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GLAUCOMA UPDATES

 

These Glaucoma Updates have been compiled for you by Professor Helen Danesh-Meyer. Helen is a consultant ophthalmologist with international expertise in glaucoma and neuro-ophthalmology and holds an academic chair in the Department of Ophthalmology, University of Auckland. She is Chairperson of Glaucoma NZ. Helen is also a consultant at Eye Institute Auckland for glaucoma, neuro-ophthalmology and cataract.

 

PAPER 1 - DOWNLOAD

 

Effect of dorzolamide hydrochloride on central corneal thickness in humans with cornea guttata.

Wirtitsch MG. Findl O. Heinzl H. Drexler W. Archives of Ophthalmology. 125(10):1345-50, 2007 Oct.

OBJECTIVE: To investigate the effect of dorzolamide hydrochloride on central corneal thickness in humans with cornea guttata.

DESIGN: Randomized, placebo-controlled, double-masked, 2-drug crossover study with 10 patients with cornea guttata and 10 healthy controls, who had mean endothelial cell counts of 988 and 2377 cells/mm2, respectively. Study medications were 2% dorzolamide and placebo drops applied 3 times a day for 4 weeks. Central corneal thickness measurements using ACMaster (Carl Zeiss Meditec AG, Jena, Germany) and Goldmann applanation tonometry were performed at baseline, 1 day, 1 week, and 4 weeks.

RESULTS: The mean increases in central corneal thickness after 4 weeks in eyes with cornea guttata treated with dorzolamide and placebo were 26.3 µm (95% confidence interval, 8.8 to 43.7) and 3.3 µm (95% confidence interval, –0.5 to 7.1), respectively. No statistically significant changes were measured in the healthy control group. Dorzolamide caused a significant decrease in intraocular pressure (P < .01) while placebo did not cause significant changes (P = .50).

CONCLUSION: Application of dorzolamide for 4 weeks resulted in a statistically significant increase in central corneal thickness in patients with compromised corneal endothelium. These results indicate that patients with corneal endothelial problems receiving dorzolamide therapy should be monitored.

Comment:

Wirtitsch et al. performed a prospective, randomized placebo-controlled two-drug crossover study in a cohort of patients with reduced endothelial counts and compared them to a matched normal group. After four weeks, central corneal thickness increased in patients with compromised endothelium, but not in patients with normal cell counts. Their data suggests that patients with pre-existing endothelial disease are more susceptible to the adverse corneal effects of topical carbonic anhydrase inhibitors.

This suggests that particular attention should be paid to the corneal endothelium especially in patients with compromised endothelium such as Fuch’s dystrophy, bulllous keratopathy, or penetrating keratoplasty. The reason for this is that the enzyme, carbonic anhydrase plays an important role in the pump function of the endothelium to keep the corneal in a relatively steady state of dehydration.

 

PAPER 2 - DOWNLOAD

 

Effects of topical antiglaucoma medications on corneal epithelium as evaluated by gene expression patterns.

Okada Y. Cornea. 26(9 Suppl 1):S46-54, 2007 Oct.

PURPOSE: To examine the expression pattern of the stress-related genes c-fos and c-jun, which encode the 2 major components of activator protein (AP)-1, and cyclooxygenase (COX)-2 in rat corneal epithelium treated with topical antiglaucoma medications and benzalkonium chloride (BAK) preservative.

METHODS: Eighty-eight male Wistar rats were used. We instilled antiglaucoma eye drops (0.5% Timoptol, 0.005% Xalatan, or 0.12% Rescula), their chemical constituents (active ingredients), or BAK preservative (0.005%, 0.01%, or 0.02%) in 1 eye of each rat. Fellow eyes served as controls. The eyes were enucleated after various intervals. In situ hybridization and immunohistochemistry were used to detect expression of c-fos, c-jun, and COX-2.

RESULTS: Expression of c-fos, c-jun, and COX-2 was minimally observed in uninjured rat corneal epithelium. Thirty minutes to 1 hour after applying the antiglaucoma eye drops, signals for c-fos and c-jun mRNA were detected in the corneal epithelium. Ninety minutes after applying 0.005% Xalatan, 0.12% Rescula, or their chemical constituents, but not 0.5% Timoptol, COX-2 was detected in corneal epithelium. Expression of c-fos and c-jun seemed more marked with prostaglandins than with timolol. Thirty minutes to 1 hour after instillation of 0.02% BAK preservative, signals for c-fos and c-jun mRNA were detected in the corneal and conjunctival epithelium. COX-2 was not induced by 0.5% Timoptol or BAK preservative. COX-2 mRNA was not affected by applying 0.005% or 0.01% BAK preservative. Proteins of these components were also detected, indicating that each mRNA expression was followed by protein synthesis.

CONCLUSIONS: Corneal and conjunctival epithelial cells are transcriptionally activated transiently at an early phase after topical administration of antiglaucoma medications and BAK preservative. Stimulatory effects of prostaglandin drugs on corneal epithelial cells were more marked than those with timolol. Expression of COX-2 may potentially be involved in inflammatory response in the corneal epithelium.

Comment:

Installation of eye drops for decades, especially when several drugs are needed and/or sensitized patients may induce conjunctival and ocular surface changes that may cause major issues over the long term. Man reports, in humans, animal or cell models confirmed that mild symptoms or signs may account for subclinical inflammatory changes impairing the tear film, eyelids, conjunctiva or cornea.

One major component responsible for those findings is the preservative benzalkonium chloride, which is cytotoxic and has detergent properties. The study by Okada et al is an experimental study evaluating the expression of stress-related genes c-fox and c-jun, and their corresponding encoded proteins activator protein(AP)-1 and cyclooxygenase (COX)-2 in rat cornea., a short time after the instillation of antiglaucoma drugs or preservative. As early as 30-60 minutes after instillation, genes were upregulated, whereas AP-1 and COX2 were induced 90 minutes after instillation. These effects were more prominent with prostaglandins and benzalkonium at a 0.02% concentration.

This study used a well validated set of complementary techniques to assess these results. Although experimentally performed in animal eyes, they showed that preserved drugs and prostaglandins may very quickly stimulate stress-induced signals in the ocular surface epithelia and they support similar studies in humans.

Such data are consistent with previous reports showing overexpression of inflammation or apoptosis related markeds in conjunctival biopsies from patients on glaucoma eye drops. This study is an example illustrating the invovlvement of the ocular surface in glaucoma and the noxious role of preservatives in corneal and conjunctival epithelia.

 

PAPER 3 - DOWNLOAD

 

Adherence in glaucoma: objective measurements of once-daily and adjunctive medication use.

Robin AL. Novack GD. Covert DW. Crockett RS. Marcic TS. American Journal of Ophthalmology. 144(4):533-40, 2007 Oct

PURPOSE: To determine with electronic monitoring an objective measurement of adherence in two populations of subjects: those using once-daily prostaglandin analogs as sole ocular hypotensive therapy (one-drug group) and those requiring an adjunctive medicine to the prostaglandin analog (two-drug group).

DESIGN: Single-site, open-label, nonrandomized, parallel design of 60 days.

METHODS: Sixty-two consecutive adult subjects with a diagnosis of open-angle glaucoma (OAG) or ocular hypertension: 31 were taking one drug and 31 were taking two drugs. An electronic event medication monitoring device was used to record each bottle opening. The main outcome measures were dosing errors (number of under-adherence or over-adherence events) and coverage (proportion of pharmacologic duration covered by dosing) relative to the ophthalmologist-prescribed regimen.

RESULTS: Adherence to the prostaglandins once daily was good in both groups by all measures (≤10% of subjects with more than five dosing errors and mean coverage of 97.2% ± 6.1%). Adherence to the second medication in the two-drug group was poorer (37% of subjects with more than five dosing errors and mean coverage of 85.6% ± 12.6%). For the subjects using _-adrenoceptor antagonists, 24.8% ± 18.4% of doses were taken at less than 10-hour intervals (over-adherence).

CONCLUSIONS: The incorporation of a time component in electronic monitoring provides more information than prescription refill rate or other methods. We found that more complex dosing regimens result in poorer adherence, although once-daily drugs in a complex dosing regimen were found to have good adherence.

Comment:

Robin et al examined the compliance to glaucoma therapy using the MEMSCAP, a device that provides an objective measure of compliance and alerts subjects to the number of times a bottle had been opened during the current 24 hour perod and how long it will be until the next dose. The study duration was 60 days in 62 adult patients.

The authors found that compliance to a once-a-day prostaglandin was good with 97% of subjects having less than five errors over the 60-day period. However, use of a second medication resulted in 37% of patients having more than five dosing errors over the 60 day period.

Overall, these results support earlier work that compliance suffers when patients are prescribed multiple medications. Also, the proportion of compliance is higher than previous studies uins electronic monitoring or pharmacy records. The authors correctly point out that their measures of compliance may be overestimated since the patients were informed several times over the course of the study that they were being monitored.

 

PAPER 4 - DOWNLOAD

 

Diagnostic accuracy of scanning laser polarimetry with enhanced versus variable corneal compensation.

Mai TA. Reus NJ. Lemij HG. Ophthalmology. 114(11):1988-93, 2007 Nov.

PURPOSE: To compare the diagnostic accuracy of scanning laser polarimetry (SLP) parameters between images taken with enhanced corneal compensation (ECC) and those with variable corneal compensation (VCC) and to explore the effect of atypical birefringence patterns on this accuracy.

DESIGN: Cross-sectional observational study.

PARTICIPANTS: Forty-one healthy subjects and 92 patients with primary open-angle glaucoma.

METHODS: Variable corneal compensation and ECC images were obtained of 1 eye per subject, selected randomly if both eyes were eligible. For both ECC and VCC, the areas under the receiver operating characteristic curves (AUROCs) and the sensitivity at a specificity of _95% were calculated per parameter in all eyes. The analyses were reperformed separately in eyes with and without atypical birefringence patterns (ABP) images.

MAIN OUTCOME MEASURES: The AUROCs and sensitivities at a specificity of _95% for various SLP parameters in all eyes and in eyes without ABP images.

RESULTS: The diagnostic accuracy for most standard parameters (temporal-superior-nasal-inferior-temporal [TSNIT] average, superior average, inferior average, and TSNIT standard deviation) in all eyes was statistically significantly higher with ECC than with VCC, except for the nerve fiber indicator (NFI). When only eyes without ABP were used for the analysis, the diagnostic accuracy of SLP parameters with VCC improved, and the differences in diagnostic accuracy between ECC and VCC for these parameters lost their statistical significance.

CONCLUSIONS: Standard SLP parameters (except for the NFI) generally had a higher diagnostic accuracy when eyes were imaged with ECC than with VCC because there were fewer ABP images with ECC than with VCC. Enhanced corneal compensation therefore may be more reliable than VCC for the detection of glaucoma. A future automated classifier, similar to the current NFI, may perform better if it is trained on data obtained with ECC. Clinically, retinal nerve fiber layer images with marked ABP, acquired with either ECC or VCC, should be viewed with caution.

Comment:

Evaluation of the retinal nerve fibre layer is important for the clinical management of glaucoma. An increasing number of practices are obtaining objective automated technologies such as GDx, HRT or OCT to assist them. Scanninly laser polarimetry (GDx) provides an indirect, objective quantification of the nerve fire layer by measuring the amount of retardation, or phase shrift or polarized light as it passes through the birefringent RNFL. As described by Mai et al, th e anterior segment, particularly the cornea, also exhibits form birefringence. The GDx VCC, designed to neutralize the influence of corneal birefringence has been shown to have better diagnostic accuracy than the original scanning laser polarimeter that assumed the same fixed magnitude and axis of corneal polarization for each eye. Unfortunately, atypical birefringence pattersn appear in a proportion of GDx VCC scans. GDx with enhanced corneal compensation (GDx ECC) was introduced to improve the RNFK measures by reduing the prevalence of these ayptical birefrincce patterns. It shold be noted that GDx EDD scans cannot be used interchangeably with GDx VCC scans. Mai et al evaluated five RNFL parameters and found that the ECC was better at compensating for birefringence.


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