Background Primary open-angle glaucoma (POAG) is one of the leading causes of blindness in the United States and worldwide. Three to 6 million people in the United States are at increased risk for developing POAG because of elevated intraocular pressure (IOP), or ocular hypertension. There is no consensus on the efficacy of medical treatment in delaying or preventing the onset of POAG in individuals with elevated IOP. Therefore, we designed a randomized clinical trial, the Ocular Hypertension Treatment Study. Objective To determine the safety and efficacy of topical ocular hypotensive medication in delaying or preventing the onset of POAG. Methods A total of 1636 participants with no evidence of glaucomatous damage, aged 40 to 80 years, and with an IOP between 24 mm Hg and 32 mm Hg in one eye and between 21 mm Hg and 32 mm Hg in the other eye were randomized to either observation or treatment with commercially available topical ocular hypotensive medication. The goal in the medication group was to reduce the IOP by 20% or more and to reach an IOP of 24 mm Hg or less. Main Outcome Measures The primary outcome was the development of reproducible visual field abnormality or reproducible optic disc deterioration attributed to POAG. Abnormalities were determined by masked certified readers at the reading centers, and attribution to POAG was decided by the masked Endpoint Committee. Results During the course of the study, the mean ± SD reduction in IOP in the medication group was 22.5% ± 9.9%. The IOP declined by 4.0%± 11.6% in the observation group. At 60 months, the cumulative probability of developing POAG was 4.4% in the medication group and 9.5% in the observation group (hazard ratio, 0.40; 95% confidence interval, 0.27-0.59; P Conclusions Topical ocular hypotensive medication was effective in delaying or preventing the onset of POAG in individuals with elevated IOP. Although this does not imply that all patients with borderline or elevated IOP should receive medication, clinicians should consider initiating treatment for individuals with ocular hypertension who are at moderate or high risk for developing POAG.

https://jamanetwork.com/journals/jamaophthalmology/articlepdf/270953/ecs20045.pdf

The Ocular Hypertension Treatment Study: A Randomized Trial Determines That Topical Ocular Hypotensive Medication Delays or Prevents the Onset of Primary Open-Angle Glaucoma

Objective To provide the results of the Early Manifest Glaucoma Trial, which compared the effect of immediately lowering the intraocular pressure (IOP), vs no treatment or later treatment, on the progression of newly detected open-angle glaucoma. Design Randomized clinical trial. Participants Two hundred fifty-five patients aged 50 to 80 years (median, 68 years) with early glaucoma, visual field defects (median mean deviation, −4 dB), and a median IOP of 20 mm Hg, mainly identified through a population screening. Patients with an IOP greater than 30 mm Hg or advanced visual field loss were ineligible. Interventions Patients were randomized to either laser trabeculoplasty plus topical betaxolol hydrochloride (n = 129) or no initial treatment (n = 126). Study visits included Humphrey Full Threshold 30-2 visual field tests and tonometry every 3 months, and optic disc photography every 6 months. Decisions regarding treatment were made jointly with the patient when progression occurred and thereafter. Main Outcome Measures Glaucoma progression was defined by specific visual field and optic disc outcomes. Criteria for perimetric progression were computer based and defined as the same 3 or more test point locations showing significant deterioration from baseline in glaucoma change probability maps from 3 consecutive tests. Optic disc progression was determined by masked graders using flicker chronoscopy plus side-by-side photogradings. Results After a median follow-up period of 6 years (range, 51-102 months), retention was excellent, with only 6 patients lost to follow-up for reasons other than death. On average, treatment reduced the IOP by 5.1 mm Hg or 25%, a reduction maintained throughout follow-up. Progression was less frequent in the treatment group (58/129; 45%) than in controls (78/126; 62%) ( P =.007) and occurred significantly later in treated patients. Treatment effects were also evident when stratifying patients by median IOP, mean deviation, and age as well as exfoliation status. Although patients reported few systemic or ocular conditions, increases in clinical nuclear lens opacity gradings were associated with treatment ( P = .002). Conclusions The Early Manifest Glaucoma Trial is the first adequately powered randomized trial with an untreated control arm to evaluate the effects of IOP reduction in patients with open-angle glaucoma who have elevated and normal IOP. Its intent-to-treat analysis showed considerable beneficial effects of treatment that significantly delayed progression. Whereas progression varied across patient categories, treatment effects were present in both older and younger patients, high- and normal-tension glaucoma, and eyes with less and greater visual field loss.

http://bmec.swbh.nhs.uk/wp-content/uploads/2013/03/Early-Manifest-Glaucoma-Trial.pdf

Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial.

Early manifest glaucoma trial group. reduction of intraocular pressure and glaucoma progression: results from the early manifest glaucoma trial

http://academic.oup.com/milmed/article-pdf/146/7/506/24126715/milmed-146-7-506.pdf

Goodman and Gilman's The Pharmacological Basis of Therapeutics

The impact of ocular blood flow in glaucoma.

• In a case-control study using an exploratory health questionnaire, we examined the relationship between primary open angle glaucoma (POAG) and a variety of personal characteristics and potential toxic exposures in patients in a general eye service. There were 83 patients with definite POAG, 121 POAG suspects, and 237 controls. Using multiple logistic regression analysis for simultaneous evaluation of potential risk factors, we found that black race (rate ratio = 6.8; 95% confidence interval [CI] = 2.8 to 16.0) and untreated systolic hypertension (rate ratio = 5.8; 95% CI = 2.2 to 15) were the most important risk factors. Current cigarette smoking was also associated with glaucoma (rate ratio = 2.9; 95% CI = 1.3 to 6.6). Suggestive associations were found with family history of glaucoma, definite or borderline diabetes, and myopia. The effects of many of these personal characteristics and exposures as risk factors were also noted for the glaucoma suspect group, though not as strongly as for the definite glaucoma cases.

A Case-Control Study of Risk Factors in Open Angle Glaucoma

Aqueous outflow resistance of enucleated human eyes was measured at 7 and 25 mm Hg before and after partial and complete (12 clock hours) internal trabeculotomy. Following complete trabeculotomy, 71% of the resistance was eliminated at 25 mm Hg while only 49% was eliminated at 7 mm Hg. In contrast to published findings in eyes with intact trabecular meshwork where the resistance increased with increasing IOP (1), following complete trabeculotomy, the resistance decreased 2% per mm Hg with increasing IOP. Experiments with trabeculotomy limited to part of the circumference showed that a one hour trabeculotomy produced 41% (25 mm Hg) to 60% (7 mm Hg) of the effect of a twelve hour trabeculotomy. The results indicate that a surprisingly high fraction of aqueous outflow resistance resides in the distal aspects of the outflow system at normal IOP, and that this distal resistance drops as IOP is increased.

Outflow resistance of enucleated human eyes at two different perfusion pressures and different extents of trabeculotomy.

A Long-term Clinical Trial of Timolol Therapy Versus No Treatment in the Management of Glaucoma Suspects

Nine eyes of five cynomolgus monkeys were perfused through the anterior chamber with cationized ferritin (CF) at normal and increased intraocular pressure. After perfusion with glutaraldehyde, the morphologic appearance of the endothelial lining of Schlemm's canal (SC) and of the adjacent regions was analyzed using tangential and sagittal serial sections. The CF, which binds to negatively charged surfaces, was observed to be adherent to the free surfaces of trabecular cell membranes and to accumulate in the cribriform layer underlining the endothelial lining of SC. Tangential sections of the inner-wall endothelium demonstrated that separations of the adjacent cell membranes occur between the tight junctions forming openings or lacunae and bent, tunnel-like channels that represent continuous paracellular pathways. Complete staining of these inner-wall paracellular pathways with CF were observed indicating that the adjoining membranes are negatively charged and that the perfused fluid had passed through these intercellular channels. These paracellular pathways appeared enlarged and were more easily identified at elevated perfusion pressure. In general, intracytoplasmic vacuoles demonstrated heavy staining with CF on their luminal surface but only faint staining on the adluminal (cribriform-facing) surface. Apparent giant vacuoles were observed to be often not real intracellular vacuoles but rather dilatations of the paracellular spaces. This study demonstrates that there are paracellular routes through the inner-wall endothelium by which high molecular-weight substances such as ferritin and macrophages can leave the anterior chamber. Probably there are both transcytoplasmic and paracellular mechanisms of aqueous outflow that may vary under different conditions of pressure or flow.

David L. Epstein

Papers

A Case-Control Study of Risk Factors in Open Angle Glaucoma

Outflow resistance of enucleated human eyes at two different perfusion pressures and different extents of trabeculotomy.

A Long-term Clinical Trial of Timolol Therapy Versus No Treatment in the Management of Glaucoma Suspects

Morphology of the trabecular meshwork and inner-wall endothelium after cationized ferritin perfusion in the monkey eye.

Obstruction of Aqueous Outflow by Sodium Hyaluronate in Enucleated Human Eyes