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To evaluate the effect of various media and Iridex MicroPulse P3 (MP3) probe angles on the power output from the Cyclo G6 Glaucoma Laser (G6) System. A laser power meter was used to measure the power output (milliwatts, mW) of the Cyclo G6 System. Each of the ten trials consisted of measurements in six different media: no substrate, balanced salt solution (BSS), artificial tears (AT), tetracaine eye drop, lubricating ointment, and lidocaine gel. The output of the MP3 probe was measured at an angle of 90° and 45°, submerged in the respective media. The output was also measured with the probe held at 90° but above the medium. The mean power outputs with the probe being held at 90° to the sensor with no substrate, BSS, AT, tetracaine eye drop, lubricating ointment, and lidocaine gel were 358 ± 16.8 mW, 612 ± 14.2 mW, 613 ± 13.3 mW, 612 ± 14.0 mW, 620 ± 9.9 mW, and 610 ± 12.2 mW, respectively. These values were statistically higher than noncontact and 45° probe angles for each medium. The values between any two media (excluding no substrate) at a 90° probe angle with full contact were not statistically significant. The highest output of the G6 System was obtained with a 90° probe angle, with full contact and any of the coupling media.

Purpose: Primary open-angle glaucoma (POAG) is a complex heterogeneous disease. While several POAG genes have been identified, a high proportion of estimated heritability remains unexplained. Elevated intraocular pressure (IOP) is a leading POAG risk factor and dysfunctional extracellular matrix (ECM) in the trabecular meshwork (TM) contributes to elevated IOP. In this study, we sought to identify missense variants in ECM genes that correlate with ocular hypertensive POAG. Methods: Whole-genome sequencing was used to identify genetic variants in five members of a large POAG family (n = 68) with elevated IOP. The remaining family members were screened by Sanger sequencing. Unrelated normal (NTM) and glaucomatous (GTM) cells were sequenced for the identified variants. The ECM protein levels were determined by Western immunoblotting and confocal and electron microscopy investigated ECM ultrastructural organization. Results: Three ECM gene variants were significantly associated with POAG or elevated IOP in a large POAG pedigree. These included rs2228262 (N700S; thrombospondin-1 (THBS1, TSP1)), rs112913396 (D563 G; collagen type VI, alpha 3 (COL6A3)) and rs34759087 (E987K; laminin subunit beta 2 (LAMB2)). Screening of unrelated TM cells (n = 27) showed higher prevalence of the THBS1 variant but not the LAMB2 variant, in GTM cells (39%) than NTM cells (11%). The rare COL6A3 variant was not detected. TSP1 protein was upregulated and COL6A3 was down-regulated in TM cells with N700S subject to mechanical stretch, an in vitro method that mimics elevated IOP. Immunofluorescence showed increased TSP1 immunostaining in cell strains with N700S compared to wild-type TM cells. Ultrastructural studies showed ECM disorganization and altered collagen type VI distribution in GTM versus NTM cells. Conclusions: Our results suggest that missense variants in ECM genes may not cause catastrophic changes to the TM, but over many years, subtle changes in ECM may accumulate and cause structural disorganization of the outflow resistance leading to elevated IOP in POAG patients.

Glucocorticoids are widely used as an ophthalmic medication. A common, sight-threatening adverse event of glucocorticoid usage is ocular hypertension, caused by dysfunction of the conventional outflow pathway. We report that netarsudil, a rho-kinase inhibitor, decreased glucocorticoid-induced ocular hypertension in patients whose intraocular pressures were poorly controlled by standard medications. Mechanistic studies in our established mouse model of glucocorticoid-induced ocular hypertension show that netarsudil both prevented and reduced intraocular pressure elevation. Further, netarsudil attenuated characteristic steroid-induced pathologies as assessed by quantification of outflow function and tissue stiffness, and morphological and immunohistochemical indicators of tissue fibrosis. Thus, rho-kinase inhibitors act directly on conventional outflow cells to prevent or attenuate fibrotic disease processes in glucocorticoid-induced ocular hypertension in an immune-privileged environment. Moreover, these data motivate the need for a randomized prospective clinical study to determine whether netarsudil is indeed superior to first-line anti-glaucoma drugs in lowering steroid-induced ocular hypertension.

Due to their similarities in anatomy, physiology, and pharmacology to humans, mice are a valuable model system to study the generation and mechanisms modulating conventional outflow resistance and thus intraocular pressure. In addition, mouse models are critical for understanding the complex nature of conventional outflow homeostasis and dysfunction that results in ocular hypertension. In this review, we describe a set of minimum acceptable standards for developing, characterizing, and utilizing mouse models of open-angle ocular hypertension. We expect that this set of standard practices will increase scientific rigor when using mouse models and will better enable researchers to replicate and build upon previous findings.

Cultured trabecular meshwork (TM) cells are a valuable model system to study the cellular mechanisms involved in the regulation of conventional outflow resistance and thus intraocular pressure; and their dysfunction resulting in ocular hypertension. In this review, we describe the standard procedures used for the isolation of TM cells from several animal species including humans, and the methods used to validate their identity. Having a set of standard practices for TM cells will increase the scientific rigor when used as a model, and enable other researchers to replicate and build upon previous findings.

To determine whether interleukin-20 receptors (IL-20R) are expressed in trabecular meshwork cells and the effect of a T104M mutation in IL-20R2 on downstream cellular functions.Evaluation of signal transducer and activator of transcription (STAT)3 phosphorylation and generic matrix metalloproteinase (MMP) activity in primary open angle glaucoma (POAG) dermal fibroblasts (pHDF) with the T104M IL-20R2 mutation were compared with normal human dermal fibroblasts (HDF). Expression of IL-20R1 and IL-20R2 in human trabecular meshwork (HTM) cells was determined by immunohistochemistry and western immunoblotting.A T104M mutation in IL20-R2 was identified in a large POAG family in which the GLC1C locus was originally mapped. pHDFs harboring this mutation had significantly increased phosphorylated STAT3 (pSTAT3) activity compared with normal HDFs. However, stimulation with either IL-19 or IL-20 for 15 min resulted in significantly decreased levels of pSTAT3 in pHDFs compared with controls. Generic MMP activity was significantly decreased in pHDFs compared with controls after stimulation with IL-20 for 24 h. Both IL-20R1 and IL-20R2 receptors were expressed in HTM cells by western immunoblot and immunofluorescence, and they appeared to be up-regulated in response to cytokine treatment.A T104M mutation in IL-20R2 significantly impacts the function of this receptor as shown by decreased pSTAT3 levels and generic MMP activity. Reduced MMP activity may affect the ability of glaucoma patients to alter outflow resistance in response to elevated intraocular pressure.

The molecular events responsible for obstruction of aqueous humor outflow and the loss of retinal ganglion cells in glaucoma, one of the main causes of blindness worldwide, remain poorly understood. We identified a synonymous variant, c.765C>T (Thr255Thr), in ankyrin repeats and suppressor of cytokine signaling box-containing protein 10 (ASB10) in a large family with primary open angle glaucoma (POAG) mapping to the GLC1F locus. This variant affects an exon splice enhancer site and alters mRNA splicing in lymphoblasts of affected family members. Systematic sequence analysis in two POAG patient groups (195 US and 977 German) and their respective controls (85 and 376) lead to the identification of 26 amino acid changes in 70 patients (70 of 1172; 6.0%) compared with 9 in 13 controls (13 of 461; 2.8%; P = 0.008). Molecular modeling suggests that these missense variants change ASB10 net charge or destabilize ankyrin repeats. ASB10 mRNA and protein were found to be strongly expressed in trabecular meshwork, retinal ganglion cells and ciliary body. Silencing of ASB10 transcripts in perfused anterior segment organ culture reduced outflow facility by ∼50% compared with control-infected anterior segments (P = 0.02). In conclusion, genetic and molecular analyses provide evidence for ASB10 as a glaucoma-causing gene.

Objective To provide an evidence-based summary of the outcomes, repeatability, and safety of laser trabeculoplasty for open-angle glaucoma. Methods A search of the peer-reviewed literature in the PubMed and the Cochrane Library databases was conducted in June 2008 and was last repeated in March 2010 with no date or language restrictions. The search yielded 637 unique citations, of which 145 were considered to be of possible clinical relevance for further review and were included in the evidence analysis. Results Level I evidence indicates an acceptable long-term efficacy of initial argon laser trabeculoplasty for open-angle glaucoma compared with initial medical treatment. Among the remaining studies, level II evidence supports the efficacy of selective laser trabeculoplasty for lowering intraocular pressure for patients with open-angle glaucoma. Level III evidence supports the efficacy of repeat use of laser trabeculoplasty. Conclusions Laser trabeculoplasty is successful in lowering intraocular pressure for patients with open-angle glaucoma. At this time, there is no literature establishing the superiority of any particular form of laser trabeculoplasty. The theories of action of laser trabeculoplasty are not elucidated fully. Further research into the differences among the lasers used in trabeculoplasty, the repeatability of the procedure, and techniques of treatment is necessary. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

Objective To review the published literature and summarize clinically relevant information about novel, or emerging, surgical techniques for the treatment of open-angle glaucoma and to describe the devices and procedures in proper context of the appropriate patient population, theoretic effects, advantages, and disadvantages. Design Devices and procedures that have US Food and Drug Administration clearance or are currently in phase III clinical trials in the United States are included: the Fugo blade (Medisurg Ltd., Norristown, PA), Ex-PRESS mini glaucoma shunt (Alcon, Inc., Hunenberg, Switzerland), SOLX Gold Shunt (SOLX Ltd., Boston, MA), excimer laser trabeculotomy (AIDA, Glautec AG, Nurnberg, Germany), canaloplasty (iScience Interventional Corp., Menlo Park, CA), trabeculotomy by internal approach (Trabectome, NeoMedix, Inc., Tustin, CA), and trabecular micro-bypass stent (iStent, Glaukos Corporation, Laguna Hills, CA). Methods Literature searches of the PubMed and the Cochrane Library databases were conducted up to October 2009 with no date or language restrictions. Main Outcome Measures These searches retrieved 192 citations, of which 23 were deemed topically relevant and rated for quality of evidence by the panel methodologist. All studies but one, which was rated as level II evidence, were rated as level III evidence. Results All of the devices studied showed a statistically significant reduction in intraocular pressure and, in some cases, glaucoma medication use. The success and failure definitions varied among studies, as did the calculated rates. Various types and rates of complications were reported depending on the surgical technique. On the basis of the review of the literature and mechanism of action, the authors also summarized theoretic advantages and disadvantages of each surgery. Conclusions The novel glaucoma surgeries studied all show some promise as alternative treatments to lower intraocular pressure in the treatment of open-angle glaucoma. It is not possible to conclude whether these novel procedures are superior, equal to, or inferior to surgery such as trabeculectomy or to one another. The studies provide the basis for future comparative or randomized trials of existing glaucoma surgical techniques and other novel procedures. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

Objective To review the published literature to summarize and evaluate the effectiveness of visual function tests in diagnosing glaucoma and in monitoring progression. Methods Literature searches of the PubMed and Cochrane Library databases were conducted last on May 7, 2010, and were restricted to citations published on or after January 1, 1994. The search yielded 1063 unique citations. The first author reviewed the titles and abstracts of these articles and selected 185 of possible clinical relevance for further review. The panel members reviewed the full text of these articles and determined that 85 met inclusion criteria. They conducted data abstraction of the 85 studies, and the panel methodologist assigned a level of evidence to each of the selected articles. One study was rated as level I evidence. The remaining articles were classified broadly as providing level II evidence. Studies deemed to provide level III evidence were not included in the assessment. Results Standard white-on-white automated perimetry remains the most commonly performed test for assessing the visual field, with the Swedish interactive threshold algorithm (SITA) largely replacing full-threshold testing strategies. Frequency-doubling technology and its refinement into Matrix perimetry, as well as short-wavelength automated perimetry, now available with SITA, have been evaluated extensively. Machine learning classifiers seem to be ready for incorporation into software to help distinguish glaucomatous from nonglaucomatous fields. Other technologies, such as multifocal visual-evoked potential and electroretinography, which were designed as objective measures of visual function, provide testing free of patient input, but issues prevent their adoption for glaucoma management. Conclusions Advances in technology and analytic tools over the past decade have provided us with more rapid and varied ways of assessing visual function in glaucoma, but they have yet to produce definitive guidance on the diagnosis of glaucoma or its progression over time. Further research on an objective measure of visual function is needed. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

A high frequency of the Cohen syndrome has been observed in a Greek island with 2,000 inhabitants and a high degree of inbreeding. All patients were homozygous for a COH1, exon 6–16 deletion suggesting a founder effect. We present the results of their first systematic ophthalmologic assessment. Myopia and chorioretinal atrophy were present in all patients of this cohort. Yet, in contrast to all groups previously reported, the majority presented with corneal changes, independently from age, gender, and family history. A pair of sisters, aged 11 and 15 years old, presented with bilateral keratoconus. More frequently (86%) than in any other ethnic group, Greek patients had cataracts that were bilateral and often graded as high as 3, even at a young age. As a whole, the ophthalmic phenotype of the Greek isolate of Cohen syndrome is characterized by the involvement of both the posterior and the anterior eye segment, bilaterally, in the majority of cases (93%). Greek Cohen patients that share a founder mutation are at a higher risk of developing blindness in respect to those of other ethnicities and genotypes. This study highlighted the need for pachymetry measurement as a means of surveillance and prediction of the visual impairment frequently observed. © 2011 Wiley-Liss, Inc.

Primary open-angle glaucoma (POAG) is a primary neuronal disease of the optic nerve without a definable cause, and is often associated with increased intraocular pressure. Worldwide, POAG is the second leading cause of blindness; there are 45 million people today with POAG and bilateral blindness is present in 4.5 million of these. In order to elucidate the possible etiologic factors in POAG, we have cataloged all known biomarkers in the aqueous humor, trabecular meshwork, optic nerve and blood into four categories, namely extracellular matrix (ECM), cell signaling molecules, aging/stress and immunity-related changes. We present a theoretical model to show possible signaling pathways of the ECM, cell signaling and innate immune response through activation of Toll-like receptor 4. Our article suggests that ECM and innate immune biomarkers are the lead candidates for developing the ‘POAG biomarker signature’. We suggest that current research is critical to pinpoint the causes of the disease so that new treatment modalities can become available for better regulation of the intraocular pressure and neuroprotection of the optic nerve.

Objective To provide an evidence-based summary of commercially available aqueous shunts currently used in substantial numbers (Ahmed [New World Medical, Inc., Rancho Cucamonga, CA], Baerveldt [Advanced Medical Optics, Inc., Santa Ana, CA], Krupin [Eagle Vision, Inc, Memphis, TN], Molteno [Molteno Ophthalmic Ltd., Dunedin, New Zealand]) to control intraocular pressure (IOP) in various glaucomas. Methods Seventeen previously published randomized trials, 1 prospective nonrandomized comparative trial, 1 retrospective case-control study, 2 comprehensive literature reviews, and published English language, noncomparative case series and case reports were reviewed and graded for methodologic quality. Results Aqueous shunts are used primarily after failure of medical, laser, and conventional filtering surgery to treat glaucoma and have been successful in controlling IOP in a variety of glaucomas. The principal long-term complication of anterior chamber tubes is corneal endothelial failure. The most shunt-specific delayed complication is erosion of the tube through overlying conjunctiva. There is a low incidence of this occurring with all shunts currently available, and it occurs most frequently within a few millimeters of the corneoscleral junction after anterior chamber insertion. Erosion of the equatorial plate through the conjunctival surface occurs less frequently. Clinical failure of the various devices over time occurs at a rate of approximately 10% per year, which is approximately the same as the failure rate for trabeculectomy. Conclusions Based on level I evidence, aqueous shunts seem to have benefits (IOP control, duration of benefit) comparable with those of trabeculectomy in the management of complex glaucomas (phakic or pseudophakic eyes after prior failed trabeculectomies). Level I evidence indicates that there are no advantages to the adjunctive use of antifibrotic agents or systemic corticosteroids with currently available shunts. Too few high-quality direct comparisons of various available shunts have been published to assess the relative efficacy or complication rates of specific devices beyond the implication that larger–surface-area explants provide more enduring and better IOP control. Long-term follow-up and comparative studies are encouraged.

Objective To evaluate published literature to assess whether central corneal thickness (CCT) is a risk factor for the presence, development, or progression of glaucomatous optic nerve damage related to primary open-angle glaucoma (POAG). Methods A PubMed literature search limited to English language articles conducted on November 15, 2004 retrieved 195 articles. The authors reviewed these abstracts and selected 57 to review in full text to determine relevance to the assessment questions. A further 24 studies of interest were identified from periodic updates to the literature search, surveillance of the literature, and reference lists of reviewed articles. From the 81 published reports identified, the first author applied specified selection criteria that yielded 37 articles for methodological review because of relevance to the assessment questions. The articles were rated according to the strength of evidence by the panel methodologist. A level I rating was assigned to well-designed properly conducted randomized clinical trials or similar quality-validated cohort studies with appropriate reference standards. A level II rating was assigned to well-designed case–control studies, exploratory cohort studies, and other nonrandomized clinical studies lacking consistently applied reference standards. A level III rating was reserved for poorly designed case–control studies, case series, and papers consisting only of expert opinion without supporting evidence. In addition, each study was graded as positive if it supported a statistical association of CCT with the risk of having or developing glaucomatous optic nerve damage or as negative if no such association was found. Results There is strong and consistent level I and level II evidence that CCT is a risk factor for progression from ocular hypertension to POAG. Studies that were rated as providing the highest quality of evidence revealed mixed results with respect to glaucoma prevalence. One population-based study (level II) showed a positive association, another larger study (level I) revealed an association of marginal significance, and 3 studies (all level I) found no association of CCT with POAG prevalence. Conclusions There is strong evidence that measuring CCT is an important component of a complete ocular examination, particularly for patients being evaluated for the risk of developing POAG. Therefore, CCT measurement should be included in the examination of all patients with ocular hypertension. Although the evidence supporting the necessity of measuring CCT as part of screening for POAG or as a risk factor for glaucoma progression is not as strong, intraocular pressure (IOP) is the only modifiable risk factor in the treatment of glaucoma, and CCT has the potential to significantly impact IOP measurement by applanation tonometry in all patients.

To correlate aqueous humor soluble CD44 (sCD44) concentration, visual field loss, and glaucoma risk factors in primary open-angle glaucoma (POAG) patients.Aqueous samples were obtained by paracentesis from normal and glaucoma patients who were undergoing elective surgery and analyzed for sCD44 concentration by enzyme-linked immunosorbent assay.In normal aqueous (n=124) the sCD44 concentration was 5.88+/-0.27 ng/mL, whereas in POAG aqueous (n=90) the sCD44 concentration was 12.76+/-0.66 ng/mL, a 2.2-fold increase (P0.000001). In POAG patients with prior successful filtration surgery (n=13), the sCD44 concentration was decreased by 43% to 7.32+/-1.44 (P=0.001) in comparison with POAG patients without filtration surgery; however, the sCD44 concentration in the prior successful filtration subgroup with no medications and normal intraocular pressure was 12.62+/-3.81 (P=0.05) compared with normal. The sCD44 concentration of normal pressure glaucoma patients was 9.19+/-1.75 ng/mL, a 1.6-fold increase compared with normal (P=0.02). Race and intraocular pressure pulse amplitude were significant POAG risk factors in this cohort of patients. In both normal and POAG patients with mild and moderate visual field loss, sCD44 concentration was greater in African Americans than in whites (P=0.04).sCD44 concentration in the aqueous of POAG patients correlated with the severity of visual field loss in all stages in white patients and in mild to moderate stages in African American patients. sCD44 concentration in aqueous is a possible protein biomarker of visual field loss in POAG.

Purpose: To evaluate production of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) after panretinal photocoagulation (PRP) of human retinal pigment epithelium (RPE) explants. Methods: Treated explants were subjected to substrate zymography to differentiate MMP-2 from MMP-9 and dot immunoblot analysis to quantify MMP-3 and TIMP activity. Tritiated thymidine uptake by RPE cells was measured to document evidence of cellular division in the laser-treated versus control explants. Results: We detected MMP-2, MMP-3, and TIMP-1. MMP-2 and MMP-3 secretion increased to twice the control values. TIMP decreased until day 4 and then increased by day 6. Tritiated thymidine uptake increased 2.5-fold until day 6, returning to baseline by day 8. Conclusion: PRP disturbs MMP/TIMP balance, inhibiting the initiation and maintenance required for active neovascularization. The efficacy of PRP may be due to changes in the expression pattern of metalloproteinases and inhibitors. This model elucidates the possible contribution of PRP to neovascularization regression by demonstrating the effect of laser on TIMP/MMP balance. The effects of PRP may be much more complex than currently understood and most likely involve more than vascular endothelial growth factor and other ischemia-related factors.

Introduction The main purpose of this study was to determine whether the optic cups of tamoxifen users and anastrozole users differ in size, with the cups of the tamoxifen users being smaller. Methods Optic nerve head (ONH) topography was measured using a commercially available, confocal scanning laser ophthalmoscope for three populations of amenorrheic women ages 40–69 years: subjects using (1) tamoxifen (20 mg/day) or (2) anastrozole (1 mg/day) for ≤ 2 years as adjuvant therapy after successful primary treatment for breast cancer, and (3) control subjects with no breast cancer histories and not using any hormonal medication. All subjects had excellent visual acuity and healthy eyes, based on conventional photographic assessment. Results The cup volumes of the tamoxifen users were shown to be significantly smaller than the cup volumes of the anastrozole users, which were indistinguishable from normal. Because the cup volumes of the tamoxifen users decreased markedly with age at about 50 years and because anastrozole is indicated only for post-menopausal women, comparisons were reassessed for subjects older than 50 years. For these subjects, the cup volumes of the tamoxifen users averaged less than half of the volumes for each of the other two subject groups, and significant between-group differences existed in both the lateral (cup area) and axial (cup depth) directions. In contrast, any between-group differences at the ONH margin were small and not significant. Conclusions The results of this study suggest that the ONH be assessed biomorphometrically for tamoxifen users reporting visual change that cannot be attributed to non-tamoxifen causes. The ability of modern intraocular imaging techniques to reveal anatomic change on the order of tens of microns may be useful for assessing tamoxifen-induced effects occurring simultaneously elsewhere in the brain, particularly since the presence of small cups is consistent with the possibility of tamoxifen-induced astrocytic swelling.

The GLC1C locus for primary open-angle glaucoma (POAG) is inherited as an autosomal dominant trait. This region on chromosome 3 is 11 cM long. DNA samples from members of a Greek and an American GLC1C family were obtained to determine whether additional typing of microsatellite markers in family members might narrow the region. GLC1C family members were evaluated clinically for POAG on the basis of open angles, intraocular pressures, cupping of discs, and visual fields. DNA samples from the Greek and Oregon GLC1C families were used to further refine the GLC1C region using microsatellite markers. A total of 22 affected members were identified in the two families. Common alleles for D3S3637 and D3S3612 were present in the disease haplotype from both families, suggesting that they may have a common founder. A newly diagnosed patient in the American family had a recombination in the distal portion of the GLC1C haplotype. This recombination narrows the GLC1C region from 11 to 4 cM.

As Posner stated in 1949, the bottom line "to the patient and to his family is..., whether his disease will follow a mild course or will lead to blindness". The final goal of genetic research is the identification of the causal genes in the patient, to aid the ophthalmologist in predicting the outcome, in determining diligent treatment is required, and ultimately, in providing the tools for preventing blindness.

Weill-Marchesani syndrome (WMS) is a rare condition characterized by short stature, brachydactyly, joint stiffness, and characteristic eye abnormalities including microspherophakia, ectopia of lens, severe myopia, and glaucoma. Both autosomal recessive (AR) and autosomal dominant (AD) modes of inheritance have been described for WMS. A locus for AR WMS has recently been mapped to chromosome 19p13.3-p13.2 while mutation within the fibrillin-1 gene (15q21.1) was found in one AD WMS family. In order to answer the question of whether or not genetic heterogeneity could be related to a clinical heterogeneity, we reviewed 128 WMS patients from the literature (including 57 AR, 50 AD, and 21 sporadic cases), with a particular attention to clinical features. Statistical analyses using Fischer exact test were used to compare the proportions of 12 clinical parameters between AR and AD patients. There was no significant difference between both groups for myopia, glaucoma, cataract, short stature, brachydactyly, thick skin, muscular build, and mental retardation. Significant results were found for microspherophakia (94% in AR, 74% in AD, Fischer 0.007), ectopia lentis (64% in AR, 84% in AD, Fischer 0.016), joint limitations (49% in AR, 77% in AD, Fischer 0.010), and cardiac anomalies (39% in AR, 13% in AD, Fischer 0.004). Nevertheless, we failed to distinguish AR from AD inheritance in individual cases. These results support the clinical homogeneity but the genetic heterogeneity of WMS.

Objective The purpose of this document is to summarize and evaluate the effectiveness of new automated perimetry tests and algorithms in diagnosing glaucoma and detecting disease progression. Methods A literature search on automated perimetry retrieved over 300 citations from 1994 to 2001, of which 71 were selected as relevant to this assessment. The quality of the evidence obtained from these studies was assessed by the methodologist. Results The four automated perimetry techniques described in this assessment are short wavelength automated perimetry (SWAP), frequency doubling technology perimetry (FDT), high-pass resolution perimetry (HPRP), and motion automated perimetry (MAP). The algorithms described are Swedish interactive threshold algorithm (SITA) and SITA fast. With the exception of SWAP, these techniques and algorithms reduce testing time and inconsistent patient performance when compared with conventional full threshold testing. Conclusions Short wavelength automated perimetry detected visual field loss earlier than standard threshold automated perimetry, with a sensitivity and specificity of about 88% and 92% respectively. However, it is a lengthy, demanding test, is sensitive to media opacities, and has a greater magnitude of long-term fluctuation compared with standard threshold automated perimetry, which make it difficult to assess disease progression accurately. When compared to standard threshold automated perimetry, FDT perimetry showed sensitivity and specificity greater than 97% for detecting moderate and advanced glaucoma, and sensitivity of 85% and specificity of 90% for early glaucoma. As FDT perimetry has a short testing time and is resistant to blur and pupil size, it may be a useful screening tool. In a longitudinal study, high-pass resolution perimetry was more effective than standard threshold automated perimetry in monitoring progressive glaucomatous loss, detecting progression at a median of 12 months earlier in 54% of patients studied. Motion automated perimetry demonstrated usefulness in detecting early glaucomatous visual loss in a longitudinal study. Studies on SITA demonstrated greater sensitivity and reproducibility and less intertest variability when compared to standard full threshold testing and a 50% reduction in testing times. A study comparing standard full threshold, SITA, and SITA fast found a sensitivity of 95% for the first two techniques and 93% for SITA fast. Long-term follow-up studies are needed to assess the ability of these techniques to detect progression of glaucoma over time.

(2000). Latanoprost-Induced Side Effects and Potential Mechanisms. Journal of Toxicology: Cutaneous and Ocular Toxicology: Vol. 19, No. 4, pp. 177-197.

Recent advances in glaucoma genetics hold potential for dramatically changing the clinical care of glaucoma patients. To date, 5 primary open-angle glaucoma genes and 2 congenital glaucoma genes have been mapped. As more glaucoma genes are identified, earlier diagnosis for glaucoma should become more readily available. Progress in molecular genetics holds considerable promise for both current and future therapy of glaucoma. Glaucoma classification will be tailored to each individual based upon that person's family history, i.e. family glaucoma genotype. In the future, the optimum treatment for a specific glaucoma patient might rely on the knowledge of the phenotype of that person's causal gene, without having to resort to 'trial and error'. At this time, glaucoma treatment is restricted to lowering intraocular pressure. In the near future, with the knowledge of the pathophysiology caused by the defective glaucoma gene, more traditional drug treatments may be used to bypass the gene defect. Ultimately, gene therapy would replace the mutant gene with a normal one before visual loss has occurred as has been done with a model for retinitis pigmentosa, the retinal degeneration mouse.

Primary open-angle glaucoma (POAG) is a primary neuronal disease of the optic nerve without a definable cause which may require surgical intervention to prevent further visual loss and/or normalize intraocular pressure. Worldwide, POAG is the second leading cause of blindness; there are 45 million people today with POAG and bilateral blindness is present in 4.5 million people. We cataloged all known ocular biomarkers in the aqueous humor, trabecular meshwork, optic nerve, as well as systemic biomarkers in blood serum/plasma into four categories, namely, extracellular matrix (ECM), cell signaling molecules, aging/stress, and immunity-related changes. We present a theoretical model to show signaling pathways of the ECM, cell signaling, and innate immune response through activation of Toll-4 receptor and monocyte activation which may impact the success of glaucoma surgery. The innate immune system is driven by the danger signal, the low molecular weight hyaluronic acid, and the activation of monocytes which collectively may be useful in predicting surgical success in POAG.

Who goes blind with glaucoma? People with a family history of blindness go blind with glaucoma. The association of open angle glaucoma and family history has been known for years; the lifetime risk for first-degree relatives of affected individuals to develop open angle glaucoma is 22% when compared with a 2% risk in controls, but clinicians routinely overlook this fact when interviewing and evaluating patients. Patients are rarely accurate in reporting family history. Three genetic loci for glaucoma were first found in a single glaucoma practice in Portland, Oregon - GLC1C, GLC1F, and GLC1G - because of repeated and persistent inquiries about affected relatives. Asking a patient only once about his or her family history is rarely effective; patients tend to confuse macular degeneration, cataracts, and glaucoma.

To determine the adjunctive 24-h efficacy obtained with brinzolamide/timolol, or brimonidine/timolol fixed combinations (FCs) in open-angle glaucoma patients insufficiently controlled on travoprost monotherapy.Prospective, observer-masked, active controlled, crossover, comparison. Qualified primary open-angle or exfoliative glaucoma patients with a baseline intraocular pressure (IOP)18 mm Hg at 10:00 on travoprost monotherapy were randomized for 3 months to either brinzolamide/timolol, or brimonidine/timolol FC therapy adjunct to travoprost. Patients were then crossed-over to the opposite therapy for another 3 months. At baseline and at the end of each treatment period, the patients underwent 24-h IOP monitoring.Fifty patients completed the study. The mean 24-h baseline IOP on travoprost monotherapy was 20.1 mm Hg [95% confidence interval (CI): 19.6, 20.7 mm Hg]. Both adjunctive FC therapies significantly reduced the IOP at each time point and for the mean 24-h IOP (P0.001) compared with travoprost monotherapy. Brinzolamide/timolol FC provided a significantly lower mean 24-h IOP (17.2 mm Hg, 95% CI: 16.4, 17.9 mm Hg) than brimonidine/timolol FC (18.0 mm Hg, 95% CI: 17.3, 18.8 mm Hg) (P0.001). For all the 3 timepoints between 18:00 and 02:00, the brinzolamide/timolol FC provided a significantly lower IOP than the brimonidine/timolol FC (P≤0.036). For the other 3 timepoints, no significant differences were detected.This study demonstrated that both FCs provide statistically and clinically significant incremental 24-h IOP lowering to travoprost monotherapy. The brinzolamide/timolol FC however achieves a better mean 24-h IOP control owing to the greater efficacy in late afternoon and during the night.

Weill-Marchesani syndrome comprises short stature, brachydactyly, microspherophakia, glaucoma, and ectopia lentis is regarded as an autosomal recessive trait (McKusick 277600). We present two families each with affected individuals in 3 generations demonstrating autosomal dominant inheritance of Weill-Marchesani syndrome. Linkage analysis in these 2 families suggests a gene for Weill-Marchesani syndrome maps to 15q21.1. The dislocated lenses and connective tissue disorder in these families suggests that fibrillin-1 and microfibril-associated protein 1, which both map to 15q21.1, are candidate genes for Weill-Marchesani syndrome. Immunohistochemistry staining of skin sections from family 1 showed an apparent decrease in fibrillin staining compared to control individuals.

Purpose: To report the results of two studies on the use of dorzolamide as adjunctive therapy to timolol in patients with elevated intraocular pressure (IOP). In the larger study, the additive effect of dorzolamide administered twice daily also was compared with 2% pilocarpine. Methods: Both studies were parallel, randomized, double-masked, placebo-controlled comparisons. In the pilot study, 32 patients received 0.5% timolol twice daily plus either 2% dorzolamide twice daily or placebo twice daily for 8 days. In the Pilocarpine Comparison Study, 261 patients received 0.5% timolol twice daily plus 0.7% dorzolamide twice daily, 2% dorzolamide twice daily, 2% pilocarpine four times daily, or placebo (twice daily or 4 times daily) for 2 weeks. Patients then entered a 6-month extension period and received 0.5% timolol twice daily plus either 0.7% dorzolamide twice daily, 2% dorzolamide twice daily, or 2% pilocarpine four times daily. Results: In the pilot study, after 8 days, additional mean percent reductions in IOP for 2% dorzolamide and placebo were 17% and 3% at morning trough and 19% and 2% at peak, respectively. In the Pilocarpine Comparison Study, after 6 months, additional mean percent reductions in IOP (morning trough) were 9%, 13%, and 10% for 0.7% dorzolamide, 2% dorzolamide, and 2% pilocarpine, respectively. Patients receiving 2% pilocarpine had the highest rate of discontinuation due to a clinical adverse experience, and the use of dorzolamide was not associated with systemic side effects commonly observed with the use of oral carbonic anhydrase inhibitors. Conclusion: Dorzolamide twice daily was effective and well tolerated by the patients in these studies as adjunctive therapy to timolol. The larger study demonstrated that both concentrations of dorzolamide produce similar IOP-lowering effects to 2% pilocarpine.

Extracellular matrix turnover in the trabecular meshwork may play a role in regulating aqueous humor outflow. Laser trabeculoplasty is a common treatment for open-angle glaucoma. The mechanism of this treatment is not understood. We investigated changes in the levels and expression of the matrix metalloproteinases and their tissue inhibitors (TIMPs) in this tissue using cultured human anterior segment explants and standard clinical-parameter laser treatment. Medium gelatinase A activity levels are relatively high for sham-treated controls and are not changed dramatically following laser treatment. Medium gelatinase B and stromelysin activity levels are low in sham-treated explants and increase significantly by 24 h after treatment. TIMP1 levels, as assessed by immunoblots of Western transfers, are initially low. However, by 24 h TIMP1 levels have increased significantly. Using semi-quantitative reverse transcription and the polymerase chain reaction, mRNA levels of stromelysin, gelatinase B and TIMP1 are shown to increase after laser treatment, while gelatinase A and TIMP2 remain relatively constant. The increases in trabecular stromelysin and gelatinase B in response to laser trabeculoplasty may have important implications for the mechanism of action of this treatment for open-angle glaucoma.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the largest-selling groups of drugs in the world. We evaluated 144 cases of possible optic nerve abnormalities associated with the use of these agents, which were reported to the National Registry of Drug-Induced Ocular Side Effects. The findings include papillitis, retrobulbar optic neuritis, and papilledema. Although several NSAIDs have been reported to cause papilledema associated with or without pseudotumor cerebri, our data suggest the possibility that on rare occasions most NSAIDs are suspect. Although 120 cases of papillitis or retrobulbar optic neuritis associated with NSAID use have been reported to the Registry, a cause-and-effect relationship cannot be established. In general, visual complaints from patients taking NSAIDs were most commonly reported by those taking indomethacin, but only at a rate of 1.14 ± 0.46 incidents per 100 patient years. Patients with significant visual complaints who are taking NSAIDs may need to be evalua...

To review the published literature and summarize clinically relevant information about novel, or emerging, surgical techniques for the treatment of open-angle glaucoma and to describe the devices and procedures in proper context of the appropriate patient population, theoretic effects, advantages, and disadvantages.Devices and procedures that have US Food and Drug Administration clearance or are currently in phase III clinical trials in the United States are included: the Fugo blade (Medisurg Ltd., Norristown, PA), Ex-PRESS mini glaucoma shunt (Alcon, Inc., Hunenberg, Switzerland), SOLX Gold Shunt (SOLX Ltd., Boston, MA), excimer laser trabeculotomy (AIDA, Glautec AG, Nurnberg, Germany), canaloplasty (iScience Interventional Corp., Menlo Park, CA), trabeculotomy by internal approach (Trabectome, NeoMedix, Inc., Tustin, CA), and trabecular micro-bypass stent (iStent, Glaukos Corporation, Laguna Hills, CA).Literature searches of the PubMed and the Cochrane Library databases were conducted up to October 2009 with no date or language restrictions.These searches retrieved 192 citations, of which 23 were deemed topically relevant and rated for quality of evidence by the panel methodologist. All studies but one, which was rated as level II evidence, were rated as level III evidence.All of the devices studied showed a statistically significant reduction in intraocular pressure and, in some cases, glaucoma medication use. The success and failure definitions varied among studies, as did the calculated rates. Various types and rates of complications were reported depending on the surgical technique. On the basis of the review of the literature and mechanism of action, the authors also summarized theoretic advantages and disadvantages of each surgery.The novel glaucoma surgeries studied all show some promise as alternative treatments to lower intraocular pressure in the treatment of open-angle glaucoma. It is not possible to conclude whether these novel procedures are superior, equal to, or inferior to surgery such as trabeculectomy or to one another. The studies provide the basis for future comparative or randomized trials of existing glaucoma surgical techniques and other novel procedures.

We studied the histopathologic changes of three eyes enucleated two weeks, eight weeks, and 17 months, respectively, after noncontact Nd:YAG cyclophotocoagulation. The histologic findings at two weeks were destruction of the nonpigmented and pigmented ciliary body epithelium, occlusion of the capillaries of the ciliary processes, and ciliary body stromal necrosis in the region of the processes. Hyperplasia of the pigmented and nonpigmented epithelium, fibrosis and near total atrophy of the ciliary processes, and partial atrophy of the ciliary muscles were present at eight weeks and 17 months. We concluded that application of treatment 1.0 to 1.5 mm posterior to the corneoscleral limbus selectively destroys the pars plicata, and that, histologically, the mechanism for reducing intraocular pressure appears to be destruction of ciliary processes with reduction of aqueous formation.

PURPOSE. Primary open-angle glaucoma (POAG) is a complex disease with a genetic architecture that can be simplified through the investigation of individual traits underlying disease risk. It has been well studied in twin models, and this study was undertaken to investigate the heritability of some of these key endophenotypes in extended pedigrees. METHODS. These data are derived from a large, multicenter study of extended, Caucasian POAG families from Australia and the United States. The study included 1181 people from 22 extended pedigrees. Variance components modeling was used to determine the heritabilities of maximum intraocular pressure (IOP), maximum vertical cup-to-disc ratio (VCDR), and mean central corneal thickness (CCT). Bivariate quantitative genetic analysis between these eye-related phenotypes and POAG itself was performed to determine whether any of these traits represent true endophenotypes. RESULTS. Heritability estimates for IOP, VCDR, and CCT (0.42, 0.66, and 0.72, respectively) were significant and show strong concordance with data in previous studies. Bivariate analysis revealed that both IOP (RhoG = 0.80; P = 9.6 x 10(-6)) and VCDR (RhoG = 0.76; P = 4.8 x 10(-10)) showed strong evidence of genetic correlation with POAG susceptibility. These two traits also correlated genetically with each other (RhoG = 0.45; P = 0.0012). Alternatively, CCT did not correlate genetically with risk of POAG. CONCLUSIONS. All the proposed POAG-related traits have genetic components. However, the significant genetic correlations observed between IOP, VCDR, and POAG itself suggest that they most likely represent true endophenotypes that could aid in the identification of genes underlying POAG susceptibility. CCT did not correlate genetically with disease and is unlikely to be a useful surrogate endophenotype for POAG.

Patients frequently ask about the applicability of stem cell research and therapy for their glaucoma. Stem cell therapies do offer significant promise in glaucoma. Like other neuro-degenerative diseases where stem cells may be of benefit, glaucoma offers logical targets for stem cell therapy. For glaucoma, these are the optic nerve and the trabecular meshwork. In Parkinson’s disease, stem cells delivered to the basal ganglia have proven to have significant therapeutic benefit.

The goals of glaucoma therapy for the patient and the physician are ultimately the same ones, but they are often approached from very different perspectives. Most patients with glaucoma visit their ophthalmologist on a regular basis because they understand that they have a potentially blinding disease that requires compliance with examinations and therapy. The patient’s goal is to preserve the vision manifested in his or her visual field. While the treating ophthalmologist’s overriding goal also is to preserve visual function for the patient, the doctor’s immediate goal is to preserve those physiological structures whose anatomy underlies the basis for the ability to see. In treating the patient, the ophthalmologist needs to take into account new understandings of risk factors as well as new concepts, such as those that suggest that aging is a major risk factor for glaucoma.

Glaucoma can be defined in many different ways, as evidenced in this text. The most common definition is based on anatomy and pressure, with open angle glaucoma being most common among Caucasians in North America, low or normal tension glaucoma being most common among the Japanese, and angle closure being most common among other Asians. (Such clear delineations are not currently recognized in other ethnic groups.) Certain regions of the world give rise to the special circumstances of exfoliation. In the U.S., I am continually surprised with the discovery of new geographic foci of exfoliation. Regionally, it has been recognized for decades that exfoliation has a higher than normal prevalence in the greater Minneapolis area and around Minnesota - it is likely that this is due to the large number of individuals of Scandinavian descent. A week before writing this, I found out that exfoliation was also very common in the Salt Lake City area, where again northern European heritage is considered the causal factor. The genetics of exfoliation may eventually be studied more extensively in the geographic areas that are most highly affected. Ultimately, what really causes glaucoma is likely to be defined in genetic terms, just as exfoliation (but not necessarily exfoliative glaucoma) has been. Risk factors and “environmental factors,” as enumerated in the first chapters of this text, will always be important and have an impact upon the susceptible eye.

The unique aspects of glaucoma care, due to its lifelong nature, represent specific medical-legal challenges. This is at least in part due to the fact that while loss of sight is infrequently life threatening, it is almost always devastating. Thus, patients who have suffered loss of sight are often well enough to personally pursue litigation. While glaucoma does not generate the most litigation in ophthalmology (cataract surgery lawsuits are more common), civil suits claiming “failure to diagnose” glaucoma are relatively common. On average, 300 ophthalmologists per year were sued between 1985 and 2007, of which roughly one-quarter resulted in judgments against the ophthalmologists. Side effects of glaucoma medications and the need to adequately warn the patient, and/or the patient’s caregiver, about these side effects represent central challenges that must be addressed to ensure the high quality of care while also minimizing legal liability.

Endothelial cells were obtained from 23 human corneal-scleral rims. Donors were 0.2-37 yr of age. Most cultures obtained from donors under 30 yr ceased to grow after the seventh passage (3-24 weeks). Growth from 17- and 25-yr-old donors were maintained for nine passages (26 weeks) and 18 passages (100 weeks), respectively. Cultures were established from 12 rims, using growth factors in uncoated culture flasks or epidermal growth factor (EGF) in an extracellular matrix-coated (ECM) flask. EGF improved the growth potential of the cells; a combination of an ECM-coated-tissue culture flask with EGF in the medium provided an improved environment for continuous growth.

Primary open-angle glaucoma is recognized as a disease of aging, and studies show a relationship between aging and trabecular meshwork (TM) cell density. Human TM cell division occurs primarily in the anterior, non-filtering region. A commonly used glaucoma treatment, laser trabeculoplasty (LTP), triggers and increases cell division, as well as cell migration of these anterior TM cells. These freshly-divided migrating cells repopulate the burned laser sites, suggesting that they are stem cells. Several studies concerning this putative TM stem cell will be discussed.