Anecdotal case reports describe the occurrence of cystoid macular edema, iritis, herpes simplex keratitis, periocular skin darkening, and headaches in patients treated with prostaglandin analogs for glaucoma. The purpose of this article is to critically analyze these anecdotal case reports in light of a few well-controlled, randomized clinical studies to determine whether conclusions can be made about a causal relationship between the use of prostaglandin analogs and the occurrence of these side effects. None of these putative side effects has been proven to be causally related to latanoprost therapy using valid scientific methodology. These possible side effects occur rarely. Cystoid macular edema, iritis, and herpes simplex keratitis occur in eyes with risk factors. To scientifically establish a causal relationship between drug therapy and rare side effects, repeated rechallenging with masked controls is required. With rare exception, such methodology has not been used with any of these putative side effects. Nevertheless, even without firm establishment of a causal relationship, caution is advised with the use of prostaglandin analogs in eyes with risk factors for cystoid macular edema, iritis, and herpes simplex keratitis until properly designed, large, controlled studies provide more definitive information.

Published reports of the occurrence of cystoid macular edema (CME) in eyes being treated with latanoprost have led to concern regarding a possible causal relation between the two. Review of all published cases (28 eyes in 25 patients), plus another case reported here for the first time, indicates that all eyes had independent risk for development of CME, so that definitive conclusions about a causal relation cannot be established. In addition, controlled clinical trials and experimental studies with latanoprost have given no indication that latanoprost causes clinical CME. Pharmacokinetic considerations indicate that the concentration of latanoprost expected in the posterior segment of the eye is too low to have a pharmacologic effect, and latanoprost is not known to exhibit vasoactive or inflammatory properties. Nevertheless, reports of a possible association between CME and latanoprost use must be given serious consideration, and in eyes that are at risk for CME, an increased level of surveillance for its development is recommended.

Prostaglandin (PG) analogues have recently been introduced for the pharmacological reduction of intraocular pressure (IOP) in the treatment of glaucoma (Alm et al. 1995; Mishima et al. 1996; Camras et al. 1996a, b; Watson etal.1996,1998).One such agent,latanoprost (13,14-dihydro-17-phenyl-18,19,20-trinor- PGF22α-isopropyl ester), has been available commercially in the United States since September 1996 and in numerous other regions worldwide soon thereafter.

PURPOSE:To create an experimental glaucoma monkey model using high-power diode laser photocoagulation of the trabecular meshwork, and to compare this with the experimental glaucoma monkey model induced by argon laser photocoagulation of the trabecular meshwork. METHODS:One eye each of eight adult cynomolgus monkeys underwent repeated application of diode laser photocoagulation of the trabecular meshwork until sustained intraocular pressure (IOP) elevation was achieved. 50 to 120 spots were applied to midtrabecular meshwork for 360 degrees; spot size, 75 microns; power, 1.2 W; duration, 0.5 seconds. Intraocular pressure, tonographic outflow facility, and ophthalmoscopically and photographically documented optic nerve head evaluations were carried out before and after treatment. Data were compared retrospectively with similar data from an experimental glaucoma monkey model after argon laser photocoagulation of the trabecular meshwork (n = 10). RESULTS:The average number of laser treatments to achieve stable IOP elevation was 3.0 with both diode and argon laser trabecular treatments (p > 0.99). On week 4 after initial pressure elevation, peak IOP was greater--(p < 0.05) 43.0 mmHg +/- 2.4 mmHg (mean +/- SEM) and 37.4 mmHg +/- 1.3 mmHg--in the diode laser-induced than in the argon laser-induced glaucomatous eyes, respectively. Outflow facility (microliter/min/mmHg) was reduced (p < 0.001) in both diode (0.09 +/- 0.01 microliter/min/mmHg) and argon (0.10 +/- 0.01 microliter/min/mmHg) laser-induced glaucomatous eyes compared with untreated fellow eyes. Both the diode and argon laser techniques produced the earliest signs of optic nerve head excavation within about one month of IOP elevation. CONCLUSIONS:Repeat diode laser photocoagulation of the trabecular meshwork produced higher (p < 0.05) IOP elevation than argon laser photocoagulation of the trabecular meshwork in this study. No significant differences in outflow facility and optic nerve head change were observed between these two laser techniques. The experimental glaucoma monkey model can be created with either the diode or argon laser photocoagulation of the trabecular meshwork.

PURPOSE: To determine the efficacy and safety of latanoprost treatment for 1 year in glaucoma patients, and to evaluate the effects of switching from timolol to latanoprost therapy.METHODS: Latanoprost 0.005% was topically applied once daily without masking for 6 months in 223 patients with elevated intraocular pressure after previous treatment with latanoprost once daily or 0.5% timolol twice daily for 6 months in a multicenter, randomized, double masked, parallel group study.RESULTS: Compared with baseline values before treatment, a significant (P < .0001) diurnal reduction in intraocular pressure of 6 to 8 mm Hg was maintained with minimal fluctuation for the duration of treatment. When treatment was switched from timolol to latanoprost, intraocular pressure was reduced by 1.5 +/- 0.3 mm Hg (mean +/- SEM; 8% change in intraocular pressure; 31% of the intraocular pressure reduction produced by timolol; P < .001) compared with the change in intraocular pressure in patients remaining on latanoprost therapy. Of the patients initially enrolled, 95% successfully completed treatment. There was a slight overall increase in conjunctival hyperemia in patients who switched from timolol to latanoprost, but no change in those who continued latanoprost. The timolol-induced reduction of resting heart rate returned to baseline levels after switching to latanoprost. Of the 247 patients treated with latanoprost during the masked and/or open label studies, 12 (5%) demonstrated a definite (n = 4) or possible (n = 8) increase in iris pigmentation.CONCLUSIONS: Latanoprost is a well-tolerated ocular hypotensive agent that appears to be more effective than timolol in reducing intraocular pressure. The increase in iris pigmentation appears to be harmless but requires further investigation. (C) 1998 by Elsevier Science Inc. All rights reserved.

PURPOSE:Neurochemical changes in nerve cells were investigated in the lateral geniculate nucleus (LGN) and primary visual cortex of macaque monkeys with experimentally induced glaucoma.METHODS:Glaucomatous damage was induced in one eye of experimental animals by elevation of intraocular pressure following laser burns to the trabecular meshwork. Staining for the metabolic marker cytochrome oxidase, as well as immunolabelling for the neuronal markers synaptophysin and neurofilament proteins, was conducted on sections of the LGN and primary visual cortex.RESULTS:In the LGN, staining for cytochrome oxidase and immunolabelling for synaptophysin were reduced in the parvocellular and magnocellular layers that received input from the glaucomatous eye and neurofilament protein labelling was reduced in the parvocellular layers. Cytochrome oxidase staining demonstrated the presence of denervated ocular dominance columns in layer IVC of the primary visual cortex of experimental animals.CONCLUSIONS:Pre- and post-synaptic neurochemical alterations in the magnocellular and parvocellular visual pathways of the brain are associated with experimentally induced glaucoma in macaque monkeys.

Objective: To explore the possibility that the excitatory amino acid glutamate might be associated with the disease process of glaucoma, which is characterized by the death of retinal ganglion cell neurons and subsequent visual dysfunction.Methods: Amino acid analyses were performed on vitreous specimens that were obtained from patients who were undergoing cataract extraction. Samples were collected prospectively from those patients who sustained inadvertent rupture of the posterior capsule between 1988 and 1993. An additional set of specimens, obtained from both eyes of monkeys, was analyzed; in these monkeys, glaucoma had been experimentally induced in one eye only.Results: A twofold elevation in the level of glutamate was detected in the vitreous body of the group of patients with glaucoma when compared with that in a control population of patients with cataracts only. An even greater elevation of the glutamate level was found in the vitreous body of glaucomatous eyes of monkeys when compared with that in control eyes. No statistical differences were detected among other amino acid levels from the vitreous body of glaucomatous and nonglaucomatous eyes in humans or monkeys.Conclusions: The excitatory amino acid glutamate is found in the vitreous body of glaucomatous eyes at concentrations that are potentially toxic to retinal ganglion cells. The increased level of this known neurotoxin is consistent with an ''excitotoxic'' mechanism for the retinal ganglion cell and optic nerve damage in glaucoma. Therapies to protect neurons against glutamate toxic effects may prove to be useful in the management of this blinding disease.

PURPOSE: We used a modified technique to construct the trabeculectomy flap. METHODS: The technique involved the creation of a scleral tunnel as is used in phacoemulsification surgery for cataract. RESULTS: We have used this technique in our most recent 90 cases. We believe it is an easier technique to perform than conventional flap dissection, and that it yields improved flap construction. CONCLUSIONS: The scleral tunnel flap technique offers a number of advantages over standard flap construction in trabeculectomy surgery.

The vulnerability of subpopulations of retinal neurons delineated by their content of cytoskeletal or calcium-binding proteins was evaluated in the retinas of cynomolgus monkeys in which glaucoma was produced with an argon laser. We quantitatively compared the number of neurons containing either neurofilament (NF) protein, parvalbumin, calbindin or calretinin immunoreactivity in central and peripheral portions of the nasal and temporal quadrants of the retina from glaucomatous and fellow non-glaucomatous eyes. There was no significant difference between the proportion of amacrine, horizontal and bipolar cells labeled with antibodies to the calcium-binding proteins comparing the two eyes. NF triplet immunoreactivity was present in a subpopulation of retinal ganglion cells, many of which, but not all, likely correspond to large ganglion cells that subserve the magnocellular visual pathway. Loss of NF protein-containing retinal ganglion cells was widespread throughout the central (59-77% loss) and peripheral (96-97%) nasal and temporal quadrants and was associated with the loss of NF-immunoreactive optic nerve fibers in the glaucomatous eyes. Comparison of counts of NF-immunoreactive neurons with total cell loss evaluated by Nissl staining indicated that NF protein-immunoreactive cells represent a large proportion of the cells that degenerate in the glaucomatous eyes, particularly in the peripheral regions of the retina. Such data may be useful in determining the cellular basis for sensitivity to this pathologic process and may also be helpful in the design of diagnostic tests that may be sensitive to the loss of the subset of NF-immunoreactive ganglion cells.

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.

Purpose: The authors evaluate a long posterior tube shunt device with a pressure sensitive valve for filtration surgery in eyes with recalcitrant glaucoma.Methods: The device consisted of an anterior chamber tube connected to an oval (13 X 18 mm) episcleral explant. The explant was designed to maximize the area of surrounding encapsulation while still allowing implantation within one quadrant. A pressure-sensitive and unidirectional slit valve in the tube provided resistance to aqueous humor flow. One-stage implantation without the use of restrictive sutures was performed in 50 eyes with various types of glaucoma unresponsive to prior glaucoma surgery.Results: Mean (+/- standard error of the mean) preoperative intraocular pressure (IOP) of 36.4 +/- 1.6 mmHg was reduced significantly (P < 0.001) to 8.3 +/- 1.3 mmHg on the first postoperative day. Mean anterior chamber depth (scale, 0-4+) was 3.4 +/- 0.1. Mean IOP 1 month after surgery was 14.1 +/- 1.3 mmHg. The implant was removed from four eyes due to IOP failure(l eye), external erosion (2 eyes), or endophthalmitis (1 eye). A suprachoroidal hemorrhage occurred in one eye on the first postoperative day. Diplopia developed in one eye after surgery. Mean IOP at last follow-up examination (mean, 25.4 +/- 2.4 months; range, 16-36 months) was 13.1 +/- 1.3 mmHg. Intraocular pressure was 19 mmHg or lower in 80% of the eyes, 59% of which were without adjunctive antiglaucoma medications.Conclusions: Design features of the Krupin Eye Valve with Disk result in a large area of encapsulation in a single ocular quadrant which functions as an external reservoir for passage of aqueous humor. The valve portion facilitates maintenance of anterior chamber depth during the early postoperative interval. This new therapeutic device can be effective in the long-term control of IOP in glaucomatous eyes not responsive to prior filtration surgery with adjunctive antimetabolite therapy.

Contemporary concepts of open angle glaucoma suggest that the current emphasis on reduction of elevated intraocular pressure could be augmented by other therapeutic approaches. In this article, we describe significant recent developments in the molecular and cellular biology and neuropharmacology of nerve damage that are likely, in coming years, to suggest new therapeutic approaches to the management of glaucoma. These developments may lead to the achievement of pharmacologic protection of the optic nerve from damage or possibly promotion of reversal of damage. We review selected studies of excitotoxins and N-methyl-D-aspartate receptor antagonists, Ca(2+)-induced damage and calcium channel blockers, the intracellular messenger nitric oxide and its perturbation, free-radical damage and scavengers, nerve regeneration, and growth factors. Several basic research questions are posed, answers to which may transform our concepts of glaucoma therapy.