IMPORTANCE Glaucoma is a worldwide leading cause of irreversible vision loss. Because it may be asymptomatic until a relatively late stage, diagnosis is frequently delayed. A general understanding of ...the disease pathophysiology, diagnosis, and treatment may assist primary care physicians in referring high-risk patients for comprehensive ophthalmologic examination and in more actively participating in the care of patients affected by this condition. OBJECTIVE To describe current evidence regarding the pathophysiology and treatment of open-angle glaucoma and angle-closure glaucoma. EVIDENCE REVIEW A literature search was conducted using MEDLINE, the Cochrane Library, and manuscript references for studies published in English between January 2000 and September 2013 on the topics open-angle glaucoma and angle-closure glaucoma. From the 4334 abstracts screened, 210 articles were selected that contained information on pathophysiology and treatment with relevance to primary care physicians. FINDINGS The glaucomas are a group of progressive optic neuropathies characterized by degeneration of retinal ganglion cells and resulting changes in the optic nerve head. Loss of ganglion cells is related to the level of intraocular pressure, but other factors may also play a role. Reduction of intraocular pressure is the only proven method to treat the disease. Although treatment is usually initiated with ocular hypotensive drops, laser trabeculoplasty and surgery may also be used to slow disease progression. CONCLUSIONS AND RELEVANCE Primary care physicians can play an important role in the diagnosis of glaucoma by referring patients with positive family history or with suspicious optic nerve head findings for complete ophthalmologic examination. They can improve treatment outcomes by reinforcing the importance of medication adherence and persistence and by recognizing adverse reactions from glaucoma medications and surgeries.
Administration of glucocorticoids induces ocular hypertension in some patients. If untreated, these patients can develop a secondary glaucoma that resembles primary open-angle glaucoma (POAG). The ...underlying pathology of glucocorticoid-induced glaucoma is not fully understood, due in part to lack of an appropriate animal model. Here, we developed a murine model of glucocorticoid-induced glaucoma that exhibits glaucoma features that are observed in patients. Treatment of WT mice with topical ocular 0.1% dexamethasone led to elevation of intraocular pressure (IOP), functional and structural loss of retinal ganglion cells, and axonal degeneration, resembling glucocorticoid-induced glaucoma in human patients. Furthermore, dexamethasone-induced ocular hypertension was associated with chronic ER stress of the trabecular meshwork (TM). Similar to patients, withdrawal of dexamethasone treatment reduced elevated IOP and ER stress in this animal model. Dexamethasone induced the transcriptional factor CHOP, a marker for chronic ER stress, in the anterior segment tissues, and Chop deletion reduced ER stress in these tissues and prevented dexamethasone-induced ocular hypertension. Furthermore, reduction of ER stress in the TM with sodium 4-phenylbutyrate prevented dexamethasone-induced ocular hypertension in WT mice. Our data indicate that ER stress contributes to glucocorticoid-induced ocular hypertension and suggest that reducing ER stress has potential as a therapeutic strategy for treating glucocorticoid-induced glaucoma.
Abstract
Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide for which 15 disease-associated loci had been discovered. Among them, only 5 loci have been ...associated with POAG in Asians. We carried out a genome-wide association study and a replication study that included a total of 7378 POAG cases and 36 385 controls from a Japanese population. After combining the genome-wide association study and the two replication sets, we identified 11 POAG-associated loci, including 4 known (CDKN2B-AS1, ABCA1, SIX6 and AFAP1) and 7 novel loci (FNDC3B, ANKRD55-MAP3K1, LMX1B, LHPP, HMGA2, MEIS2 and LOXL1) at a genome-wide significance level (P < 5.0×10−8), bringing the total number of POAG-susceptibility loci to 22. The 7 novel variants were subsequently evaluated in a multiethnic population comprising non-Japanese East Asians (1008 cases, 591 controls), Europeans (5008 cases, 35 472 controls) and Africans (2341 cases, 2037 controls). The candidate genes located within the new loci were related to ocular development (LMX1B, HMGA2 and MAP3K1) and glaucoma-related phenotypes (FNDC3B, LMX1B and LOXL1). Pathway analysis suggested epidermal growth factor receptor signaling might be involved in POAG pathogenesis. Genetic correlation analysis revealed the relationships between POAG and systemic diseases, including type 2 diabetes and cardiovascular diseases. These results improve our understanding of the genetic factors that affect the risk of developing POAG and provide new insight into the genetic architecture of POAG in Asians.
We evaluated 2-year safety and efficacy of supraciliary microstenting (CyPass Micro-Stent; Transcend Medical, Inc., Menlo Park, CA) for treating mild-to-moderate primary open-angle glaucoma (POAG) in ...patients undergoing cataract surgery.
Multicenter (24 US sites), interventional randomized clinical trial (RCT) (ClinicalTrials.gov identifier, NCT01085357).
Subjects were enrolled beginning July 2011, with study completion in March 2015. Subjects had POAG with mean diurnal unmedicated intraocular pressure (IOP) 21-33 mmHg and were undergoing phacoemulsification cataract surgery.
After completing cataract surgery, subjects were intraoperatively randomized to phacoemulsification only (control) or supraciliary microstenting with phacoemulsification (microstent) groups (1:3 ratio). Microstent implantation via an ab interno approach to the supraciliary space allowed concomitant cataract and glaucoma surgery.
Outcome measures included percentage of subjects achieving ≥20% unmedicated diurnal IOP lowering versus baseline, mean IOP change and glaucoma medication use, and ocular adverse event (AE) incidence through 24 months.
Of 505 subjects, 131 were randomized to the control group and 374 were randomized to the microstent group. Baseline mean IOPs in the control and microstent groups were similar: 24.5±3.0 and 24.4±2.8 mmHg, respectively (P > 0.05); mean medications were 1.3±1.0 and 1.4±0.9, respectively (P > 0.05). There was early and sustained IOP reduction, with 60% of controls versus 77% of microstent subjects achieving ≥20% unmedicated IOP lowering versus baseline at 24 months (P = 0.001; per-protocol analysis). Mean IOP reduction was ↓7.4 mmHg for the microstent group versus ↓5.4 mmHg in controls (P < 0.001), with 85% of microstent subjects not requiring IOP medications at 24 months. Mean 24-month medication use was 67% lower in microstent subjects (P < 0.001); 59% of control versus 85% of microstent subjects were medication free. Mean medication use in controls decreased from 1.3±1.0 drugs at baseline to 0.7±0.9 and 0.6±0.8 drugs at 12 and 24 months, respectively, and in the microstent group from 1.4±0.9 to 0.2±0.6 drugs at both 12 and 24 months (P < 0.001 for reductions in both groups at both follow-ups vs. baseline). No vision-threatening microstent-related AEs occurred. Visual acuity was high in both groups through 24 months; >98% of all subjects achieved 20/40 best-corrected visual acuity or better.
This RCT demonstrated safe and sustained 2-year reduction in IOP and glaucoma medication use after microinterventional surgical treatment for mild-to-moderate POAG.
To compare the effectiveness and safety of the MicroShunt versus trabeculectomy in patients with primary open-angle glaucoma (POAG).
One-year results from a 2-year, prospective, randomized, ...multicenter, noninferiority study (NCT01881425) conducted in the United States and Europe.
Eligible patients were aged 40-85 years with intraocular pressure (IOP) ≥15 and ≤40 mmHg and mild-to-severe POAG inadequately controlled on maximum tolerated medical therapy.
Patients were randomized 3:1 to undergo stand-alone MicroShunt implantation or trabeculectomy, both performed with adjunctive mitomycin C (0.2 mg/ml for 2 minutes).
The primary effectiveness end point was surgical success, defined as ≥20% reduction in mean diurnal IOP from baseline (no medication washout) at year 1 without increasing the number of glaucoma medications. Secondary effectiveness end points at year 1 were the mean IOP change from baseline and requirement for postoperative intervention. Additional end points included glaucoma medication use and adverse events.
Overall, 395 (MicroShunt) and 132 (trabeculectomy) patients were randomized (mean Humphrey visual field mean deviation, -12.34 decibels dB). At year 1, probability of success was lower in the MicroShunt group compared with the trabeculectomy group (53.9% vs. 72.7%, respectively; P < 0.01). In the MicroShunt group, mean IOP ± standard deviation decreased from 21.1 ± 4.9 mmHg at baseline to 14.3 ± 4.3 mmHg (-29.1%; P < 0.01) at year 1, with a mean of 0.6 ± 1.1 glaucoma medications (baseline 3.1 ± 1.0; P < 0.01). In the trabeculectomy group, mean IOP decreased from 21.1 ± 5.0 mmHg to 11.1 ± 4.3 mmHg (-45.4%; P < 0.01), with a mean of 0.3 ± 0.9 glaucoma medications (baseline 3.0 ± 0.9; P < 0.01). Postoperative interventions, including laser suture lysis, were reported in 40.8% (MicroShunt) versus 67.4% (trabeculectomy) of patients (P < 0.01). Reported incidence of transient hypotony was higher in the trabeculectomy group versus the MicroShunt group (49.6% vs. 28.9%; P < 0.01). Vision-threatening complications were uncommon and reported in 1.0% of MicroShunt versus 0.8% of trabeculectomy patients.
Probability of success was lower with MicroShunt compared with trabeculectomy. Although reductions in IOP and glaucoma medications over 1 year were observed in both groups, the trabeculectomy group had a lower mean IOP on fewer medications.
Mutations in myocilin (MYOC) are the most common genetic cause of primary open angle glaucoma (POAG), but the mechanisms underlying MYOC-associated glaucoma are not fully understood. Here, we report ...the development of a transgenic mouse model of POAG caused by the Y437H MYOC mutation; the mice are referred to herein as Tg-MYOC(Y437H) mice. Analysis of adult Tg-MYOC(Y437H) mice, which we showed express human MYOC containing the Y437H mutation within relevant eye tissues, revealed that they display glaucoma phenotypes (i.e., elevated intraocular pressure IOP, retinal ganglion cell death, and axonal degeneration) closely resembling those seen in patients with POAG caused by the Y437H MYOC mutation. Mutant myocilin was not secreted into the aqueous humor but accumulated in the ER of the trabecular meshwork (TM), thereby inducing ER stress in the TM of Tg-MYOC(Y437H) mice. Furthermore, chronic and persistent ER stress was found to be associated with TM cell death and elevation of IOP in Tg-MYOC(Y437H) mice. Reduction of ER stress with a chemical chaperone, phenylbutyric acid (PBA), prevented glaucoma phenotypes in Tg-MYOC(Y437H) mice by promoting the secretion of mutant myocilin in the aqueous humor and by decreasing intracellular accumulation of myocilin in the ER, thus preventing TM cell death. These results demonstrate that ER stress is linked to the pathogenesis of POAG and may be a target for treatment in human patients.
Primary congenital glaucoma (PCG) is a severe disease characterized by developmental defects in the trabecular meshwork (TM) and Schlemm's canal (SC), comprising the conventional aqueous humor ...outflow pathway of the eye. Recently, heterozygous loss of function variants in TEK and ANGPT1 or compound variants in TEK/SVEP1 were identified in children with PCG. Moreover, common variants in ANGPT1and SVEP1 have been identified as risk alleles for primary open angle glaucoma (POAG) in GWAS studies. Here, we show tissue-specific deletion of Angpt1 or Svep1 from the TM causes PCG in mice with severe defects in the adjacent SC. Single-cell transcriptomic analysis of normal and glaucomatous Angpt1 deficient eyes allowed us to identify distinct TM and SC cell populations and discover additional TM-SC signaling pathways. Furthermore, confirming the importance of angiopoietin signaling in SC, delivery of a recombinant ANGPT1-mimetic promotes developmental SC expansion in healthy and Angpt1 deficient eyes, blunts intraocular pressure (IOP) elevation and RGC loss in a mouse model of PCG and lowers IOP in healthy adult mice. Our data highlight the central role of ANGPT1-TEK signaling and TM-SC crosstalk in IOP homeostasis and provide new candidates for SC-targeted glaucoma therapy.
To report clinical efficacy, predictors of success, and safety of primary selective laser trabeculoplasty (SLT) used in treatment-naive patients with open-angle glaucoma (OAG) or ocular hypertension ...(OHT).
Post hoc analysis of a multicenter, prospective, randomized, controlled trial.
Treatment-naive patients with OAG or OHT.
Patients randomized to SLT or topical medication and treated to predefined target intraocular pressures (IOPs) requiring ≥20% IOP reduction from baseline for all disease severity levels.
Initial (early) absolute IOP-lowering at 2 months. Achievement of drop-free disease-control: meeting target IOP without disease progression or need for additional topical medication over 36 months after SLT. Predictors of early absolute IOP-lowering and drop-free disease-control after single initial SLT. Frequency of laser-related complications.
A total of 611 eyes (195 OHT and 416 OAG) of 355 patients received SLT, and 622 eyes (185 OHT and 437 OAG) of 362 patients received topical medication at baseline. Early absolute IOP-lowering after SLT was no different between OHT and OAG eyes (adjusted mean difference = -0.05 mmHg; 95% confidence interval CI, -0.6 to 0.5 mmHg; P = 0.85). No difference was noted in early absolute IOP-lowering between topical medication and primary SLT (adjusted mean difference = -0.1 mmHg; 95% CI, -0.6 to 0.4 mmHg; P = 0.67). Early absolute IOP-lowering with primary SLT was positively associated with baseline IOP (coefficient 0.58; 95% CI, 0.53-0.63; P < 0.001) and negatively with female gender (coefficient -0.63; 95% CI, -1.23 to -0.02; P = 0.04). At 36 months, 536 eyes (87.7% of 611 eyes) of 314 patients (88.5% of 355 patients) were available for analysis. Some 74.6% of eyes (400 eyes) treated with primary SLT achieved drop-free disease-control at 36 months; 58.2% (312 eyes) after single SLT. Total SLT power and 2-month IOP were predictors of drop-free disease-control at 36 months after single SLT. Six eyes of 6 patients experienced immediate post-laser IOP spike (>5 mmHg from pretreatment IOP) with 1 eye requiring treatment.
Primary SLT achieved comparable early absolute IOP-lowering in OHT versus OAG eyes. Drop-free disease-control was achieved in approximately 75% eyes at 36 months after 1 or 2 SLTs, the majority of these after single SLT. These analyses are exploratory but support primary SLT to be effective and safe in treatment-naive OAG and OHT eyes.
To investigate the prevalence of visual field defects in glaucomatous eyes, glaucoma suspects, and ocular hypertensives with 24-2 and 10-2 visual fields.
Prospective, cross-sectional study.
Patients ...with or suspected glaucoma tested with 24-2 and 10-2. Patients were classified into 3 groups on the basis of the presence of glaucomatous optic neuropathy (GON) and 24-2 visual field abnormalities: early glaucoma (GON and abnormal visual field, mean deviation >-6 decibels dB), glaucoma suspects (GON and normal visual field), and ocular hypertensives (normal disc, normal visual field, and intraocular pressure >22 mmHg). For the classification of visual field abnormalities, 24-2 and 10-2 tests performed on the same visit were analyzed.
Comparison of the prevalence of abnormal 24-2 versus 10-2 visual field results based on cluster criteria in each diagnostic group.
A total of 775 eyes (497 patients) were evaluated. A total of 364 eyes had early glaucoma, 303 eyes were glaucoma suspects, and 108 eyes were ocular hypertensives. In the glaucoma group, 16 of the 26 eyes (61.5%) classified as normal based on cluster criteria on 24-2 tests were classified as abnormal on 10-2 visual fields. In eyes with suspected glaucoma, 79 of the 200 eyes (39.5%) classified as normal on the 24-2 test were classified as abnormal on 10-2 visual fields. In ocular hypertensive eyes, 28 of the 79 eyes (35.4%) classified as normal on the 24-2 were classified as abnormal on the 10-2. Patients of African descent were more likely to have an abnormal 10-2 result (67.3 vs. 56.8%, P = 0.009).
Central visual field damage seen on the 10-2 test is often missed with the 24-2 strategy in all groups. This finding has implications for the diagnosis of glaucoma and classification of severity.
Primary open-angle glaucoma Weinreb, Robert N; Khaw, Peng Tee
The Lancet (British edition),
05/2004, Letnik:
363, Številka:
9422
Journal Article
Recenzirano
Primary open-angle glaucoma is a progressive optic neuropathy and, perhaps, the most common form of glaucoma. Because the disease is treatable, and because the visual impairment caused by glaucoma is ...irreversible, early detection is essential. Early diagnosis depends on examination of the optic disc, retinal nerve fibre layer, and visual field. New imaging and psychophysical tests can improve both detection and monitoring of the progression of the disease. Recently completed long-term clinical trials provide convincing evidence that lowering intraocular pressure prevents progression at both the early and late stages of the disease. The degree of protection is related to the degree to which intraocular pressure is lowered. Improvements in therapy consist of more effective and better-tolerated drugs to lower intraocular pressure, and more effective surgical procedures. New treatments to directly treat and protect the retinal ganglion cells that are damaged in glaucoma are also in development.
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