The effectiveness of early lens extraction with intraocular lens implantation for the treatment of primary angle-closure glaucoma (EAGLE): Study protocol for a randomized controlled trial

BACKGROUND: Glaucoma is the leading cause of irreversible blindness. Although primary open-angle glaucoma is more common, primary angle-closure glaucoma (PACG) is more likely to result in irreversible blindness. By 2020, 5·3 million people worldwide will be blind because of PACG. The current standard care for PACG is a stepped approach of a combination of laser iridotomy surgery (to open the drainage angle) and medical treatment (to reduce intraocular pressure). If these treatments fail, glaucoma surgery (eg, trabeculectomy) is indicated. It has been proposed that, because the lens of the eye plays a major role in the mechanisms leading to PACG, early clear lens extraction will improve glaucoma control by opening the drainage angle. This procedure might reduce the need for drugs and glaucoma surgery, maintain good visual acuity, and improve quality of life compared with standard care.EAGLE aims to evaluate whether early lens extraction improves patient-reported, clinical outcomes, and cost-effectiveness, compared with standard care.

METHODS/DESIGN: EAGLE is a multicentre pragmatic randomized trial. All people presenting to the recruitment centres in the UK and east Asia with newly diagnosed PACG and who are at least 50 years old are eligible.The primary outcomes are EQ-5D, intraocular pressure, and incremental cost per quality adjusted life year (QALY) gained. Other outcomes are: vision and glaucoma-specific patient-reported outcomes, visual acuity, visual field, angle closure, number of medications, additional surgery (e.g., trabeculectomy), costs to the health services and patients, and adverse events.A single main analysis will be done at the end of the trial, after three years of follow-up. The analysis will be based on all participants as randomized (intention to treat). 400 participants (200 in each group) will be recruited, to have 90% power at 5% significance level to detect a difference in EQ-5D score between the two groups of 0·05, and a mean difference in intraocular pressure of 1·75 mm Hg. The study will have 80% power to detect a difference of 15% in the glaucoma surgery rate.

TRIAL REGISTRATION: ISRCTN44464607.

Issues in the epidemiology and population-based screening of primary angle-closure glaucoma

Among Caucasians, it is well known that 75-95% of primary glaucoma is due to open-angle glaucoma (POAG), with angle-closure (PACG) comprising only a very small minority of cases. These figures are reversed among other groups such as Asians and Eskimos, where PACG makes up 80-90% of primary glaucoma. Among Eskimos, the prevalence of PACG has been reported as 2-8%, as compared to 0.1% among Caucasians. It appears that a population tendency toward shallow anterior chambers may explain the excess burden of PACG morbidity. Among Asians, the prevalence of PACG is intermediate between Caucasians and Eskimos. Existing biometrical data do not show a clear tendency toward shallower anterior chambers among Asians. PACG may be screened for on a population basis by means of various techniques that estimate axial or limbal anterior chamber depth, measure intraocular pressure, or evaluate the optic disc or visual fields. Demographic information and medical and family history will also be of great importance in screening for PACG in large populations. Groups at increased risk for the disease include women, individuals over 50, first-degree relatives of PACG probands, and hyperopes.

Angle-closure glaucoma: impact, etiology, diagnosis, and treatment.

PURPOSE OF REVIEW:

Recent studies underscore the importance of angle-closure glaucoma (ACG) as a cause of world blindness. A major contribution in assessing the true impact of this disease has been an article estimating the number of persons with occludable angles, angle closure, and blindness from ACG in China as 28.2 million, 9.1 million, and 1.7 million, respectively. Although these numbers are based on data from Singapore and Mongolia, which may be applied to China only with caution, they emphasize the blinding potential of ACG, which is three times as likely to be associated with blindness as open-angle glaucoma (OAG).

RECENT FINDINGS:

Recent reports in the Chinese literature on ACG prevalence suffer from definitional problems that would appear to lead to systematic overestimates of ACG prevalence and underestimates of OAG prevalence. Nonetheless, data from studies by Chinese investigators further emphasize the strong association between ACG and blindness, with fully 16% of subjects with ACG blind in one report-a far higher proportion than for OAG in China and elsewhere. The importance of topiramate as a cause of secondary angle closure has recently been understood, in part, because of a series of 19 such cases reported by investigators at the Food and Drug Administration.

SUMMARY:

Angle closure in this setting appears to be caused by uveal effusion and anterior rotation of the ciliary body with resultant closure of the angle. The condition is not always responsive to laser iridectomy, and elimination of the causative agent appears to be critical. Ultrasonic biomicroscopy is a potential new diagnostic modality for ACG, allowing the measurement of novel parameters, such as the angle opening distance (AOD) at 500 microm (AOD 500). The efficacy of such parameters in improving screening for ACG can only be established by prospective studies of potentially at-risk eyes. A number of novel treatments for AC and angle closure have recently been proposed, including cataract extraction, paracentesis, and argon laser iridoplasty. As with proposed new diagnostic modalities, the efficacy of these treatments remains to be demonstrated with prospective studies, ideally organized in a controlled, randomized fashion.

Identification des gènes modifiant l’âge d’apparition du glaucome primaire à angle-ouvert dans une famille canadienne-française fondatrice.

Le glaucome est un groupe hétérogène de maladies qui sont caractérisées par l’apoptose des cellules ganglionnaires de la rétine et la dégénérescence progressive du nerf optique. Il s’agit de la première cause de cécité irréversible, qui touche environ 60 millions de personnes dans le monde. Sa forme la plus commune est le glaucome à angle ouvert (GAO), un trouble polygénique causé principalement par une prédisposition génétique, en interaction avec d’autres facteurs de risque tels que l’âge et la pression intraoculaire élevée (PIO). Le GAO est une maladie génétique complexe, bien que certaines formes sévères sont autosomiques dominantes. Dix-sept loci ont été liés à la maladie et acceptés par la « Human Genome Organisation » (HUGO) et cinq gènes ont été identifiés à ces loci (MYOC, OPTN, WDR36, NTF4, ASB10). Récemment, des études d’association sur l’ensemble du génome ont identifié plus de 20 facteurs de risque fréquents, avec des effets relativement faibles. Depuis plus de 50 ans, notre équipe étudie 749 membres de la grande famille canadienne-française CA où la mutation MYOCK423E cause une forme autosomale dominante de GAO dont l’âge de début est fortement variable. Premièrement, il a été montré que cette variabilité de l’âge de début de l’hypertension intraoculaire possède une importante composante génétique causée par au moins un gène modificateur. Ce modificateur interagit avec la mutation primaire et altère la sévérité du glaucome chez les porteurs de MYOCK423E. Un gène modificateur candidat WDR36 a été génotypé dans 2 grandes familles CA et BV. Les porteurs de variations non-synonymes de WDR36 ainsi que de MYOCK423E de la famille CA ont montré une tendance à développer la maladie plus jeune. Un outil de forage de données a été développé pour représenter des informations connues relatives à la maladie et faciliter la priorisation des gènes candidats. Cet outil a été appliqué avec succès à la dépression bipolaire et au glaucome. La suite du projet consiste à finaliser un balayage de génome sur la famille CA et à séquencer les loci afin d’identifier les variations modificatrices du glaucome. Éventuellement, ces variations permettront d’identifier les individus dont le glaucome risque d’être plus agressif.

Visual impairment, postural stability and falls among older adults with glaucoma

Purpose: To investigate the impact of glaucomatous visual impairment on postural sway and falls among older adults.Methods: The sample comprised 72 community-dwelling older adults with open-angle glaucoma, aged 74.0 5.8 years (range 62 to 90 years). Measures of visual function included binocular visual acuity (high-contrast), binocular contrast sensitivity (Pelli- Robson) and binocular visual fields (merged monocular HFA 24-2 SITA-Std). Postural stability was assessed under four conditions: eyes open and closed, on a firm and on a foam surface. Falls were monitored for six months with prospective falls diaries. Regression models, adjusting for age and gender, examined the association between vision measures and postural stability (linear regression) and the number of falls (negative binomial regression). Results: Greater visual field loss was significantly associated with poorer postural stability with eyes open, both on firm (r = 0.34, p < 0.01) and foam (r = 0.45, p < 0.001) surfaces. Eighteen (25 per cent) participants experienced at least one fall: 12 (17 per cent) participants fell only once and six (eight per cent) participants fell two or more times (up to five falls). Visual field loss was significantly associated with falling; the rate of falls doubled for every 10 dB reduction in field sensitivity (rate ratio = 1.08, 95% CI = 1.02–1.13). Importantly, in a model comprising upper and lower field sensitivity, only lower field loss was significantly associated with the number of falls (rate ratio = 1.17, 95% CI = 1.04–1.33). Conclusions: Binocular visual field loss was significantly associated with postural instability and falls among older adults with glaucoma. These findings provide valuable directions for developing falls risk assessment and falls prevention strategies for this population.

Inferior visual field reductions are associated with poorer functional status among older adults with glaucoma

Purpose: To examine the relationship between visual impairment and functional status in a community-dwelling sample of older adults with glaucoma. Methods: This study included 74 community-dwelling older adults with open-angle glaucoma (aged 74 ± 6 years). Assessment of central vision included high-contrast visual acuity and Pelli-Robson contrast sensitivity. Binocular integrated visual fields were derived from merged monocular Humphrey Field Analyser visual field plots. Functional status outcome measures included physical performance tests (6-min walk test, timed up and go test and lower limb strength), a physical activity questionnaire (Physical Activity Scale for the Elderly) and an overall functional status score. Correlation and linear regression analyses, adjusting for age and gender, examined the association between visual impairment and functional status outcomes. Results: Greater levels of visual impairment were significantly associated with lower levels of functional status among community-dwelling older adults with glaucoma, independent of age and gender. Specifically, lower levels of visual function were associated with slower timed up and go performance, weaker lower limb strength, lower self-reported physical activity, and lower overall functional status scores. Of the components of vision examined, the inferior visual field and contrast factors were the strongest predictors of these functional outcomes, whereas the superior visual field factor was not related to functional status. Conclusions: Greater visual impairment, particularly in the inferior visual field and loss of contrast sensitivity, was associated with poorer functional status among older adults with glaucoma. The findings of this study highlight the potential links between visual impairment and the onset of functional decline. Interventions which promote physical activity among older adults with glaucoma may assist in preventing functional decline, frailty and falls, and improve overall health and well-being.

Inferior field loss increases rate of falls in older adults with glaucoma

PURPOSE: To examine the visual predictors of falls and injurious falls among older adults with glaucoma. METHODS: Prospective falls data were collected for 71 community-dwelling adults with primary open-angle glaucoma, mean age 73.9 ± 5.7 years, for one year using monthly falls diaries. Baseline assessment of central visual function included high-contrast visual acuity and Pelli-Robson contrast sensitivity. Binocular integrated visual fields were derived from monocular Humphrey Field Analyser plots. Rate ratios (RR) for falls and injurious falls with 95% confidence intervals (CIs) were based on negative binomial regression models. RESULTS: During the one year follow-up, 31 (44%) participants experienced at least one fall and 22 (31%) experienced falls that resulted in an injury. Greater visual impairment was associated with increased falls rate, independent of age and gender. In a multivariate model, more extensive field loss in the inferior region was associated with higher rate of falls (RR 1.57, 95%CI 1.06, 2.32) and falls with injury (RR 1.80, 95%CI 1.12, 2.98), adjusted for all other vision measures and potential confounding factors. Visual acuity, contrast sensitivity, and superior field loss were not associated with the rate of falls; topical beta-blocker use was also not associated with increased falls risk. CONCLUSIONS: Falls are common among older adults with glaucoma and occur more frequently in those with greater visual impairment, particularly in the inferior field region. This finding highlights the importance of the inferior visual field region in falls risk and assists in identifying older adults with glaucoma at risk of future falls, for whom potential interventions should be targeted. KEY WORDS: glaucoma, visual field, visual impairment, falls, injury

Genome-wide association study of intraocular pressure identifies the GLCCI1/ICA1 region as a glaucoma susceptibility locus

To discover quantitative trait loci for intraocular pressure, amajor risk factor for glaucoma and the only modifiable one,weperformed agenome-wide association studyonadiscoverycohort of2175individualsfromSydney, Australia. We found a novel association between intraocular pressure and a common variant at 7p21 near to GLCCI1 and ICA1. The findings in this region were confirmed through two UK replication cohorts totalling 4866 individuals (rs59072263, Pcombined = 1.10 × 10-8). A copy of the G allele at this SNP is associated with an increase in mean IOP of 0.45 mmHg (95%CI = 0.30-0.61 mmHg). These results lend support to the implication of vesicle trafficking and glucocorticoid inducibility pathways in the determination of intraocular pressure and in the pathogenesis of primary open-angle glaucoma.

Rab8 and Rab8-interacting proteins as players in cell polarization

Rab8 and its interacting proteins as regulators of cell polarization During the development of a multi-cellular organism, progenitor cells have to divide and migrate appropriately as well as organize their differentiation with one another, in order to produce a viable embryo. To divide, differentiate and migrate cells have to undergo polarization, a process where internal and external components such as actin, microtubules and adhesion receptors are reorganized to produce a cell that is asymmetric, with functionally different surfaces. Also in the adult organism there is a continuous need for these processes, as cells need to migrate in response to tissue damage and to fight infection. Improper regulation of cell proliferation and migration can conversely lead to disease such as cancer. GTP-binding proteins function as molecular switches by cycling between a GTP-bound (active) conformation and a GDP-bound (inactive) conformation. The Ras super-family of small GTPases are found in all eukaryotic cells. They can be functionally divided into five subfamilies. The Ras family members mainly regulate gene expression, controlling cell proliferation and differentiation. Ras was in fact the first human oncogene to be characterized, and as much as 30% of all human tumors may be directly or indirectly caused by mutations of Ras molecules The Rho family members mainly regulate cytoskeletal reorganization. Arf proteins are known to regulate vesicle budding and Rab proteins regulate vesicular transport. Ran regulates nuclear transport as well as microtubule organization during mitosis. The focus of the thesis of Katarina Hattula, is on Rab8, a small GTPase of the Rab family. Activated Rab8 has previously been shown to induce the formation of new surface extensions, reorganizing both actin and microtubules, and to have a role in directed membrane transport to cell surfaces. However, the exact membrane route it regulates has remained elusive. In the thesis three novel interactors of Rab8 are presented. Rabin8 is a Rab8-specific GEF that localizes to vesicles where it presumably recruits and activates its target Rab8. Its expression in cells leads to remodelling of actin and the formation of polarized cell surface domains. Optineurin, known to be associated with a leading cause of blindness in humans (open-angle glaucoma), is shown to interact specifically with GTP-bound Rab8. Rab8 binds to an amino-terminal region and interestingly, the Huntingtin protein binds a carboxy-terminal region of optineurin. (Aberrant Huntingtin protein is known to be the cause Huntington s disease in humans.) Co-expression of Huntingtin and optineurin enhanced the recruitment of Huntingtin to Rab8-positive vesicular structures. Furthermore, optineurin promoted cell polarization in a similar way to Rab8. A third novel interactor of Rab8 presented in this thesis is JFC1, a member of the synaptogamin-like protein (Slp) family. JFC1 interacts with Rab8 specifically in its GTP-bound form, co-localizes with endogenous Rab8 on tubular and vesicular structures, and is probably involved in controlling Rab8 membrane dynamics. Rab8 is in this thesis work clearly shown to have a strong effect on cell shape. Blocking Rab8 activity by expression of Rab8 RNAi, or by expressing the dominant negative Rab8 (T22N) mutant leads to loss of cell polarity. Conversely, cells expressing the constitutively active Rab8 (Q67L) mutant exhibit a strongly polarized phenotype. Experiments in live cells show that Rab8 is associated with macropinosomes generated at ruffling areas of the membrane. These macropinosomes fuse with or transform into tubules that move toward the cell centre, from where they are recycled back to the leading edge to participate in protrusion formation. The biogenesis of these tubules is shown to be dependent on both actin and microtubule dynamics. The Rab8-specific membrane route studied contained several markers known to be internalized and recycled (1 integrin, transferrin, transferrin receptor, cholera toxin B subunit (CTxB), and major histocompatibility complex class I protein (MHCI)). Co-expression studies revealed that Rab8 localization overlaps with that of Rab11 and Arf6. Rab8 is furthermore clearly functionally linked to Arf6. The data presented in this thesis strongly suggests a role for Rab8 as a regulator for a recycling compartment, which is involved in providing structural and regulatory components to the leading edge to participate in protrusion formation.

Detection of visual-field deterioration by Glaucoma Progression Analysis and Threshold Noiseless Trend programs

BACKGROUND: To compare the ability of Glaucoma Progression Analysis (GPA) and Threshold Noiseless Trend (TNT) programs to detect visual-field deterioration.

METHODS: Patients with open-angle glaucoma followed for a minimum of 2 years and a minimum of seven reliable visual fields were included. Progression was assessed subjectively by four masked glaucoma experts, and compared with GPA and TNT results. Each case was judged to be stable, deteriorated or suspicious of deterioration

RESULTS: A total of 56 eyes of 42 patients were followed with a mean of 7.8 (SD 1.0) tests over an average of 5.5 (1.04) years. Interobserver agreement to detect progression was good (mean kappa = 0.57). Progression was detected in 10-19 eyes by the experts, in six by GPA and in 24 by TNT. Using the consensus expert opinion as the gold standard (four clinicians detected progression), the GPA sensitivity and specificity were 75% and 83%, respectively, while the TNT sensitivity and specificity was 100% and 77%, respectively.

CONCLUSION: TNT showed greater concordance with the experts than GPA in the detection of visual-field deterioration. GPA showed a high specificity but lower sensitivity, mainly detecting cases of high focality and pronounced mean defect slopes.

Direct costs of glaucoma and severity of the disease:A multinational long term study of resource utilisation in Europe

Background: Resource utilisation and direct costs associated with glaucoma progression in Europe are unknown. As population progressively ages, the economic impact of the disease will increase. Methods: From a total of 1655 consecutive cases, the records of 194 patients were selected and stratified by disease severity. Record selection was based on diagnoses of primary open angle glaucoma, glaucoma suspect, ocular hypertension, or normal tension glaucoma; 5 years minimum follow up were required. Glaucoma severity was assessed using a six stage glaucoma staging system based on static threshold visual field parameters. Resource utilisation data were abstracted from the charts and unit costs were applied to estimate direct costs to the payer. Resource utilisation and estimated direct cost of treatment, per person year, were calculated. Results: A statistically significant increasing linear trend (p = 0.018) in direct cost as disease severity worsened was demonstrated. The direct cost of treatment increased by an estimated €86 for each incremental step ranging from €455 per person year for stage 0 to €969 per person year for stage 4 disease. Medication costs ranged from 42% to 56% of total direct cost for all stages of disease. Conclusions: These results demonstrate for the first time in Europe that resource utilisation and direct medical costs of glaucoma management increase with worsening disease severity. Based on these findings, managing glaucoma and effectively delaying disease progression would be expected to significantly reduce the economic burden of this disease. These data are relevant to general practitioners and healthcare administrators who have a direct influence on the distribution of resources.

Lower corneal hysteresis in glaucoma patients with acquired pit of the optic nerve (APON)

Objective: Acquired pit-like changes of the optic nerve head (APON) are characteristic of glaucomatous damage and may be a sign of a localized susceptibility of the optic nerve. Thus, it is possible that biomechanical properties of the ocular tissues may play a pressure-independent role in the pathogenesis of glaucoma. Corneal hysteresis (CH) appears to provide information of the biomechanical properties of the ocular hull tissues. The purpose of this study was to compare CH of patients with primary open angle glaucoma (POAG) with and without APON. Methods: A prospective case control study was done. POAG patients with and without APON were measured using the Ocular Response Analyzer by masked investigators. Patients in both groups were matched for sex, age, corneal thickness, and type of glaucoma according to maximal IOP (NTG or POAG). Statistical analysis was done using ANOVA. Results: Corneal hysteresis of 16 glaucomatous eyes with APON and 32 controls (glaucoma without APON) was measured. The mean (±SD) CH in the APON group was 8.89 (±1.53) and 10.2 (±1.05) in the control group. The difference is statistically significant (p = 0.005). Conclusions: Corneal hysteresis in POAG patients with APON was significantly lower than in patients that did not have such structural changes of the optic disc. These findings may reflect pressure-independent mechanisms involved in the pathogenesis of such glaucomatous optic nerve changes. © Springer-Verlag 2007.

Agreement between clinical and ultrasound biomicroscopy findings in different types of glaucoma

Purpose. To evaluate agreement between clinical examination (slit lamp examination and gonioscopy) and ultrasound biomicroscopy (UBM) in characterizing various features of the anterior chamber angle and adjacent structures. Methods. Twenty-eight patients (51 eyes) with open angle glaucoma (14), closed angle glaucoma (4), narrow angle and/or plateau iris (10), who had undergone UBM between March 94 and September 95 were studied. Evaluated parameters included angle width, iris configuration and presence of angle closure. The UBMs were reviewed in a masked fashion. Results. In 87.8% of cases there was agreement (within 10 degrees) between gonioscopic and UBM estimates of angle width. In all cases with greater than 10 degrees difference (12.2%) the angle size estimated by UBM was less than that estimated clinically. Iris configuration was graded identically in 51% of cases; the majority of disagreements (76.1%) occurred in cases graded as "regular" by gonioscopy and as "steep" by UBM. Angle closure was judged to be present more frequently by UBM. Conclusions. UBM and gonioscopy do not necessarily yield identical values for angle width, iris configuration, and presence of angle closure.

Effect of cataract extraction on SITA perimetry in patients with glaucoma

PURPOSE: To evaluate the effect of cataract extraction on Swedish Interactive Thresholding Algorithm (SITA) perimetry in patients with coexisting cataract and glaucoma. PATIENTS AND METHODS: This is a retrospective noncomparative interventional study. Thirty-seven consecutive patients with open-angle glaucoma who had cataract extraction alone or combined with trabeculectomy were included. All patients had SITA-standard 24-2 visual fields before and after the surgery. The main outcome measures were changes in mean deviation (MD) and pattern standard deviation (PSD). Additionally, changes in best-corrected visual acuity, intraocular pressure, and number of glaucoma medications were also studied. RESULTS: Visual field tests were performed 3.9±4.4 months before surgery and 4.1±2.8 months after surgery. Mean visual acuity improved after the surgery, from 0.41±0.21 to 0.88±0.32 (P

Effect of sublingual application of cannabinoids on intraocular pressure:A pilot study

PURPOSE: The purpose of this study was to assess the effect on intraocular pressure (IOP) and the safety and tolerability of oromucosal administration of a low dose of delta-9-tetrahydrocannabinol (?-9-THC) and cannabidiol (CBD). PATIENTS AND METHODS: A randomized, double-masked, placebo-controlled, 4 way crossover study was conducted at a single center, using cannabis-based medicinal extract of ?-9-THC and CBD. Six patients with ocular hypertension or early primary open angle glaucoma received a single sublingual dose at 8 AM of 5 mg ?-9-THC, 20 mg CBD, 40 mg CBD, or placebo. Main outcome measure was IOP. Secondary outcomes included visual acuity, vital signs, and psychotropic effects. RESULTS: Two hours after sublingual administration of 5 mg ?-9-THC, the IOP was significantly lower than after placebo (23.5 mm Hg vs. 27.3 mm Hg, P=0.026). The IOP returned to baseline level after the 4-hour IOP measurement. CBD administration did not reduce the IOP at any time. However, the higher dose of CBD (40 mg) produced a transient elevation of IOP at 4 hours after administration, from 23.2 to 25.9 mm Hg (P=0.028). Vital signs and visual acuity were not significantly changed. One patient experienced a transient and mild paniclike reaction after ?-9-THC administration. CONCLUSIONS: A single 5 mg sublingual dose of ?-9-THC reduced the IOP temporarily and was well tolerated by most patients. Sublingual administration of 20 mg CBD did not reduce IOP, whereas 40 mg CBD produced a transient increase IOP rise. Copyright © 2006 by Lippincott Williams & Wilkins.