Tony Realini

Anterior uveitis associated with latanoprost

PURPOSE To report the association of anterior uveitis with the use of latanoprost. METHODS We studied four patients with complicated open-angle glaucoma who had anterior uveitis associated with the use of latanoprost. The uveitis was unilateral and occurred only in the eye receiving latanoprost in three patients. In one patient, latanoprost was used in both eyes, and the uveitis was bilateral. Four of five eyes had a history of prior inflammation and/or prior incisional surgery. All patients were rechallenged with the drug. RESULTS The uveitis improved after cessation of latanoprost with or without topical corticosteroids. It recurred after rechallenging with latanoprost in all eyes. CONCLUSION There is a possible association between latanoprost and anterior uveitis. Topical prostaglandin analogs may be relatively contraindicated in patients with a history of uveitis or prior ocular surgery. This association may also be possible in eyes that have not had previous uveitis or incisional surgery.

Fixed combinations of topical glaucoma medications.

Purpose of review Topical medical therapy remains the first line of treatment in the management of glaucoma. Utilization studies and clinical trials have demonstrated that many patients with glaucoma require multiple medications to achieve adequate control of intraocular pressure. Fixed combinations of commonly used drugs have been developed, tested, and in some (but not all) cases, approved for use in the United States and abroad. In this review the authors discuss the principles of fixed combination therapy and examine the existing fixed combinations. Recent findings The first modern combination product was the dorzolamide–timolol fixed combination. It works better than either constituent and at least as well as concomitant therapy with both constituents. In comparison with newer agents, the dorzolamide–timolol fixed combination was equal in efficacy to latanoprost monotherapy, timolol and unoprostone concomitant therapy, and timolol and brimonidine concomitant therapy. Concomitant latanoprost and brimonidine demonstrated better efficacy than the dorzolamide–timolol fixed combination. The latanoprost–timolol fixed combination is available in many countries but not the United States. This combination has demonstrated modest additional efficacy over latanoprost monotherapy. The latanoprost–timolol fixed combination provided greater efficacy than concomitant timolol and brimonidine. Summary Fixed combinations offer benefits of convenience, cost, and safety, but limit individualization of dosing. Understanding the advantages and disadvantages of prescribing fixed combinations facilitates success in using these products in clinical practice.

Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma

Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10−11) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10−10); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10−10). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies.

Use of Fixed-Dose Combination Drugs for the Treatment of Glaucoma

Glaucoma is a leading cause of irreversible visual loss. This potentially blinding disease is a progressive optic neuropathy associated with elevated intraocular pressure (IOP). Initial therapy for glaucoma typically consists of topical medications or laser treatment to lower IOP. Frequently, more than one medication is required to achieve adequate control of IOP. However, more medications means more bottles and greater complexity for the patient. There are several potential benefits of fixed combination medications compared with using the individual components separately. These include a reduction in the total number of drops and preservative instilled per day, cost savings, improved tolerability and compliance and avoiding the washout effect resulting from rapid-sequence instillation of multiple drops. Attempts to develop effective fixed combinations of glaucoma medications date back several decades. In recent years, fixed combinations of commonly paired drugs have been approved by various regulatory bodies in different countries and have gained wide acceptance. Current commercially available, fixed combination drugs include the topical β-adrenoceptor antagonist timolol 0.5% combined with a prostaglandin, a topical carbonic anhydrase inhibitor or an α-adrenoceptor agonist. Although there is no uniformity among registration trial designs, most published literature compares the efficacy of the fixed combination to the individual components and to concomitant use of both components. Various factors inherent to study design such as medication run-in, washout periods and peak and trough effects have to be taken into consideration when analysing the demonstrated efficacy of fixed combinations. Fixed combination treatments offer effective IOP control while reducing the washout effect and exposure to preservatives. They are also convenient. However, fixed combinations also remove the possibility of titrating the individual components both in terms of concentration and timing of administration. In addition, fixed combinations might not always provide the same efficacy as proper use of the individual components. The clinician must make individualised assessments when weighing the convenience of these medications against their limitations for specific patients.

Short-Term Repeatability of Diurnal Intraocular Pressure Patterns in Glaucomatous Individuals

PURPOSE To evaluate the short-term repeatability of diurnal intraocular pressure (IOP) patterns in eyes with primary open-angle glaucoma (POAG). DESIGN Observational cohort study. PARTICIPANTS Forty-seven subjects with treated POAG. METHODS Subjects underwent assessment of IOP using Goldmann tonometry every 2 hours from 0800 to 2000 on 2 visits 1 week apart. Intervisit agreement of IOP by time point and of IOP change between time points was assessed using intraclass correlation coefficients (ICCs). MAIN OUTCOME MEASURES Diurnal IOP patterns. RESULTS Between-visit agreement of IOP values at each time point was generally fair to good, with ICCs ranging from 0.45 to 0.71 in right eyes and from 0.51 to 0.71 in left eyes. Between-visit agreement of IOP change over time periods between time points was uniformly poor, with ICCs ranging from -0.08 to 0.38 in right eyes and from -0.11 to 0.36 in left eyes. CONCLUSIONS Treated POAG patients do not manifest a repeatable diurnal IOP pattern from day to day when measured by Goldmann tonometry. Measurement of single-day IOP variation poorly characterized short-term IOP variation.

Association of CAV1/CAV2 Genomic Variants with Primary Open-Angle Glaucoma Overall and by Gender and Pattern of Visual Field Loss

PURPOSE The CAV1/CAV2 (caveolin 1 and caveolin 2) genomic region previously was associated with primary open-angle glaucoma (POAG), although replication among independent studies has been variable. The aim of this study was to assess the association between CAV1/CAV2 single nucleotide polymorphisms (SNPs) and POAG in a large case-control dataset and to explore associations by gender and pattern of visual field (VF) loss further. DESIGN Case-control study. PARTICIPANTS We analyzed 2 large POAG data sets: the Glaucoma Genes and Environment (GLAUGEN) study (976 cases, 1140 controls) and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium (2132 cases, 2290 controls). METHODS We studied the association between 70 SNPs located within the CAV1/CAV2 genomic region in the GLAUGEN and NEIGHBOR studies, both genotyped on the Illumina Human 660WQuadv1C BeadChip array and imputed with the Markov Chain Haplotyping algorithm using the HapMap 3 reference panel. We used logistic regression models of POAG in the overall population and separated by gender, as well as by POAG subtypes defined by type of VF defect (peripheral or paracentral). Results from GLAUGEN and NEIGHBOR were meta-analyzed, and a Bonferroni-corrected significance level of 7.7 × 10(-4) was used to account for multiple comparisons. MAIN OUTCOME MEASURES Overall POAG, overall POAG by gender, and POAG subtypes defined by pattern of early VF loss. RESULTS We found significant associations between 10 CAV1/CAV2 SNPs and POAG (top SNP, rs4236601; pooled P = 2.61 × 10(-7)). Of these, 9 were significant only in women (top SNP, rs4236601; pooled P = 1.59 × 10(-5)). Five of the 10 CAV1/CAV2 SNPs were associated with POAG with early paracentral VF (top SNP, rs17588172; pooled P = 1.07 × 10(-4)), and none of the 10 were associated with POAG with peripheral VF loss only or POAG among men. CONCLUSIONS CAV1/CAV2 SNPs were associated significantly with POAG overall, particularly among women. Furthermore, we found an association between CAV1/CAV2 SNPs and POAG with paracentral VF defects. These data support a role for caveolin 1, caveolin 2, or both in POAG and suggest that the caveolins particularly may affect POAG pathogenesis in women and in patients with early paracentral VF defects.

Diurnal intraocular pressure patterns are not repeatable in the short term in healthy individuals.

PURPOSE To evaluate the short-term repeatability of diurnal intraocular pressure (IOP) patterns in eyes of subjects without glaucoma. DESIGN Observational cohort study. PARTICIPANTS Forty healthy subjects without glaucoma. METHODS Subjects underwent 12-hour diurnal IOP assessment sessions from 8:00 am to 8:00 pm on 2 visits 1 week apart. Intraocular pressure was assessed by Goldmann applanation tonometry. An analysis was performed to determine the agreement of individual diurnal IOP patterns from the first visit to the second visit. The intraclass correlation coefficient (ICC) was used to analyze both agreement of IOP values at each time point between visits and IOP change over periods between time points between visits. MAIN OUTCOME MEASURES Diurnal IOP patterns. RESULTS Between-visit agreement of IOP values at each time point generally was fair to good, with ICCs ranging from 0.37 to 0.62 in right eyes and from 0.35 to 0.71 in left eyes. Between-visit agreement of IOP change over time between time points was uniformly poor and often below that expected by chance alone, with ICCs ranging from -0.25 to 0.15 in right eyes and from -0.40 to 0.22 in left eyes. CONCLUSIONS Eyes of healthy individuals do not manifest a sustained and reproducible diurnal IOP pattern when measured by Goldmann tonometry. A single-day assessment of IOP incompletely characterizes the diurnal IOP pattern.

Frequency of asymmetric intraocular pressure fluctuations among patients with and without glaucoma

PURPOSE To describe the frequency and magnitude of asymmetric fluctuations of intraocular pressure (IOP) between fellow eyes of glaucoma patients and normal subjects. DESIGN Observational case series. PARTICIPANTS Forty-two subjects without glaucoma and 38 glaucoma patients. METHODS By means of retrospective chart review, bilateral IOP measurements were examined over time for subjects without glaucoma and for glaucoma patients whose drug regimens remained unchanged during the period included in the study (at least five readings over at least 1 year). Asymmetric IOP fluctuations of at least 3 mmHg and representing at least a 15% change from baseline were identified. MAIN OUTCOME MEASURE Occurrence of spontaneous asymmetric IOP fluctuations. RESULTS Twenty-one of 42 subjects without glaucoma exhibited an asymmetric IOP fluctuation between two consecutive visits compared with 24 of 38 glaucoma patients (50% vs. 63.2%, respectively, P = 0.24). Compared with normal subjects, asymmetric IOP fluctuations were observed in 13 of 16 glaucoma patients with prior symmetrical bilateral ocular surgery (50% vs. 81.2%, respectively, P = 0.031), and 11 of 22 ocular surgery-naive glaucoma patients (50% vs. 50%, respectively, P = 1.0). No differences in the magnitudes of the asymmetric IOP fluctuations were noted between groups. Overall, asymmetric IOP fluctuations were observed in 13.7% of follow-up visits among normal subjects versus 16.3% of follow-up visits among glaucoma patients (P = 0.4). CONCLUSIONS Spontaneous asymmetric fluctuations of intraocular pressure between fellow eyes occur commonly in normal subjects and glaucoma patients. The frequency and magnitude of observed spontaneous asymmetric IOP fluctuations between consecutive clinical visits in glaucoma patients are sufficiently large to potentially confound the interpretation of monocular therapeutic drug trials.

Long-term incidence and timing of intraocular hypertension after intravitreal triamcinolone acetonide injection.

PURPOSE To describe the long-term incidence and timing of steroid-induced ocular hypertension after intravitreal triamcinolone acetonide (IVTA) therapy. DESIGN Retrospective case series of 929 eyes of 841 patients. PARTICIPANTS Patients with a variety of posterior segment disorders in a single group practice. INTERVENTION Pars plana injection of IVTA. MAIN OUTCOME MEASURES Intraocular pressure (IOP) and requirement for glaucoma surgery. RESULTS Overall, 929 eyes received >or=1 injections (mean, 1.6) of 4 mg of IVTA. During a mean follow-up period of 14+/-6.9 months, the Kaplan-Meier cumulative incidences of IOP elevations >21 mmHg at 6, 12, 18, and 24 months post-injection were 28.2%, 34.6%, 41.2%, and 44.6%, respectively; similarly, the incidences of eyes with IOP measurements >25 mmHg were 14.6%, 19.1%, 24.1%, and 28.2%, respectively. At the same time points, IOP-lowering medications were required by 13.0%, 16.9%, 20.7%, and 24.2% of eyes, respectively. Only 3 eyes (0.3%) required IOP-lowering surgery. Preexisting glaucoma, younger age, and a history of an IOP elevation after a previous IVTA injection were risk factors for IOP elevations after IVTA injection. The minimum and maximum follow-up were 3 weeks and 37 months. The mean rate of attrition in this study was 3% per month. CONCLUSIONS Elevations in IOP after IVTA injection are common. Younger patients and eyes with preexisting glaucoma or a history of a steroid response should be monitored more closely for IOP elevations after IVTA therapy.

Correlation of Intraocular Pressure Measured With Goldmann and Dynamic Contour Tonometry in Normal and Glaucomatous Eyes

PurposeTo compare intraocular pressure (IOP) values measured by both Goldmann applanation tonometry (GAT) and dynamic contour tonometry (DCT) in both normal and glaucomatous eyes, and to determine the relationship between these parameters and central corneal thickness (CCT). Patients and MethodsForty-seven subjects with primary open-angle glaucoma and 38 normal subjects attended a 12-hour session during which IOP was assessed at 7 time points, every 2 hours, by both GAT and DCT. CCT was also assessed at the same visit. Mean IOP was calculated for each eye of each subject by each method from the 7 diurnal IOP measurements obtained. ResultsMean IOP was higher when measured by DCT than by GAT in both normal (by 1.1 mm Hg, P<0.0001) and glaucomatous (by 1.6 mm Hg, P<0.0001) eyes. IOP measurements by GAT and DCT were moderately correlated in both normal (r2=0.354, P<0.0001) and glaucomatous (r2=0.552, P<0.0001) eyes. In normal eyes, there was a weak positive correlation between GAT IOP and CCT (r2=0.088, slope=0.022 mm Hg/μm, P=0.009) and no correlation between DCT IOP and CCT (r2=0.007, slope=0.005 mm Hg/μm, P=0.468). In glaucomatous eyes, there was no correlation between GAT IOP and CCT (r2=0.006, slope=0.007 mm Hg/μm, P=0.473) and a weak inverse correlation between DCT IOP and CCT (r2=0.075, slope=−0.021 mm Hg/μm, P=0.008). ConclusionsBoth GAT and DCT are affected by CCT, albeit in different ways. Normal and glaucomatous eyes exhibit different relationships between CCT and IOP measured by either GAT or DCT. The relationships between CCT and transcorneal IOP measurements are complex and incompletely characterized, which limits the clinical interpretation of GAT and DCT measurements of IOP in both normal and glaucomatous eyes.