Plasma GDF-15 concentration is not elevated in open-angle glaucoma.

AIM: Recently, the level of growth differentiation factor 15 (GDF-15) in blood, was proposed as biomarker to detect mitochondrial dysfunction. In the current study, we evaluate this biomarker in open-angle glaucoma (OAG), as there is increasing evidence that mitochondrial dysfunction plays a role in the pathophysiology of this disease. METHODS: Plasma GDF-15 concentrations were measured with ELISA in 200 OAG patients and 61 age-matched controls (cataract without glaucoma). The OAG patient group consisted of high tension glaucoma (HTG; n = 162) and normal tension glaucoma (NTG; n = 38). Groups were compared using the Kruskal-Wallis nonparametric test with Dunn's multiple comparison post-hoc correction. GDF-15 concentration was corrected for confounders identified with forward linear regression models. RESULTS: Before correcting for confounders, median plasma GDF-15 levels was significantly lower in the combined OAG group (p = 0.04), but not when analysing HTG and NTG patients separately. Forward linear regression analysis showed that age, gender, smoking and systemic hypertension were significant confounders affecting GDF-15 levels. After correction for these confounders, GDF-15 levels in OAG patients were no longer significantly different from controls. Subgroup analysis of the glaucoma patients did not show a correlation between disease severity and plasma GDF-15, but did reveal that for NTG patients, intake of dietary supplements, which potentially improve mitochondrial function, correlated with lower plasma GDF-15. CONCLUSION: The present study suggests that plasma GDF-15 is not suited as biomarker of mitochondrial dysfunction in OAG patients.

The effect of daily life activities on intraocular pressure related variations in open-angle glaucoma.

The recent advent of continuous intraocular pressure (IOP) telemetry has led to an increased awareness of the importance of IOP fluctuations, and theories have emerged that IOP variations could play as much a role in glaucoma progression as the mean level of IOP. The aim of the present study was to evaluate the direct effect of common daily activities on IOP-related profiles. Primary open-angle glaucoma and glaucoma suspect patients were prospectively enrolled from specialist clinics at the University of California San Diego (UCSD), USA. Patients were fitted with a SENSIMED Triggerfish (TF) contact lens sensor (CLS) and were instructed to return to their usual daily activities for 24 h. They were asked to record each specific activity or event in a diary. The protocol was repeated twice. The following events were recorded: "walking/cycling", "resistance training", "yoga/meditation", and "emotional stress". CLS measurements recorded 60-to-30 min prior to each event were used as a baseline reference, and all IOP-related fluctuations for 120 min after the start of each event were reported in relation to this reference. Forty relevant events from 22 CLS recordings in 14 patients were retrieved from the diaries. Walking/cycling (n = 10) caused a small but statistically significant elevation of the IOP-related profile during the activity (p = 0.018). Resistance training (n = 11) caused a persistent elevation of the IOP-related profile from the onset of the activity (p = 0.005) through 120 min after the activity was stopped (p = 0.007). Yoga/meditation (n = 4) caused a sustained drop in the IOP-related profiles through to 120 min, although this was not statistically significant (p > 0.380). Emotional stress (n = 13) was associated with a gradual elevation of the IOP-related profile from the start of the stressful stimulus. Both early and late variations were statistically significant (p = 0.038 and p = 0.021, respectively). The present study suggests that emotional stress and resistance training may be associated with persistent IOP-related profile elevation.

A neuroglia-based interpretation of glaucomatous neuroretinal rim thinning in the optic nerve head.

Neuroretinal rim thinning (NRR) is a characteristic glaucomatous optic disc change. However, the precise mechanism of the rim thinning has not been completely elucidated. This review focuses on the structural role of the glioarchitecture in the formation of the glaucomatous NRR thinning. The NRR is a glia-framed structure, with honeycomb geometry and mechanically reinforced astrocyte processes along the transverse plane. When neural damage selectively involves the neuron and spares the glia, the gross structure of the tissue is preserved. The disorganization and loss of the glioarchitecture are the two hallmarks of optic nerve head (ONH) remodeling in glaucoma that leads to the thinning of NRR tissue upon axonal loss. This is in contrast to most non-glaucomatous optic neuropathies with optic disc pallor where hypertrophy of the glioarchitecture is associated with the seemingly absent optic disc cupping. Arteritic anterior ischemic optic neuropathy is an exception where pan-necrosis of ONH tissue leads to NRR thinning. Milder ischemia indicates selective neuronal loss that spares glia in non-arteritic anterior ischemic optic neuropathy. The biological reason is the heterogeneous glial response determined by the site, type, and severity of the injury. The neuroglial interpretation explains how the cellular changes underlie the clinical findings. Updated understandings on glial responses illustrate the mechanical, microenvironmental, and microglial modulation of activated astrocytes in glaucoma. Findings relevant to the possible mechanism of the astrocyte death in advanced glaucoma are also emerging. Ultimately, a better understanding of glaucomatous glial response may lead to glia-targeting neuroprotection in the future.

Changes in the Anterior Lamina Cribrosa Morphology with Glaucoma Severity.

This study was designed to evaluate if primary open angle glaucoma (POAG) and its severity are associated with the shape of the lamina cribrosa (LC) as measured by a global shape index (LC-GSI), or other indices of LC curvature or depth. Optical coherence tomography (OCT) scans of the optic nerve head (OHN) were obtained from subjects with POAG (n = 99) and non-glaucomatous controls (n = 76). ONH structures were delineated, the anterior LC morphology reconstructed in 3D, and the LC-GSI calculated (more negative values denote greater posterior concavity). Anterior LC depth and 2D-curvature were also measured. Severity of glaucoma was defined by the extent of visual field loss, based on the Hodapp-Parrish-Anderson grading. Linear regression analyses compared LC characteristics between controls, mild-moderate, and advanced POAG groups. After adjusting for age, gender, ethnicity, intraocular pressure, axial length and corneal curvature, the LC-GSI was most negative in the advanced POAG group (mean [standard error] = -0.34 [0.05]), followed by the mild-moderate POAG group (-0.31 [0.02]) and then controls (-0.23 [0.02], PTrend = 0.01). There was also a significant trend of increasing LC depth and greater LC horizontal curvature with increasing severity of glaucoma (PTrend = 0.04 and 0.02, respectively). Therefore, with more severe glaucoma, the LC-GSI was increasingly more negative, and the anterior LC depth and curvature greater. These observations collectively correspond to greater cupping of the ONH at the level of the LC. As the LC-GSI describes the 3D anterior LC morphology, its potential usage may be complementary to existing ONH parameters measured on OCT.

Combined Use of Retinal Nerve Fiber Layer and Ganglion Cell-Inner Plexiform Layer Event-based Progression Analysis.

PURPOSE: To evaluate patterns of glaucomatous structural progression using the combined retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GCIPL) event-based progression analysis feature provided by spectral-domain optical coherence tomography (SD-OCT)'s - (GPA) software. DESIGN: Retrospective observational case series. METHODS: Seventy-nine (79) patients were identified with open-angle glaucoma (OAG) showing clinically confirmed structural progression within a minimum 3-year follow-up period. For each eye, RNFL and GCIPL GPA data were obtained from serial SD-OCT data from 2012 to 2017. An integrated GPA map thereafter was merged by vascular landmark-guided superimposition of RNFL and GCIPL GPA event-based progression maps onto the RNFL imagery (resulting in what we call the GPA PanoMap). The GPA PanoMap progression patterns were classified as (1) RNFL-only, (2) GCIPL-only, (3) concurrent (both RNFL and GCIPL), (4) GCIPL after RNFL, and (5) RNFL after GCIPL. The locations of structural progression were classified, based on an earlier schematic model, as (1) superior vulnerability zone (SVZ), (2) papillomacular bundle (PM), (3) macular vulnerability zone (MVZ), and (4) inferoinferior portion. Structural progression patterns on the GPA PanoMap were evaluated according to the location of progression. Among the eyes with progression in the inferior hemiretina, structural progression patterns on the GPA PanoMap were evaluated according to the baseline structural damage. RESULTS: On the GPA PanoMap, when structural progression was located in the SVZ or inferoinferior portion, it was detected only in the RNFL area; when progression was located in the PM or MVZ, various patterns were observed, among which the concurrent pattern was the majority in both areas (43.8% and 45.6% in the PM and MVZ, respectively). Among the eyes with progression in the inferior hemiretina (n = 66), the location of progression varied but did not differ significantly according to the baseline deviation map (P = .440). The progression patterns of MVZ were significantly different among the baseline deviation map patterns (P = .023); however, all of the progression patterns of the inferoinferior portion were RNFL-only. CONCLUSION: The various progression patterns were confirmed according to the locations and baseline patterns of glaucomatous structural change on the integrated GPA map (GPA PanoMap). Combined use of RNFL and GCIPL GPA or the GPA PanoMap could be useful for determination of structural progression and understanding of its patterns in patients with glaucoma.

Role of the water-drinking test in medically treated primary open angle glaucoma patients.

PURPOSE: The water-drinking test (WDT) has recently re-emerged as a possible way to determine the competency of the trabecular meshwork. We performed a prospective interventional study to test the hypothesis that the WDT could be useful in assessing fluctuations in patients undergoing treatment for primary open angle glaucoma (POAG). METHODS: We included 122 patients; 62 on medical treatment for POAG (n=123 eyes) and 60 controls (n=120 eyes). The study group had been on intraocular pressures (IOP) lowering treatment continuously for at least 3months with stable IOP. The WDT was performed during fasting and was considered positive if it fluctuated ≥6mmHg. RESULTS: The patients on medical treatment had a mean age of 50.56±18.45 years vs. 51.35±11.22 for the controls (P=0.34); with 71% being female in the study group and 77% in the control group. In the study group; 52% were on beta blockers (n=64), 27% combination of two or more medications (n=33), 19% prostaglandin analogues (n=24) and 2% alpha agonists (n=2). The WDT was positive in 17.07% (n=21) in the study group and 2.5% (n=3) in the control group (P=0.0001). The mean fluctuation was 7.14±2.15mmHg in the study group and 6.00±0mmHg in the controls (P=0.33). A positive WDT was found in 33.33% (n=11) of those on combination therapy; 12.5% (n=3) prostaglandin analogues and 10.94% (n=7) beta blockers (P=0.03). Combination therapy had the highest positive WDT fluctuation (7.54±2.87) followed by prostaglandin analogues (7.00±1.00) and beta blockers (6.57±0.78) with a P value of 0.44. CONCLUSIONS: The WDT can identify significant fluctuations in eyes with POAG that are medically treated.

Life under pressure: The role of ocular cribriform cells in preventing glaucoma.

Primary open-angle glaucoma is a multifactorial blinding disease often impacting the two pressure-sensitive regions of the eye: the conventional outflow pathway and the optic nerve head (ONH). The connective tissues that span these two openings in the globe are the trabecular meshwork of the conventional outflow pathway and the lamina cribrosa of the ONH. Resident cribiform cells of these two regions are responsible for actively remodeling and maintaining their connective tissues. In glaucoma, aberrant maintenance of the juxtacanalicular tissues (JCT) of the conventional outflow pathway results in ocular hypertension and pathological remodeling of the lamina cribrosa results in ONH cupping, damaging retinal ganglion cell axons. Interestingly, cells cultured from the lamina cribrosa and the JCT of the trabecular meshwork have similarities regarding gene expression, protein production, plus cellular responses to growth factors and mechanical stimuli. This review compares and contrasts the current knowledge of these two cell types, whose health is critical for protecting the eye from glaucomatous changes. In response to pressure gradients across their respective cribiform tissues, the goal is to better understand and differentiate healthy from pathological behavior of these two cell types.

Comparison of prelaminar thickness between primary open angle glaucoma and normal tension glaucoma patients.

MAIN OBJECTIVE: The thinning of prelaminar tissue and prelamina cupping is known to occur by ischemia, as we see in anterior ischemic optic neuropathy. Since normal tension glaucoma (NTG) is thought to be more related to vascular factor than in primary open-angle glaucoma (POAG), we hypothesized that prelamina thinning may occur prominently in NTG patients. This study investigated the difference in prelaminar tissue thickness between patients with POAG and NTG and verified the factors related to prelaminar thinning. METHODS: Complete ophthalmic examination including standard automatic perimetry was performed in all patients. The prelaminar tissue thickness was measured in all patients by performing enhanced depth imaging with a Heidelberg Spectralis Optical Coherence Tomography. The retinal nerve fiber layer and optic nerve head parameters were obtained using the Heidelberg Retina Tomography II and Cirrus Optical Coherence Tomography. Various ocular factors and their relationships with prelaminar thickness were analyzed. RESULTS: The mean prelaminar tissue thickness was significantly thinner in patients with POAG than in those with NTG. The difference in the prelaminar thickness between patients with POAG and those with NTG was greater in the early field defect group than in the moderate and severe field groups. In multivariate analysis, the mean prelaminar thickness was related to the intraocular pressure, mean deviation, cup-disc ratio, and cup volume. CONCLUSIONS: The prelaminar tissue was thinner in patients with POAG than in patients with NTG, and intraocular pressure had a strong influence on the prelaminar thickness in both POAG and NTG. This may indicate that mechanical compression is the main pathogenic factor in both POAG and NTG.

Osteogenesis imperfecta and primary open angle glaucoma: genotypic analysis of a new phenotypic association.

PURPOSE: Osteogenesis imperfecta (OI) is a group of inherited disorders characterized by bone fragility. Ocular findings include blue sclera, low ocular rigidity, and thin corneal thickness. However, there are no documented cases linking OI and primary open angle glaucoma (POAG). In this report, we describe three individuals, one isolated case and two from a multiplex family, with OI type I and POAG. METHODS: Available family members with OI and POAG had a complete eye examination, including visual acuity, intraocular pressure (IOP), pachymetry, slit-lamp exam, dilated fundus exam, and visual fields. DNA from blood samples was sequenced and screened for mutations in COL1A1/2 and myocilin (MYOC). RESULTS: All subjects had OI type I. Findings of POAG included elevated IOP, normal gonioscopy, and glaucomatous optic disc cupping and visual field loss. POAG cosegregated with OI in the multiplex family. The multiplex family had a single nucleotide insertion (c.540_541insC) in COL1A1 resulting in a frameshift mutation and a premature termination codon. The sporadic case had a COL1A1 splice acceptor site mutation (c.2452-2A>T or IVS36-2A>T) predicted to result in a premature termination codon due to intron inclusion or a cryptic splice site. None of the glaucoma cases had mutations or sequence changes in MYOC. CONCLUSIONS: We identified two novel mutations in COL1A1 in individuals with OI type I and POAG. Thus, some mutations in COL1A1 may be causative for OI and POAG. Alternatively, susceptibility genes may interact with mutations in COL1A1 to cause POAG.

Cupping reversal in pediatric glaucoma--evaluation of the retinal nerve fiber layer and visual field.

PURPOSE: To identify optic nerve head (ONH) cupping reversal and associated optical coherence tomography (OCT) and Humphrey visual field changes in pediatric glaucoma. DESIGN: Retrospective observational case series. METHODS: Sequential surgical cases of juvenile open-angle glaucoma (OAG) or primary congenital glaucoma (PCG) with sustained postoperative intraocular pressure (IOP) reduction. Group 1 had preoperative and postoperative ONH photographs and OCT; Group 2 had preoperative clinical ONH assessment and postoperative imaging. Cupping evaluation was confirmed by masked glaucoma and neuro-ophthalmology specialists. RESULTS: Of 80 cases, 9 eyes (9 children) met criteria for Group 1; 24 eyes (19 children) met criteria for Group 2. Group 1: Five of 9 eyes (56%) demonstrated cupping reversal, with preoperative vs postoperative mean IOP 34.2 ± 6.6 mm Hg vs 10.6 ± 4.1 mm Hg (P < .00001) and mean average retinal nerve fiber layer (RNFL) 71.0 ± 30 µm vs 62.8 ± 24 µm (P = .4), respectively. RNFL was stable in 4 of 5 eyes (all juvenile OAG), but thinned (Δ = -41 µm) in 1 eye with PCG. Humphrey visual fields (reliable in 2 of 3 eyes) showed no significant change. Group 2: Fourteen of 24 PCG eyes (58%) demonstrated cupping reversal, with preoperative vs postoperative mean IOP 36.1 ± 8.9 mm Hg vs 13.3 ± 2.1 mm Hg (P < .00001). Two eyes had thin RNFL postoperatively despite healthy-appearing ONH. Postoperative RNFL showed statistically significant linear correlation with preoperative (but not postoperative) cup-to-disc ratio. Limitations include small numbers, few reliable Humphrey visual fields, and absent preoperative imaging (Group 2). CONCLUSION: Some eyes with IOP reduction and ONH cupping reversal show continued RNFL thinning postoperatively. The preoperative ONH cup-to-disc ratio predicted the postoperative RNFL better than the postoperative "reversed and smaller" cup-to-disc ratio. Cupping reversal in pediatric glaucoma may not predict improved ONH health and deserves further study.

Family-based analysis identified CD2 as a susceptibility gene for primary open angle glaucoma in Chinese Han population.

Primary open angle glaucoma (POAG) is characterized by optic disc cupping and irreversible loss of retinal ganglion cells. Few genes have been detected that influence POAG susceptibility and little is known about its genetic architecture. In this study, we employed exome sequencing on three members from a high frequency POAG family to identify the risk factors of POAG in Chinese population. Text-mining method was applied to identify genes associated with glaucoma in literature, and protein-protein interaction networks were constructed. Furthermore, reverse transcription PCR and Western blot were performed to confirm the differential gene expression. Six genes, baculoviral inhibitors of apoptosis protein repeat containing 6 (BIRC6), CD2, luteinizing hormone/choriogonadotropin receptor (LHCGR), polycystic kidney and hepatic disease gene 1 (PKHD1), phenylalanine hydroxylase (PAH) and fucosyltransferase 7 (FUT7), which might be associated with POAG, were identified. Both the mRNA expression levels and protein expression levels of HSP27 were increased in astrocytes from POAG patients compared with those from normal control, suggesting that mutation in CD2 might pose a risk for POAG in Chinese population. In conclusion, novel rare variants detected by exome sequencing may hold the key to unravelling the remaining contribution of genetics to complex diseases such as POAG.

Changes in the morphological and functional patterns of the ocular surface in patients treated with prostaglandin analogues after the use of TSP 0.5%® preservative-free eyedrops: a prospective, multicenter study.

AIM: To investigate and compare the effects of topical benzalkonium chloride-preserved prostaglandins (PGAs) on the ocular surface in patients with primary open-angle glaucoma before and after 3 months of treatment with additional 0.5% preservative-free tamarind seed polysaccharide single-dose eyedrops (TSP®, Oftagen, Pisa, Italy). METHODS: This was a prospective, longitudinal, multicenter study. From 5 different Italian glaucoma centers, 10 glaucomatous patients were recruited in each center. All the patients were treated with a PGA with preservative for at least 1 year. Preservative-free artificial tears 3 times per day were prescribed. The participants were subjected to clinical and instrumental evaluation at baseline, after 1 month and after 3 months of treatment. All patients were examined with a digital corneal confocal laser scanning microscope (HRT II Rostock Cornea Module). RESULTS: After 3 months of TSP 0.5% treatment, an improvement of some ocular signs and symptoms was found. The percentage of conjunctival hyperemia decreased from 67 to 13%. Schirmer's test and breakup time significantly changed from the baseline after 3 months. Confocal microscopy showed a significant increase in conjunctival goblet cells. CONCLUSION: Artificial substitutes, in particular TSP 0.5%, might protect the ocular surface hence giving higher compliance, adherence and quality of life to the patients.

Effects of the time of antihypertensive drugs administration on the stage of primary open-angle glaucoma in patients with arterial hypertension.

Many patients with glaucoma suffer from arterial hypertension (AH). It has been proved that both AH and low blood pressure (BP) at night are important vascular risk factors for primary open-angle glaucoma (POAG). The aims of this study were to assess the severity of pathological changes within the optic nerve and characteristics of blood flow in selected arteries of the eyeball and orbit in patients with POAG and controlled hypertension, in relation to the time of hypotensive drugs administration. Eighty-eight patients with POAG and treated, controlled hypertension were examined. The patients were divided into two subgroups, consisting of group A (n = 43), in whom hypotensive drugs were dosed only in the morning and group B (n = 45), in whom hypotensive drugs were also taken in the evening. In patients who were taking hypotensive drugs also in the evening (group B), there was a statistically significant lower mean perfusion pressure at night, a greater visual field loss and reduced amplitude of evoked potentials. Our analysis showed significantly worse changes in the parameters relating to the optic nerve in patients taking hypertensive medicines in the evening and also significantly lower perfusion pressures at night.

Visual prognosis, intraocular pressure control and complications in phacomorphic glaucoma following manual small incision cataract surgery.

AIMS: To evaluate intraocular pressure (IOP) control, visual prognosis and complications following manual small incision cataract surgery among eyes with phacomorphic glaucoma. MATERIALS AND METHODS: This prospective, non-randomized interventional consecutive case series included all patients with phacomorphic glaucoma who presented to a tertiary eye care referral center in South India between March 2006 and April 2007. All patients underwent slit-lamp bio-microscopy, applanation tonometry and gonioscopy of the other eye to rule out angle closure. Small incision cataract surgery with intraocular lens implantation was performed in all affected eyes. Complete ophthalmic examination was done at each follow-up visit. RESULTS: A total of 74 eyes with phacomorphic glaucoma were included in this study. The preoperative mean IOP was 38.4+/-14.3 mmHg and mean IOP at last follow-up was 12.7+/-2.4 mmHg. There was a statistically significant difference between IOP at presentation and IOP at last follow-up (P< 0.001). None of the eyes required long-term antiglaucoma medication. No significant intraoperative complications were noted. The final postoperative best corrected visual acuity was 20/40 or better in 51 patients. Eighteen eyes had corneal edema and 36 eyes had anterior chamber inflammation. Both conditions resolved with standard medical therapy. CONCLUSION: Manual small incision cataract surgery is safe and effective in controlling IOP and achieving good functional visual acuity with minimal complications in the management of phacomorphic glaucoma in developing countries.

Retinal ganglion cell neuroprotection in a rat model of glaucoma following brimonidine, latanoprost or combined treatments.

The aim of the present study is to evaluate the neuroprotective effect of two antiglaucomatous substances, regardless of their hypotensive effect in the eye. Brimonidine, which does not reduce IOP when administered intraperitoneally, and latanoprost, which has a renowned hypotensive effect topically. We examined rat retinal ganglion cell (RGC) survival and size distribution in experimental glaucoma in response to different glaucomatous agents. IOP was elevated by episcleral vein cauterization (EVC) prior to the application of different treatments: (I) PBS application (control group), (II) intraperitoneal administration of brimonidine (a general hypotensive agent), (III) topical application of latanoprost (an ocular hypotensive agent), and (IV) latanoprost combined with brimonidine. After 12 weeks, RGCs were retrogradely labeled with fluorogold and RGC density was analyzed. EVC caused a significant increase (42%) in IOP in each group before drug treatment. After 12weeks of EVC, RGC survival in control vs. EVC rats was 78.9+/-3.2%. No IOP reduction was observed in brimonidine injected rats, but RGC survival at 12 weeks was total (103.7+/-2.7%). In latanoprost treated rats, IOP dropped by around 22% and 94.7+/-3.7% of the RGC population survived. Finally in the latanoprost+brimonidine combined group, IOP was significantly reduced by 25% and 94.4+/-2.2% of RGCs survived. Surprisingly, whereas EVC led to a 6% increase in RGC soma size, brimonidine treatment was associated with a 9% reduction in the soma size of RGCs at 12 weeks. We conclude that brimonidine exerts a neuroprotective effect via a mechanism which is independent of IOP reduction. These findings indicate that cell survival in glaucoma may be enhanced by neuroprotective strategies which are independent of IOP reduction. No synergistic neuroprotective effect was observed when both treatments were applied simultaneously.

Feline primary open angle glaucoma.

OBJECTIVES: We have documented the histomorphological features of feline primary open angle glaucoma. DESIGN: A retrospective morphologic study of eight affected eyes from eight cats, from 1992 to 2006 extracted from a pathology collection, which includes 4000 feline submissions and 1100 cases of feline glaucoma. PROCEDURE: Sections of affected globes, stained with H&E or with alcian blue were examined with a light microscope. Eyes that did not fulfill the criteria for primary open angle glaucoma were excluded from the study. RESULTS: The mean age was 9.1 years. Five cats were female and three cats were male. The breeds included five DSH, two Burmese, and one DLH cat. Significant histomorphological findings included an open irido-corneal angle with an open ciliary cleft in all cases, loss of ganglion cells in eight of eight cases, cupping and gliosis of the optic nerve head in four of four cases in which the optic nerve was adequately sampled, and myxomatous changes of the stroma surrounding the vortex veins in seven of eight cases. CONCLUSIONS: Primary open angle glaucoma in cats is a rare disease that should be taken into consideration when investigating cases of feline glaucoma. The pathogenesis of aqueous outflow obstruction in these cases is not known. This study describes eight additional cases of feline primary open angle glaucoma in cats without an identified cause.

Mitomycin C induces multidrug resistance in glaucoma surgery.

BACKGROUND: Despite the adjuvant use of mitomycin C during trabeculectomy, failures still occur. We investigated whether cultured human Tenon fibroblasts exposed to low-dose mitomycin C developed a multidrug resistance phenotype in vitro, and whether mitomycin C treatment during previous filtration surgery induces P-glycoprotein expression in vivo. METHODS: Cultured human Tenon fibroblasts treated with low-dose 0.01 nM mitomycin C for 2 weeks were subsequently treated with 0.1 to 100 microM mitomycin C in the absence or presence of 4 microM verapamil, and allowed to recover for 24 hours. Low-dose mitomycin C-treated fibroblasts were analysed for P-glycoprotein expression using flow cytometry, immunoblotting, and RT-PCR for mdr-1 mRNA. In addition, fibroblasts were treated with low dose 0.1 nM 5-fluorouracil for 2 weeks and analysed for P-glycoprotein expression using flow cytometry. Expression of P-glycoprotein was analysed in surgically removed Tenon tissue (n = 30) using immunohistochemistry. Of the 30 patients, 20 had a previous trabeculectomy, of which nine had previous adjuvant therapy with mitomycin C during trabeculectomy. RESULTS: Partial resistance to mitomycin C after low-dose mitomycin C pre-treatment was significantly neutralised by the addition of verapamil. Low-dose mitomycin C up-regulated P-glycoprotein expression, but not mdr-1 mRNA expression. 5-Fluorouracil did not induce P-glycoprotein expression. P-glycoprotein expression was detected in all nine patients exposed to mitomycin C during previous trabeculectomies. Only six of 21 specimens from patients not previously exposed to mitomycin C showed faint P-glycoprotein expression. CONCLUSION: The induction of P-glycoprotein by mitomycin C could explain some failures that occur after repeated use of mitomycin C during trabeculectomy. The concomitant use of verapamil or the use of 5-fluorouracil alone could increase the success rate of repeat trabeculectomies.

Optic disc topography and peripapillary retinal nerve fiber layer thickness in nonarteritic ischemic optic neuropathy and open-angle glaucoma.

OBJECTIVE: To evaluate the results of scanning laser tomography and scanning laser polarimetry (SLP) and the correlations with visual field damage (VFD) in eyes with nonarteritic ischemic optic neuropathy (n-AION) compared with eyes with open-angle glaucoma (OAG). DESIGN: Cross-sectional study. PARTICIPANTS: Thirty-three eyes of 33 patients with n-AION and 33 eyes with OAG whose age and VFD evaluated with the Humphrey field analyzer were matched to those of the n-AION eyes. MAIN OUTCOME MEASURES: The parameters of optic disc topography obtained with the Heidelberg Retina Tomograph II (HRT II) and retinal nerve fiber layer (RNFL) thickness with GDx with variable corneal compensation and the correlation to VFD. RESULTS: The cup area, cup-to-disc area ratio, and mean cup depth were significantly smaller, and the cup shape measure more negative, in the n-AION eyes than in the OAG eyes (P<0.001), whereas rim area was significantly greater (P<0.001). Multivariate analyses showed that none of disc area, rim area, and mean cup depth in the n-AION eyes and only rim area (P = 0.029) in the OAG eyes was significantly associated with mean deviation (MD). Ellipse average of RNFL thickness significantly correlated with MD in the n-AION eyes (P = 0.045) and in the OAG eyes (P = 0.022). CONCLUSIONS: Disc topography of eyes with n-AION was quantitatively characterized by small and shallow cupping and a relatively large rim area compared to eyes with OAG matched for age and VFD. In eyes with n-AION, significant correlation with VFD was found only for the RNFL thickness evaluated with SLP but not for the HRT II parameters.

Glaucoma phenotype in pedigrees with the myocilin Thr377Met mutation.

OBJECTIVE: To investigate the phenotype and age-related penetrance of primary open-angle glaucoma (POAG) in Australian families with the myocilin mutation Thr377Met. METHOD AND DESIGN: Cross-sectional genetic study. Four unrelated pedigrees carrying the Thr377Met mutation were ascertained from more than 2000 consecutive cases of POAG in the Glaucoma Inheritance Study in Tasmania and from families with glaucoma referred to the study from throughout Australia. Index cases and available family members were examined for signs of glaucoma, and the presence of the GLC1A Thr377Met mutation was ascertained by single-strand conformation polymorphism analysis and subsequent direct sequencing. RESULTS: From the 4 pedigrees carrying the Thr377Met mutation, 23 individuals with either ocular hypertension (OHT) or POAG were found, with a mean +/- SD age at diagnosis of 41.2 +/- 11.5 years, and a mean peak intraocular pressure of 31.7 +/- 9.9 mm Hg. A further 9 mutation carriers older than 18 years were studied who as yet showed no signs of OHT or POAG (6 of these 9 were younger than 30 years). A single individual with POAG was identified who did not carry the Thr377Met mutation. For Thr377Met carriers, age-related penetrance for OHT or POAG was 88% at age 30 years. A positive family history of POAG was present for 3 of the 4 index cases. Thirteen (57%) of the 23 Thr377Met carriers with OHT or POAG had undergone glaucoma drainage surgery. Although the glaucoma in these families appears to be pressure dependent, 2 individuals showed optic disc cupping before detected elevation in intraocular pressure. One family was of British origin, with a different background haplotype from the other 3 families from Greece or Macedonia, who shared a common haplotype. CONCLUSIONS: The GLC1A Thr377Met mutation is associated with POAG that, in the pedigrees studied, had a younger age at onset and higher peak intraocular pressure than in pedigrees with the more common Gln368STOP mutation. In addition, patients with glaucoma with the Thr377Met mutation were more likely to have undergone glaucoma drainage surgery.

Observer variability in optic disc assessment: implications for glaucoma shared care.

Demonstrating that optometrists can make valid and reliable assessments of optic disc features is an important prerequisite for establishing schemes for shared care/co-management. Previous studies have estimated observer variability among experts in the assessment of optic disc cupping, but there has been a paucity of information on observer variability amongst optometrists. This paper describes a study to investigate intra- and inter-observer variability for a range of disc features, as graded by both ophthalmologists and optometrists. Five observers (three optometrists and two ophthalmologists) graded 48 stereo-pairs of optic disc photographs from 48 patients on two separate occasions. Each observer graded the following features: vertical and horizontal C/D ratios, narrowest rim width, the presence/absence of a disc haemorrhage, focal pallor of the neuroretinal rim, peri-papillary atrophy, the steepness of the cup-edge and the presence/absence of the cribriform sign. The average intra- and inter-observer standard deviation (SD) of differences are, respectively, 0.11 and 0.19 for the vertical C/D ratios and 0.10 and 0.18 for the horizontal C/D ratios. For the vertical C/D ratio the average weighted kappa (kappa w) is 0.79 within observers and 0.46 between observers. Percentage agreements for the presence/absence of a disc haemorrhage range from 96 to 100% (average kappa = 0.92) within observers and from 90 to 98% (average kappa = 0.77) between observers. For other disc features, average kappa w values range from 0.67 to 0.71 within observers and from 0.23 to 0.46 between observers. Intra- and inter-observer comparisons (within and between different professionals) across all disc features are comparable for the optometrists and ophthalmologists, thus demonstrating that optometrists can make valid assessments of disc features. The implications for shared care are discussed.