Steven M. Podos

Abnormalities of Central Contrast Sensitivity in Glaucoma

The detectability of foveally presented low-contrast flickering stimuli was determined for glaucoma patients, ocular hypertensives, and normal control subjects. Two types of stimuli, a homogeneous flickering field, and a counterphase flickering grating of low spatial frequency, were presented on a screen subtending 4 degrees of visual angle. The average of the contrast sensitivities to these two simuli (defined as the dynamic response coefficient) was consistently lower in glaucomatous than in normotensive eyes. The dynamic response coefficient was also below normal in half the ocular hypertensive eyes.

Pattern electroretinograms and visual-evoked potentials in glaucoma and multiple sclerosis.

Steady-state visual-evoked potentials and electroretinograms were simultaneously recorded in four patients with glaucoma and in five patients with multiple sclerosis. The stimuli included a homogenous field and a 2.3 cycles per degree sinusoidal grating that were counter-phase modulated at the rate of 7.5 Hz. We used narrow bandwidth spectral analysis to measure the response amplitudes and signal-to-noise ratios. Transient pattern visual-evoked potentials (1 Hz) were also measured for latency in each eye. We found abnormal pattern electroretinograms, based on the absence of a significant second harmonic component, in three of the four glaucomatous eyes although the homogenous field electroretinograms were normal. In the patients with multiple sclerosis, the pattern electroretinograms were abnormal in two eyes, but the transient visual-evoked potential latency had the highest diagnostic yield (seven of ten eyes).

Maintaining Mitochondrial Membrane Impermeability: An Opportunity for New Therapy in Glaucoma?

Apoptosis may contribute to retinal ganglion cell loss in glaucoma and glaucoma models. Recent research has suggested that mitochondrially dependent apoptosis signaling may contribute to apoptosis in a rat model of glaucoma involving chronic increases in intraocular pressure. In some forms of apoptosis, mitochondrially dependent signaling involves increases in mitochondrial membrane permeability and the mitochondrial release of factors that signal for cell degradation. Opening of a multi-protein, mitochondrial megapore is one factor that contributes to the increased permeability and some anti-apoptotic proteins, particularly BCL-2 and BCL-X(L), bind at the megapore and facilitate megapore closure and reduce increases in mitochondrial membrane permeability. Phosphorylated protein kinase B (Akt) serves as an integrator for cellular survival signals and facilitates the megapore actions of BCL-2 and BCL-X(L), which could protect retinal ganglion cells against insults that induce apoptosis. Several anti-apoptotic agents are being evaluated for use in glaucoma, including brimonidine and propargylamines, which oppose mitochondrially dependent apoptosis through pathways involving phosphorylated Akt.

Maintained reduction of intraocular pressure by prostaglandin F2α-1-isopropyl ester applied in multiple doses in ocular hypertensive and glaucoma patients

In a randomized, double-masked, placebo-controlled study, 0.25 microgram (n = 11) or 0.5 microgram (n = 13) of prostaglandin F2 alpha-1-isopropyl ester (PGF2 alpha-IE) was applied topically twice daily for 8 days to one eye of ocular hypertensive or chronic open-angle glaucoma patients. Compared with contralateral, vehicle-treated eyes, PGF2 alpha-IE significantly (P less than 0.05) reduced intraocular pressure (IOP), beginning 4 hours after the first 0.5-microgram dose and lasting at least 12 hours after the fourteenth dose, with a significant (P less than 0.005) mean reduction of 4 to 6 mmHg maintained throughout the last day of therapy with either dose. A contralateral effect was not observed. Mean tonographic outflow facility was significantly (P less than 0.05) higher in PG-treated compared with vehicle-treated eyes (0.17 +/- 0.02 versus 0.12 +/- 0.01 microliter/minute/mmHg, respectively; +/- standard error of the mean) for the 0.5 microgram dose. Conjunctival hyperemia reached a maximum at 30 to 60 minutes after PGF2 alpha-IE application. Some patients reported mild irritation lasting several minutes after some doses. Visual acuity, accommodative amplitude, pupillary diameter, aqueous humor flare, anterior chamber cellular response, Schirmers test, pulse rate, and blood pressure were not significantly altered. Our findings show that PGF2 alpha-IE is a potent ocular hypotensive agent and a promising drug for glaucoma therapy.

A comparative study of latanoprost (Xalatan) and isopropyl unoprostone (Rescula) in normal and glaucomatous monkey eyes

Latanoprost (PhXA41, Xalatan) and isopropyl unoprostone (UF-021, unoprostone, Rescula) two new prostanoid derivatives, have been shown to reduce intraocular pressure (IOP) significantly in patients with glaucoma or ocular hypertension. This study was designed to compare the ocular hypotensive effects of latanoprost and unoprostone in cynomologus monkeys with glaucoma and characterizes the prostanoids mechanisms of action in normal cynomolgus monkey eyes. Intraocular pressure was measured daily at 0, 0.5, and 1 hour and hourly for 5 additional hours during 1 baseline day, 1 vehicle-treated day, and 5 days of therapy with either 0.005% latanoprost or 0.12% unoprostone applied twice daily, at 9:30 AM and 3:30 PM, to the glaucomatous eye of eight monkeys with unilateral laser-induced glaucoma. Outflow facility was measured in six normal monkeys 3 hours prior to dosing and 1 hour after unilateral dosing with either drug. Aqueous humor flow rates were measured in six normal monkeys hourly for 4 hours on 1 baseline day and on 1 treatment day beginning 1 hour after administration of either drug to one eye. Intraocular pressure was significantly (P < 0.005) reduced after the first application for 4 hours with latanoprost and for 2 hours with unoprostone, up to 5.4 +/- 0.8 mm Hg (mean +/- SEM) (latanoprost) and 3.8 +/- 0.5 mm Hg (unoprostone). Intraocular pressure was significantly (P < 0.005) reduced for at least 18 hours following each PM dose of latanoprost. Intraocular pressure was not reduced (P > .05) 18 hours after each PM dose of unoprostone. An enhancement of the ocular hypotensive effect was observed from day 1 to day 5 with repeated dosing of either drug. Latanoprost produced a greater magnitude of IOP reduction for a longer duration of time than unoprostone after each application. Neither drug altered outflow facility or aqueous humor flow rates. Latanoprost and unoprostone appear to reduce IOP in monkeys by enhancing uveoscleral outflow. Latanoprost appears to be more efficacious and potent than unoprostone in reducing IOP in glaucomatous monkey eyes.

Signs of early damage in glaucomatous monkey eyes: Low spatial frequency losses in the pattern ERG and VEP

Experimental glaucoma was created in one eye of three cynomolgus monkeys by argon laser application to the mid-trabecular meshwork. Simultaneous pattern electroretinograms (PERG) and pattern visual evoked potentials (PVEP) were measured in both control and glaucoma eyes to spatial frequencies of 0.5, 1.25, 2.5, and 3.5 cpd which were counterphase modulated at 6 Hz. The transient flash electroretinogram was also measured. While normal flash electroretinograms were recorded in all eyes both before and after the unilateral production of elevated intraocular pressure (IOP), reductions in PERG and PVEP amplitude were seen in the eyes with glaucoma as early as two weeks following a sustained increase of IOP, despite the absence of cupping of the optic nervehead judged by ophthalmoscopic examination and analysis of photograph by two observers. Optic nervehead abnormalities occurred subsequently. In glaucomatous monkey eyes, the earliest PERG and PVEP changes were most evident with lower spatial frequencies of stimulation. Our data suggest that the optimal stimulus parameters for the detection of early glaucoma are low spatial frequency patterns presented at a rapid rate of temporal modulation.

Long-Term Results of Valve Implants in Filtering Surgery for Eyes with Neovascular Glaucoma

Filtration surgery was performed with a pressure-sensitive, unidirectional valve implant in 79 eyes with neovascular glaucoma. The device consisted of an open Supramid tube (outside diameter 0.58 mm) sealed to a Silastic tube with a slit valve. The Supramid tube was inserted at the corneoscleral limbus 1 to 4 mm into the anterior chamber. The Silastic portion was located under a scleral flap. Of the 79 eyes, 53 had postoperative intraocular pressures less than or equal to 24 mm Hg after a mean follow-up period of 23.7 +/- 10.9 months. Bleb revision for external scarring was required in ten of these 53 eyes and postoperative medical therapy was required in 26. The valve implant failed to control intraocular pressure in 26 of the 79 eyes. Failure was secondary to scarring of the external bleb in 18 eyes and to closure of the internal Supramid tube in five eyes. Mortality during the follow-up period was high: 12 of the 53 successfully treated patients and five of the unsuccessfully treated patients died.

Filtering Valve Implant Surgery for Eyes with Neovascular Glaucoma

We performed filtration surgery with a unidirectional, pressure-sensitive valve implant in 40 eyes with neovascular glaucoma. The device consisted of an open Supramid tube (outside diameter 0.58 mm, inside diameter 0.38 mm) sealed to a Silastic tube with a slit valve. The Supramid tube was inserted at the corneoscleral limbus 1 to 4 mm into the anterior chamber and the Silastic portion was located under a lamellar scleral flap. Twenty-seven of 40 eyes (68%) had a postoperative IOP less than or equal to 24 mm Hg with a mean follow-up of 13.8 months. Ten of these 27 eyes required postoperative medical therapy to achieve this level of IOP control. The glaucoma valve implant failed to return IOP to normal in 13 of the 40 eyes (32%), 11 of these as a consequence of scarring of the external bleb.

The Effect of Topically Administered Carbonic Anhydrase Inhibitors on Aqueous Humor Dynamics in Rabbits

Repeated topical administration of 2.5% trifluormethazolamide, a halogenated derivative of methazolamide, resulted in a unilateral decrease in intraocular pressure in rabbits. Mean (+/- S.E.M.) baseline intraocular pressure (19.8 +/- 2.1 mm Hg) was significantly (P less than .05) decreased 30 minutes (16.1 +/- 2.2 mm Hg) and 60 minutes (15.8 +/- 2.7 mm Hg) after drug administration. Trifluormethazolamide did not alter outflow facility. Aqueous humor flow calculated from the tonographic data was reduced 44% and flow measured by fluorophotometry was reduced 29%. Topical delivery of trifluormethazolamide decreased the level of carbon dioxide in the aqueous humor in the treated eye in a manner similar to that observed after systemic administration of carbonic anhydrase inhibitors. Topical administration of 10% acetazolamide did not decrease intraocular pressure. However, topical administration of either trifluormethazolamide or acetazolamide before oral administration of water resulted in a blunting of the water-induced ocular hypertensive response.

Microbial contamination of medications used to treat glaucoma.

AIMS--A study was conducted to estimate the frequency of contamination of topical antiglaucoma medications used by asymptomatic patients. METHODS--The drops and the bottle tips of 194 in use topical medications and the conjunctiva from 109 treated glaucoma patients were cultured. RESULTS--Bacteria were recovered from 55 (28%) medications. The bottle tip was more frequently contaminated than the drops (p = 0.008). Gram positive organisms were cultured from 50 (91%) of 55 contaminated medications. Thirteen patients (12%) had the same microorganism recovered from the conjunctiva and from the contaminated medication. The frequency of contamination of medications increased with increasing duration of use. Bacterial contamination occurred in 19% of eyedrops less than 8 weeks old in contrast with 40% of bottles used for more than 8 weeks. CONCLUSION--Our data suggest that ocular medications to treat glaucoma frequently become contaminated with bacteria and that contamination is related to duration of use. We therefore recommend that opened topical antiglaucoma eyedrops should be replaced on a regular basis.