculectomy without the implant to serve as a control group. A 1-2 mm diameter circular conjunctival defect was created in all eyes. Six rabbits in the group receiving the implant were sacrificed on days 3, 5, 7, 21, and 28. Rabbits in the control group were sacrificed on day 28. Perkins applanation tonometry, Seidel test and measurement of both the extent of the conjunctival defect and the anterior chamber depth were performed. Enucleated eyes were fixed in 4% formaldehyde and stained with hematoxylin and eosin (H&E) for general histological observation, and with Sirius and Fast-green stains to assess collagen deposition and cell migration. RESULTS: Seidel tests were negative for all operated and control eyes. No flat anterior chamber occurred in either group. With the exception of days 5 and 7, post-operative mean IOP difference is significant in both groups, (P>0.05 for day 5, 7 and P<0.05 for day 3, 14, 21 and 28). In the implant group, the mean IOP was reduced by between 42% and 35% at days 14, 21, and 28, whereas the mean IOP in the control group was reduced by between only 12% and 2%. In the implant group, histology showed randomized collagen deposition and microcyst formation in the bleb after the matrix had degraded completely at day 28. In the control group, histology showed dense collagen deposition subconjunctivally at day 28. CONCLUSIONS: OloGen successfully serves as a 3-dimensional scaffold for cell migration and proliferation, and can prevent failure by maintaining the size of the bleb in the presence of a large wound defect. It might also be successful at repairing postoperative bleb leaks.

Special considerations in low-tension glaucoma.

Low-pressure (low-tension) glaucoma is reviewed in relation to neuroprotection, that is, the therapeutic strategy to keep neurons living and functionally connected to targets within the brain. Baseline results of the Low-Pressure Glaucoma Treatment Study (LoGTS) are reviewed.

Visual field and intraocular pressure asymmetry in the low-pressure glaucoma treatment study.

OBJECTIVE: To explore the relationship between asymmetric baseline intraocular pressure (IOP) and asymmetric visual field (VF) loss in the Low-Pressure Glaucoma Treatment Study. DESIGN: Randomized, multicenter, controlled clinical trial. PARTICIPANTS: Low-pressure glaucoma (LPG) patients 30 years or older were identified. Exclusion criteria included an untreated pressure > 21 mmHg, advanced VF loss, and contraindications to study medications. INTERVENTIONS: A baseline VF was created using the average of 2 reliable Humphrey full-threshold examinations. A baseline diurnal IOP curve was performed without IOP-lowering medication. MAIN OUTCOME MEASURES: Mean diurnal, peak, trough, IOP range (peak - trough), and standard deviation (SD) of IOP measurements, and mean deviation (MD) and corrected pattern SD (CPSD) of VF examinations. RESULTS: One hundred ninety patients were enrolled (mean age, 64.9+/-10.7 years). Mean deviation and CPSD were not correlated with mean, peak, trough, or peak minus trough (P - T) IOP (Ps = 0.2-0.9). Among patients with unilateral VF loss (n = 53 [27.9%]), there were no differences (Ps = 0.3-0.9) in any IOP parameter between the normal VF eye and fellow glaucomatous eyes. Among patients with bilateral VF loss (n = 137 [72.1%]), mean, peak, trough, and P - T IOPs were similar in eyes with a better VF MD compared with eyes with a worse VF MD (Ps = 0.2-0.7). Cross-classified contingency tables demonstrated no relationship (Ps = 0.1-0.3) between IOP and VF MD or CPSD using chi-square analysis. CONCLUSIONS: Intraocular pressure asymmetry is unrelated to VF asymmetry in the Low-Pressure Glaucoma Treatment Study, suggesting an unclear pathogenic relationship between IOP and glaucomatous damage in eyes with LPG.

Control of filtering bleb structure through tissue bioengineering: An animal model.

PURPOSE: To devise a means of providing controlled resistance between the anterior chamber and the subconjunctival space after trabeculectomy by implantation of a biodegradable, porous collagen matrix. METHODS: Matrices were implanted in the right eyes of 17 rabbits after trabeculectomy, while left eyes served as surgical controls. The scleral flap was sutured loosely, and the implant provided pressure on the scleral flap to reduce overfiltration. Trabeculectomy in the control eyes was performed with tight sutures using standard methodology. Intraocular pressure (IOP) was measured before surgery and on days 3, 7, 14, 21, and 28 after surgery. Masson trichrome and alpha-smooth muscle actin stains were used for histologic study of the filtering blebs. RESULTS: The initial postoperative IOP reduction was approximately equal, at 14% to 16%, for both groups. In the implanted group, the IOP continued to decrease to 55% below baseline at day 28 as the implant gradually degraded. In the control group, IOP had returned to the preoperative level by day 21. Histologic examination with Masson trichrome and alpha-smooth muscle actin stains showed a prominent bleb in the implanted group compared with scar formation and limited bleb formation in the control group. CONCLUSIONS: Implantation of a biodegradable, porous collagen matrix in the subconjunctival space offers the potential for a new means of avoiding early scar formation and maintaining long-term IOP control by creating a loosely structured filtering bleb.

The Low-pressure Glaucoma Treatment Study (LoGTS) study design and baseline characteristics of enrolled patients.

OBJECTIVE: The Low-Pressure Glaucoma Treatment Study (LoGTS) seeks to evaluate visual field stability in low-pressure glaucoma patients randomized to intraocular pressure reduction in both eyes with topical twice daily brimonidine tartrate 0.2% versus twice daily timolol maleate 0.5%. This article describes the LoGTS design and presents baseline characteristics of the subjects. DESIGN: Randomized, multicenter, double-masked clinical trial. PARTICIPANTS: Low-pressure glaucoma patients 30 years of age or older were identified. Exclusion criteria included an untreated pressure of more than 21 mmHg, advanced visual field loss, and contraindications to study medications. INTERVENTIONS: Randomization of both eyes to double-masked monotherapy with brimonidine or timolol. Follow-up visits included Humphrey 24-2 full-threshold perimetry, tonometry every 4 months, and annual optic disc photography. MAIN OUTCOME MEASURE: Progression of visual field loss. RESULTS: One hundred ninety patients were randomized between 1998 and 2000. Mean age (+/-standard deviation) was 64.9+/-10.7 years. Women comprised 59.5% of the patients. Fifty-three patients (27.9%) had unilateral field loss. The 137 patients with bilateral field loss were older than those with unilateral field loss: 65.7 versus 62.3 years of age (P<0.05). Mean untreated diurnal intraocular pressures were similar between the eyes of the bilateral patients (mean, 15.5 mmHg in both eyes) and unilateral patients (mean, 16.0 mmHg in field loss vs. 15.6 mmHg in fellow eyes). Visual field mean deviation for all eyes was -5.4+/-4.7 decibels. Central corneal thickness in 168 phakic patients was 543 +/- 35 microm (range, 435-655 microm); thickness was less than 500 microm in 15 eyes and was more than 600 microm in 11 eyes. Mean vertical cup-to-disc ratio for all eyes was 0.67+/-0.15. Unilateral field loss patients had a larger cup-to-disc ratio in the field loss eye (0.75+/-0.12) than the fellow eye with a normal field (0.60+/-0.17, P<0.0001). Disc hemorrhage was present at baseline in 29 patients (32 eyes). CONCLUSIONS: The LoGTS was successfully able to recruit and enroll patients with open-angle glaucoma and statistically normal intraocular pressure into a longitudinal, prospective clinical trial comparing 2 different glaucoma medications. Baseline characteristics of note were a preponderance of females, unilateral field loss in 27.9% of participants, and frequent optic disc hemorrhage. Central corneal thickness had a normal distribution and did not account for false low-pressure measurements in LoGTS patients.

(-)-Isoproterenol modulation of maxi-K(+) channel in nonpigmented ciliary epithelial cells through a G-protein gated pathway.

PURPOSE: Adrenergic agents decrease intraocular pressure by reducing aqueous humor secretion from ciliary epithelial cells. Since the ionic concentration of aqueous humor contributes to intraocular pressure, we have investigated the effect of (-)-isoproterenol, a beta-adrenergic agonist on the maxi-K( +) channel in rabbit nonpigmented ciliary epithelial (NPE) cells. METHODS: Single-channel currents were recorded from the basolateral surface of acutely isolated NPE cells using patch clamp techniques. RESULTS: A calcium dependent maxi-K(+) channel was identified in 31% of cell-attached patches. In the excised condition the channel was activated in presence of calcium. In symmetrical K(+) solution a linear current-voltage relationship and unitary conductance of 158 +/- 15 pS was observed. Replacing K(+) with Na(+) the current-voltage curve shifted to the right and approached a reversal potential for K( +) ( approximately -80 mV). Barium (2 mM) from the intracellular side or iberiotoxin (50 nM) from the extracellular side blocked the channel activity. In cell-attached patches, the beta-receptor agonist (-)-isoproterenol (2.5 microM) increased channel open probability (P(o)) only when applied directly through the patch pipette. beta(2)-adrenoceptor antagonists (ICI-118, 551, l-timolol) blocked the channel activity more efficiently than the beta(1)-adrenoceptor antagonist betaxolol. In excised patches, (-)-isoproterenol increased baseline P(o) 5-fold (0.5 +/- 0.13) when GTP (100 microM) and GTPgammaS (100 microM) were present at the cytosolic surface of the pipette (control; P(o), 0.12 +/- 0.006). GTP augmented baseline channel activity (0.1 +/- 0.004) 7-fold (0.7 +/- 0.03) when (-)-isoproterenol was included in patch pipette. CONCLUSIONS: Rabbit NPE cells expressed maxi-K(+) channels on their basolateral surface. The adrenergic agonist (-)-isoproterenol activated these channels via a beta(2)-adrenoceptor that was modulated by a direct G-protein gated pathway.

Adult-onset primary open-angle glaucoma caused by mutations in optineurin.

Primary open-angle glaucoma (POAG) affects 33 million individuals worldwide and is a leading cause of blindness. In a study of 54 families with autosomal dominantly inherited adult-onset POAG, we identified the causative gene on chromosome 10p14 and designated it OPTN (for "optineurin"). Sequence alterations in OPTN were found in 16.7% of families with hereditary POAG, including individuals with normal intraocular pressure. The OPTN gene codes for a conserved 66-kilodalton protein of unknown function that has been implicated in the tumor necrosis factor-alpha signaling pathway and that interacts with diverse proteins including Huntingtin, Ras-associated protein RAB8, and transcription factor IIIA. Optineurin is expressed in trabecular meshwork, nonpigmented ciliary epithelium, retina, and brain, and we speculate that it plays a neuroprotective role.