David L. Epstein

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

One hundred seven patients with intraocular pressures (IOPs) between 22 and 28 mmHg with normal visual fields on Goldmann perimetry and without evidence of optic nerve damage were randomly assigned to either a timolol treatment (TT) or a no treatment (NT) arm in a prospective clinical trial. The patients were followed for an average of 56 and 51 months, respectively. Criteria for failure were a confirmed IOP of greater than 32 mmHg, stereophotographically documented optic nerve progression, or development of glaucomatous visual field loss by Goldmann or Octopus perimetry. Nine patients failed in the TT group and 17 in the NT group (P = 0.07). Of the nine TT group failures, six had discontinued timolol before failure (4 for greater than 6 months). In a Cox proportional hazards analysis controlling for confounding variables, timolol was found to be significantly protective with an adjusted risk ratio of 0.38 (95% confidence interval = 0.16-0.89, P = 0.03). When only field and disc failure criteria were considered, timolol treatment was found to be significantly protective in an analysis considering patients who stopped timolol as being lost to follow-up (P = 0.05). A higher tonographic facility of outflow was protective in all analyses. A trend toward a substantial loss of effectiveness of timolol on IOP was not observed. Seasonal fluctuations in IOP were observed (P = 0.0007), with higher IOP occurring in the winter. The results demonstrate a favorable influence of timolol therapy on the clinical course of patients with mildly elevated IOP.(ABSTRACT TRUNCATED AT 250 WORDS)

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

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.

Obstruction of Aqueous Outflow by Sodium Hyaluronate in Enucleated Human Eyes

Instillation of sodium hyaluronate into the anterior chambers of enucleated human eyes caused a 65% decrease in outflow facility (from 0.33 +/- 0.16 microliters/min/mm Hg to 0.08 +/- 0.02 microliters/min/mm Hg). Vigorous anterior chamber irrigation, performed either immediately or three hours after introduction of the sodium hyaluronate, failed to relieve this obstruction. However, irrigation with hyaluronidase restored the facility values to baseline. Tying limbal or corneal 9-0 nylon sutures (for example, in cataract surgery), followed by instillation of sodium hyaluronate into the anterior chamber and subsequent irrigation, produced an overall decrease of 76% in outflow facility (final outflow values were 0.08 +/- 0.03 microliters/min/mm Hg in eyes with corneal wounds and 0.08 +/- 0.04 microliter/min/mm Hg in eyes with limbal wounds). Postoperative intraocular pressure should be monitored closely when sodium hyaluronate is used in cataract surgery. Irrigating the anterior chamber with balanced salt solution after using sodium hyaluronate does not eliminate the possibility of severe postoperative glaucoma.

A Double-Masked Comparison of Betaxolol vs Timolol in the Treatment of Open-Angle Glaucoma

We conducted a six-month prospective, double-masked randomized trial comparing betaxolol with timolol at 0.25% and 0.5% concentrations in the treatment of primary open-angle glaucoma in 38 patients. To qualify, patients had to demonstrate an average intraocular pressure in at least one eye of greater than or equal to 26 mm Hg without treatment. The median intraocular pressure was consistently lower in the timolol group than in the betaxolol group (after four weeks of therapy, it was 20.2 mm Hg for timolol vs 22.5 mm Hg for betaxolol; P less than .04). Adjunctive therapy was required in eight patients in the betaxolol group compared to one in the timolol group (P less than .05). Betaxolol appears to be a clinically effective and safe agent in the treatment of open-angle glaucoma. However, the magnitude of the decrease in intraocular pressure with it may not be as great as that with timolol and there may be a greater need for adjunctive therapy with it than with timolol.

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.

Experimental perfusions through the anterior and vitreous chambers with possible relationships to malignant glaucoma.

Enucleated eyes were perfused alternately via the anterior and vitreous chambers. At low intraocular pressure (IOP), vitreous humor presented considerable resistance to forward flow of perfusion fluid in calf eyes, but not in human eyes. In human eyes when the perfusion pressure was increased to 60 mm Hg, the resistance to flow forward from the vitreous body increased, but became practically nil again when the IOP was decreased. At high pressure the volume of the vitreous body apparently increases and the anterior hyaloid membrane probably presses against the ciliary body, reducing the area of hyaloid membrane through which fluid can flow. Whether increased perfusion pressure can in some other manner change the permeability of human vitreous to resemble that of the calf remains unanswered. Our results suggest that factors other than, or in addition to, simple diversion of aqeous humor must be important in malignant glaucoma.

Neodymium-Yag Laser Therapy to the Anterior Hyaloid in Aphakic Malignant (Ciliovitreal Block) Glaucoma

In three aphakic eyes and two eyes with intraocular lens implants (five patients, four women and one man, ranging in age from 65 to 76 years) persistent shallow or flat anterior chamber was observed despite multiple patent laser or surgical iridectomies. In each case direct application of the neodymium-YAG laser (3 to 11 mJ) to the anterior hyaloid face resulted in immediate deepening of the anterior chamber. This deepening was sustained in four of the cases. These results confirm previous observations suggesting that the anterior hyaloid can be the locus of abnormality in aphakic malignant (ciliovitreal block) glaucoma. Neodymium-YAG hyaloidotomy may be better than penetrating surgery in such cases.

Serum Obstruction of Aqueous Outflow in Enucleated Eyes

We perfused enucleated human eyes via the anterior chamber by the constant pressure technique. Infusion of human serum into the anterior chamber of enucleated human eyes for 30 minutes at 23 mm Hg pressure induced a 42% decrease in facility of outflow, which was not relieved by irrigation of the anterior chamber with balanced salt solution or alpha-chymotrypsin. Diluted serum also reduced the facility of outflow. Measured in a glass viscometer, diluted serum had less viscosity than undiluted, but interfered with outflow from the eye more than anticipated on the basis of viscosity alone. When we used lens depression to induce tension on the iridocorneal angle to simulate the effects of contraction of the ciliary muscle, outflow facility increased in control eyes that had not been exposed to serum and in serum-perfused eyes. However, the partial obstruction to outflow that had been induced by serum persisted. Normal serum components may become adsorbed or entrapped in the aqueous outflow system so as to obstruct outflow, and this may result in secondary glaucoma in eyes with chronic uveitis.

Trabecular meshwork recovery after phagocytic challenge

The short and long term response of the trabecular meshwork to a phagocytic challenge and the response of the meshwork to different types of foreign particles was studied by injecting one eye of 25 adult cats with a phagocytic agent (zymosan, blood, or latex microspheres) while the fellow eye received a control solution. Eyes were examined histologically at various intervals from one day to five months after infusion. Active trabecular cell phagocytosis and changes in cell shape were found with all agents. The extent of these changes varied with the agent used. Zymosan caused marked changes and inflammation, with numerous macrophages found throughout the meshwork. Trabecular cell migration and cell loss occurred, although it was often difficult to distinguish macrophages from rounded trabecular cells. The meshwork eventually recovered from this inflammatory insult, as trabecular lamellae became less edematous and once again acquired a lining of trabecular cells. Blood and latex microspheres caused less disruption, with microspheres often found in otherwise normal appearing cells. Trabecular cellularity was quantitated after the blood and the zymosan infusions. No cell loss was observed after the blood infusion, while zymosan-infused eyes had an initial 15% cell loss (p less than .04) when compared with fellow control eyes. This zymosan-associated trabecular cell loss may have been due to phagocytosis, inflammation, or a combination of both. The cell loss had recovered by the end of 150 days (p less than .02), as trabecular cell numbers in experimental eyes became comparable to fellow control eyes.

Diagnosis and management of lens-induced glaucoma.

Lens-induced glaucoma may occur as either secondary angle-closure or open-angle glaucoma. Dislocation or swelling of the lens can cause pupillary block and subsequent angle-closure glaucoma. Leakage of soluble lens proteins from a relatively intact cataractous lens can result in a severe secondary open-angle glaucoma (phacolytic glaucoma). Heavy molecular weight protein, believed to be of lens origin, has now been identified in 12 of 12 anterior chamber specimens from such patients. This liberated lens protein can directly obstruct the trabecular outflow pathways. After extracapsular cataract surgery or after lens trauma, liberated fragments of lens material may mechanically impair the drainage of aqueous humor through the outflow channels (lens particle glaucoma). The diagnosis and management of these different lens-induced glaucomas are reviewed. With proper recognition, these glaucomas are promptly cured by the surgical removal of the lens (material).