Vascular tone pathway polymorphisms in relation to primary open-angle glaucoma.

AIMS: Vascular perfusion may be impaired in primary open-angle glaucoma (POAG); thus, we evaluated a panel of markers in vascular tone-regulating genes in relation to POAG. METHODS: We used Illumina 660W-Quad array genotype data and pooled P-values from 3108 POAG cases and 3430 controls from the combined National Eye Institute Glaucoma Human Genetics Collaboration consortium and Glaucoma Genes and Environment studies. Using information from previous literature and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, we compiled single-nucleotide polymorphisms (SNPs) in 186 vascular tone-regulating genes. We used the 'Pathway Analysis by Randomization Incorporating Structure' analysis software, which performed 1000 permutations to compare the overall pathway and selected genes with comparable randomly generated pathways and genes in their association with POAG. RESULTS: The vascular tone pathway was not associated with POAG overall or POAG subtypes, defined by the type of visual field loss (early paracentral loss (n=224 cases) or only peripheral loss (n=993 cases)) (permuted P≥0.20). In gene-based analyses, eight were associated with POAG overall at permuted P<0.001: PRKAA1, CAV1, ITPR3, EDNRB, GNB2, DNM2, HFE, and MYL9. Notably, six of these eight (the first six listed) code for factors involved in the endothelial nitric oxide synthase activity, and three of these six (CAV1, ITPR3, and EDNRB) were also associated with early paracentral loss at P<0.001, whereas none of the six genes reached P<0.001 for peripheral loss only. DISCUSSION: Although the assembled vascular tone SNP set was not associated with POAG, genes that code for local factors involved in setting vascular tone were associated with POAG.

The Advanced Glaucoma Intervention Study (AGIS): 10. Variability among academic glaucoma subspecialists in assessing optic disc notching.

PURPOSE: An analysis of data from the Advanced Glaucoma Intervention Study (AGIS) has found eyes reported to have partial optic disc rim notching (not to the edge) at baseline to have less risk of subsequent visual field loss than eyes with no notching. Because this is counterintuitive and because classification of notching had not been defined in the AGIS protocol, we have assessed AGIS ophthalmologists interobserver and intraobserver agreement on notching. METHODS: Fourteen glaucoma subspecialists classified notching in 26 pairs of stereoscopic disc photographs of eyes with mild to severe glaucomatous optic neuropathy. They classified images as showing either no notching, notching not to the edge, or notching to the edge. Several hours later, 10 of them classified the same images a second time. RESULTS: In an analysis of interobserver agreement, of 26 stereoscopic images, a plurality of ophthalmologists classified notching as absent in 9 (35%), as present but not to the edge in 7 (27%), and as present and not to the edge in 10 (38%). All 14 ophthalmologists (100%) agreed on the classification of 7 (27%) of the images, and 13 of the 14 ophthalmologists (93%) agreed on the classification of 4 additional images (15%). Of these 11 images with at least 93% agreement, notching was reported as absent in 3 (27%) and to the edge in 8 (73%). In the remaining 15 images, there was substantial disagreement about whether notching was present and, if so, whether it was to the edge. In an analysis of intraobserver agreement, none of the 10 ophthalmologists who completed the viewing a second time classified all eyes exactly the same as the first time, though 5 ophthalmologists made 4 or fewer reclassifications. Overall, 80% of the original classifications were reproduced on second reading. Of the initial classifications that were not reproduced, slightly more than half were first classified as having notching not to the edge. CONCLUSION: Without definitions or examples of optic disc rim notching, the glaucoma subspecialists had relatively high intraobserver agreement but were likely to disagree with each other in characterizing the degree of disc rim notching. We recommend development of a standard photographic classification of disc rim notching. The classification should be tested for inter- and intra-observer agreement.

The Advanced Glaucoma Intervention Study (AGIS): 5. Encapsulated bleb after initial trabeculectomy.

PURPOSE: To compare the incidence of encapsulated bleb after trabeculectomy in eyes with and without previous argon laser trabeculoplasty and to assess other risk factors for encapsulated bleb development. METHODS: After medical treatment failure, eyes enrolled in the Advanced Glaucoma Intervention Study (AGIS) were randomly assigned to sequences of interventions starting with either argon laser trabeculoplasty or trabeculectomy. In the present study we compared the clinical course for 1 year after trabeculectomy in 119 eyes with failed argon laser trabeculoplasty with that of 379 eyes without previous argon laser trabeculoplasty. Data on bleb encapsulation were collected at the time that the encapsulation was diagnosed, and 3 and 6 months later. RESULTS: Of multiple factors examined in the AGIS data for the risk of developing encapsulated bleb, only male gender and high school graduation without further formal education were statistically significant. Encapsulation occurred in 18.5% of eyes with previous argon laser trabeculoplasty failure and 14.5% of eyes without previous argon laser trabeculoplasty (unadjusted relative risk, 1.27; 95% confidence limits = 0.81, 2.00; P = .23). After adjusting for age, gender, educational achievement, prescribed systemic beta-blockers, diabetes, visual field score, and years since glaucoma diagnosis, this difference remains statistically not significant. Four weeks after trabeculectomy, mean intraocular pressure was 7.5 mm Hg higher in eyes with (22.5 mm Hg) than without (15.0 mm Hg) encapsulated bleb; at 1 year after trabeculectomy and the resumption of medical therapy when needed, this excess was reduced to 1.4 mm Hg. CONCLUSIONS: This study, as did two previous studies, found male gender to be a risk factor for bleb encapsulation. Four studies, including the present study, have reported a higher rate of encapsulation in eyes with previous argon laser trabeculoplasty; in two of the studies, one of which was the present study, the rate was not statistically significantly higher; in the other two studies the rate was significantly higher. The 4-week postoperative mean intraocular pressure was higher in eyes with than without encapsulated bleb; with the resumption of medical treatment the two means converged after 1 year.

Effect of fiberoptic diameter in diode laser transscleral cyclophotocoagulation in human autopsy eyes.

PURPOSE: Contact fiberoptic laser transscleral cyclophotocoagulation (TSCPC) is an aqueous inflow-reducing surgical treatment for glaucoma. One delivery device uses a 600-microm diameter quartz glass fiberoptic with a hemispheric tip. A larger fiberoptic diameter would reduce fluence through conjunctiva and sclera. This study determined the relation of fiberoptic to ciliary body burn diameters after TSCPC with the IRIS Medical SLx diode laser system in human autopsy eyes. MATERIALS AND METHODS: Laser energy was applied with two models of delivery probe that were identical except for fiberoptic diameter (600 or 800 microm). Both had hemispheric tips, each with the hemisphere radius equal to the radius of the fiberoptic. Six fresh human autopsy eyes (three pairs) were used, each receiving eight diode laser applications at 1.75 (2 eyes) or 2.0 (4 eyes) watts for 2.5 seconds-four applications per eye with the 600-microm fiberoptic and four with the 800-microm fiberoptic. Eyes were fixed in 10% formalin then opened coronally at the equator. Inner surface burn diameters were measured parallel and perpendicular to the limbus using calipers and an operating microscope at 10x magnification. RESULTS: Ciliary body burns with the 600- and 800-microm fiberoptic tips had nearly the same average diameter, range of diameter, average area, and range of areas. CONCLUSION: The 800-microm fiber, which has a 78% larger cross-sectional area than a 600-microm fiber, reduces fluence through ocular surface tissue during diode laser TSCPC, theoretically decreasing the risk of surface bums. In this study, the larger fiber gives essentially the same size ciliary body coagulation as obtained with the 600-microm fiberoptic. This suggests that the larger fiberoptic, compared with the standard 600-microm fiberoptic, will be more safe yet equally effective for TSCPC.

A multicenter comparison study of the Humphrey Field Analyzer I and the Humphrey Field Analyzer II.

PURPOSE: The purpose of the study is to determine the comparability of the 30-2 full-threshold program in the original Humphrey Field Analyzer (HFA) I to the same test procedure in the new Humphrey Field Analyzer II. METHODS: At each of five clinical centers, one eye of patients with ocular hypertension and normal visual fields, patients with early glaucomatous visual field loss, and patients with more advanced visual field loss were tested with the two instruments plus a retest on a separate HFA I. All participants had undergone at least one prior visual field examination. To minimize the influence of any residual learning or fatigue effects, the order of testing for the three visual field examinations was counterbalanced across subjects. A total of 250 patients were tested (81 patients with ocular hypertension, 81 patients with early glaucomatous visual field loss, and 88 patients with more advanced glaucomatous visual field loss). RESULTS: No statistically significant differences were observed between thresholds, visual field indices, or reliability indices obtained with the HFA I and the HFA II. The small differences between the two instruments were equivalent to the variation observed for test-retest measures using only the HFA I. These results were consistent across the range of visual field characteristics shown by the ocular hypertensive, early glaucoma, and moderate glaucoma patient groups. CONCLUSIONS: The authors' results indicate that there are no differences in the visual field results obtained with the HFA I and the HFA II. These findings suggest that with careful attention to test protocols, the HFA I and HFA II may be used interchangeably to observe patients, even within the context of multicenter clinical trials.

Response of filtered eyes to digital ocular pressure.

PURPOSE: To examine the effect of digital ocular pressure (DOP) on the intraocular pressure (IOP) of eyes 3 months or longer after successful glaucoma filtering surgery. METHODS: Fifteen patients participated in this study. Each had one eye with a successful filtering operation (IOP < or = 21 mmHg without medications) and a fellow eye that was not operated on, which served as a control. The authors measured IOP in both eyes before and serially after DOP until return to baseline or for 3 hours to determine the amounts and durations of reductions. The authors monitored changes of bleb morphology and searched for complications. RESULTS: Digital ocular pressure 3 months or more after successful filtering surgery reduced IOP by approximately 50% of baseline. The time after DOP for 50% of eyes to have intraocular pressure return to within 2 mmHg of baseline was 95 minutes; 40% recovered within 20 minutes and 30% had not recovered by 3 hours. Eyes with localized blebs recovered faster than did eyes with diffuse blebs. Transient shallowing of the anterior chamber developed in one eye. Otherwise, there were no adverse effects. Time since surgery and baseline IOP were not correlated with response. Fellow eyes had minimal response to DOP and recovered within 30 minutes. CONCLUSION: This study shows that a substantial, transient decrease of IOP after DOP occurs in glaucomatous eyes with a well-functioning bleb 3 months to 6 years after filtering surgery. The duration exceeds 90 minutes in more than 50% of the eyes tested and 180 minutes in more than 30% of the eyes tested.

Long-term outcome of initial ciliary ablation with contact diode laser transscleral cyclophotocoagulation for severe glaucoma. The Diode Laser Ciliary Ablation Study Group.

PURPOSE: To learn the long-term outcome of ciliary ablation with diode laser contact transscleral cyclophotocoagulation (TSCPC) in eyes with recalcitrant, severe glaucoma. METHODS: Twenty-seven eyes of 27 patients with medically and surgically uncontrollable glaucoma and no previous ciliary ablation enrolled in this study. After baseline measurements and informed consent, the authors performed contact TSCPC. There were 14 pseudophakic, 7 aphakic, and 6 phakic eyes; 15 of these had primary open angle glaucoma and the remainder had various secondary or open- or closed-angle glaucomas. Median follow-up was 19 months (range, 6 weeks to 27 months). Initially after laser surgery, glaucoma medications were continued, except for a 2-week interruption of miotics; the ophthalmologist later adjusted medications in accordance with the patient's status. The authors define failure of TSCPC in two ways, based on IOP measurements during two consecutive study examinations 6 weeks or more after intervention or at the final examination: (1) less than 20% intraocular pressure (IOP) reduction from baseline, and (2) either less than 20% reduction of IOP from baseline or IOP greater than 22 mmHg. RESULTS: For 27 eyes, the baseline IOP (mean +/- standard deviation) was 36.4 +/- 12.4 mmHg (range, 20-70 mmHg). The mean IOP at last examination was 20.3 +/- 8.7 mmHg. With failure definition 1, the cumulative probability of success was 84% at 1 year and 62% at 2 years. With failure definition 2 the cumulative probability of success was 72% at 1 year and 52% at 2 years. At the last examination, 19 eyes (70%) had visual acuity improved within one line of visual acuity at eligibility. One of these eyes, with light perception vision at entry, declined to no light perception. Three eyes (11%) lost two lines of vision and five (19%) lost three or more lines. CONCLUSIONS: Contact diode laser TSCPC yields long-term improvement of IOP and preservation of visual acuity in a substantial proportion of eyes with severe, medically uncontrolled glaucoma.

Translating research into practice: controlled clinical trials and their influence on glaucoma management.

Historically, management strategies for glaucoma have stressed reduction of IOP as the primary goal. Yet, if we question this principle, we find a deficiency of information to support it as the optimal strategy for managing glaucoma patients and those at risk of developing glaucoma. Thus, the practice of lowering IOP in glaucoma management was placed on trial by the 1987 Eddy and Billings report (D. M. Eddy and J. Billings, 1987). Although generally denounced by clinicians, this report nonetheless alerted the ophthalmologic community that success of glaucoma treatment must be measured by endpoints unrelated to IOP and that a controlled trial to demonstrate glaucoma treatment efficacy was necessary. A clinical trial is an experiment. As such, it is the best study design for inferring causality between an exposure (e.g., IOP) and an outcome (e.g., glaucoma), and it is the best methodology for demonstrating treatment efficacy. However, it is important to understand that efficacy is not the same as effectiveness. Whereas "efficacy" is the extent to which a specific intervention produces a beneficial result under ideal conditions, "effectiveness" is the extent to which a specific intervention, when deployed in the field, does what it is intended to do. The influence of study results on the practice of medicine is more a function of demonstrated effectiveness than efficacy of an intervention. All of the completed glaucoma clinica trials reviewed were well performed, and many have had a substantial influence on the philosophy and practice of glaucoma management. The glaucoma clinical trials currently being performed represent the highest standards of clinical trial methodology. This is an exciting time for clinical research on glaucoma. Well accepted dogmas are being challenged, and the ophthalmic community is aggressively addressing difficult issues. Questions being asked are of fundamental importance and addressing them is essential. Particularly exciting in these trials is the fact that IOP is not being considered as an endpoint and that consideration is being given to the previously ignored but extremely important issue of overall patient well-being. Only with time will the ultimate impact of these trials on the philosophy and practice of glaucoma management become evident.

The Advanced Glaucoma Intervention Study (AGIS): 1. Study design and methods and baseline characteristics of study patients.

Medical therapy has been the standard initial treatment for open-angle glaucoma. When some visual field has been lost and maximum tolerated and effective medical therapy does not succeed in controlling the disease, the patient is considered to have advanced glaucoma, and the first of a potential sequence of surgical treatments is usually indicated. Little is known about the long-term course and prognosis of advanced glaucoma or about the long-term effectiveness of sequential surgical treatments in controlling the disease and preventing vision loss and blindness. The Advanced Glaucoma Intervention Study was designed to study, in advanced glaucoma, the long-term clinical course and prognosis, and, in a randomized trial, the comparative outcomes of two sequences of surgical treatments. Toward these goals, 789 eyes in 591 patients were enrolled at 11 clinical centers between 1988 and 1992. Follow-up will continue until 1996. Eyes were randomly assigned to one of two sequences of surgical treatments. One sequence begins with argon laser trabeculoplasty (ALT), is followed by trabeculectomy, an incisional surgical filtering procedure, should ALT fail to control the disease, and by a second trabeculectomy should the first trabeculectomy fail. The other sequence begins with trabeculectomy, is followed by ALT should the trabeculectomy fail, and by a second trabeculectomy should ALT fail. The main outcome of interest is visual function (visual field and visual acuity). Other important outcomes are intraocular pressure, complications of surgery, time to treatment failure, and extent of need for additional medical therapy. We present in this paper the rationale, objectives, design and methods of the study, and the baseline characteristics of study patients and eyes.

Comparison of analytic algorithms for detecting glaucomatous visual field loss.

The sensitivity and specificity of alternate analytic strategies for recognizing glaucomatous visual field loss from automated threshold perimetry (C-30-2 test of the Humphrey Field Analyzer) were compared among one eye each of 106 patients with glaucoma and 249 normal subjects. Algorithms included commercially available global indexes and cross-meridional differences (Statpac 1 and Statpac 2), as well as cross-meridional and cluster analyses that were developed independently for natural history studies and clinical trials. The sensitivity of most algorithms was high, except for those that used only diffuse loss as an indicator of abnormality. Specificity was acceptably high for all algorithms. Subjects who failed to meet the manufacturer's standard for reliability had much reduced specificity, but sensitivity was also affected. Algorithms that were based on any of the alternate definitions of localized reduction in retinal sensitivity performed equally well, which suggests that any of these approaches is useful in searching for glaucomatous visual loss as typified by this database. Availability, familiarity, and convenience may govern the selection of any one analytic approach for use in a particular setting.

Endocapsular hematoma. Description and treatment of a unique form of postoperative hemorrhage.

Endocapsular hematoma, to our knowledge, is a previously unreported type of postoperative hemorrhage. In this condition, blood collects in the narrow space between the anterior surface of the posterior capsule and the posterior optic surface of a posterior chamber intraocular lens. Endocapsular hematoma differs from anterior chamber hyphema in several ways: the location of the blood is in the endocapsular space, a small amount of endocapsular blood can cause visually disabling symptoms, the blood in the endocapsular space often fails to reabsorb, and neodymium-YAG laser capsulotomy can be used to drain the endocapsular blood into the vitreous cavity. We present six cases of endocapsular hematoma. Neodymium-YAG laser capsulotomy was successfully used to drain the endocapsular hematoma in three of these cases.

Trans-scleral application of a semiconductor diode laser.

We used a diode laser with an output power of 1 W through a fiberoptic light pipe (200 microns diameter) to deliver laser energy through the sclera of pigmented rabbits. Ciliary body destruction occurred with energy levels of 300-400 mW and exposure time of 0.5 sec. Retinal photocoagulation was achieved with energy levels of 200-500 mW in 0.5 sec. Histologic examination of acute lesions demonstrated thermal destruction of ciliary body processes and retina. Chorioretinal scar formation was observed clinically and histologically within 2-3 weeks. Our data indicate that the transscleral diode laser may be used for destruction of the ciliary body processes or peripheral retinal coagulation in pigmented eyes.

A review of surgical alternatives to medical therapy for glaucoma.

Results of four uncontrolled studies, with short-term follow-up, of argon laser trabeculoplasty (ALT) as initial treatment for various open-angle glaucomas indicate short-term success varies from 65 to 90 percent. The success rates are less impressive when the definition of success, usually intraocular pressure 22 mmHg or less, and the short follow-up, usually limited to months, are considered. The ongoing, multicenter, random-assignment, controlled Glaucoma Laser Trial in the United States will provide additional information about short- and long-term follow-up of primary ALT that will clarify the accuracy of the results of these preliminary trials.Results of another study suggest that initial filtering surgery is as effective at controlling intraocular pressure and preserving visual function as medical treatment for newly diagnosed glaucoma. All these clinical studies are difficult to interpret and suffer from the lack of data analysis using the life-table method. The comparatively low rate of long-term success of ALT for open-angle glaucoma performed after failure of medical management, particularly in blacks, cautions that ALT may not be a good substitute for medications or filtering surgery in newly diagnosed glaucoma.

Infantile glaucoma in Down's syndrome (trisomy 21).

We examined five patients with Down's syndrome and bilateral infantile glaucoma. In the first few months of life four patients had large cloudy corneas, breaks in Descemet's membrane, increased intraocular pressure, photophobia, and tearing. In one patient the diagnosis was delayed until 3 1/2 years of age because of concomitant nasolacrimal duct obstruction. Two patients developed cataracts and retinal detachment and have undergone multiple surgical procedures. The clinical course in these two older patients suggests that coexistence of congenital glaucoma, severe myopia, and cataracts in patients with trisomy 21 strongly predisposes for the development of retinal detachment and poor visual outcome.

ALO 2145 reduces the intraocular pressure elevation after anterior segment laser surgery.

The effect of an alpha adrenergic agonist, ALO 2145 (para-amino-clonidine [PAC]), was examined in a double-masked, multicenter study on the postoperative intraocular pressure (IOP) elevation after laser surgery in 165 patients (83 trabeculoplasty, 36 iridotomy, and 46 capsulotomy). One drop of 1.0% ALO 2145 or vehicle was instilled 1 hour before and immediately after laser surgery. The mean IOP increase in the ALO 2145-treated group was lower (P less than 0.05) than in the placebo group at each of the first three postoperative hours. Overall, 18% of placebo-treated eyes experienced IOP increases greater than or equal to 10 mmHg as compared with 4% of ALO 2145-treated eyes (P less than 0.003). Ocular and systemic side effects were minimal and did not differ between the treatment groups. ALO 2145 safely and effectively reduced the incidence and magnitude of potentially harmful IOP elevations after anterior segment laser surgery.