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Surgical outcome of phacoemulsification combined with the Pearce trabeculectomy in patients with glaucoma.

The safety and efficacy of phacoemulsification and posterior chamber lens insertion combined with the Pearce trabeculectomy (PE/PCL/P-TRX) in patients with coexistent cataract and glaucoma was evaluated retrospectively. The Pearce trabeculectomy is a form of nonfiltration glaucoma surgery in which an inner block containing trabecular meshwork is excised under a scleral-pocket incision which is closed tightly. Thirty consecutive eyes sustained a reduction of mean intraocular pressure from 21.0 +/- 4.4 mm Hg to 16.6 +/- 3.3 mm Hg after PE/PCL/P-TRX at one year (P less than .001). The average number of glaucoma medications used was reduced from 1.9 to 0.8 postoperatively. At one year, 60% (18 of 30) of eyes treated with PE/PCL/P-TRX had intraocular pressures less than 21 mm Hg without medications.

Aged↗

Prospective study of intraocular pressure 2 1/2 years after intracapsular cataract extraction and implantation of a semiflexible anterior chamber lens.

Fifty-one patients available for a 2 1/2 year follow-up after intracapsular cataract extraction and implantation of the semiflexible McGhan/3M, style 70 anterior chamber lens were evaluated for intraocular pressure (IOP). No significant change in the IOP could be demonstrated despite progression of iris-like tissue adhesions between the iris and lens haptics at or close to the trabecular meshwork. Four eyes (7.8%) had IOPs greater than or equal to 22 mm Hg without medication, and four other eyes used timolol eyedrops with subsequent IOPs less than or equal to 18 mm Hg. Eight eyes (15.7%) demonstrated an IOP increase greater than or equal to 25% over baseline pressures.

Anterior Chamber↗

Current perspectives on the TIGR/MYOC gene (Myocilin) and glaucoma.

Over the past several years, many groups worldwide have confirmed the presence of probable disease-causing mutations in the coding region of the (TIGR/MYOC) gene associated with glaucoma. Disease-associated point mutations are often found in the third exon of TIGR/MYOC and are predicted to exert a substantial influence on protein structure. Although there has been speculation as to the mechanisms involved in the pathogenic effects for a number of the mutations, the processes leading to the development of glaucoma involving TIGR/MYOC remain to be elucidated. In addition to ongoing mutation studies, efforts are underway to follow up on TIGR/MYOC gene regulation studies in human trabecular meshwork cells and other possibly relevant cell types. Potentially by altering gene regulation, a major variant (-1000 G/C), present in 15-20% of individuals, appears to be associated with a more rapid progression of glaucomatous disease. This article addresses several of these areas of research on the TIGR/MYOC gene and glaucoma, briefly presenting currently available evidence and considering or updating information presented previously.

Cytoskeletal Proteins↗

Pax6 heterozygous eyes show defects in chamber angle differentiation that are associated with a wide spectrum of other anterior eye segment abnormalities.

The development of the chamber angle was studied in the eyes of heterozygous Pax6(lacZ/+) mutant mice (Nature 387 (1997) 406). Mutations in PAX6 cause aniridia, a condition that is frequently associated with glaucoma, a blinding disease that may be associated with chamber angle defects. Mesenchymal cells were seen in the chamber angle at P1-P5. In wild-type mice, these cells differentiated into typical trabecular meshwork (TM) cells next to Schlemm's canal. In Pax6(lacZ/+) mice, TM cells remained undifferentiated and Schlemm's canal was absent. From P1 to P4, staining for beta-galactosidase and immunoreactivity for Pax6 were observed in chamber angle mesenchyme, but were absent later. Cultured murine TM cells expressed Pax6. The defects in chamber angle and TM differentiation were associated with a wide spectrum of other anterior eye defects, which included various degrees of iris hypoplasia and corneal haze, isolated iridocorneal adhesions and atypical coloboma, and a vascularized cornea in all adult animals. A third of the animals showed Peters' anomaly including corneal opacity and iridocorneal adhesions. The separation of the lens from the cornea was incomplete, and epithelial layers of lens and cornea were continuous. Pax6 activity is directly required for differentiation of the chamber angle. Variations in phenotype of Pax6(lacZ/+) mice appear not to involve direct dominant-negative or dose-dependent effects.

Animals↗

TIGR is upregulated in the chronic glial scar in response to central nervous system injury and inhibits neurite outgrowth.

Reactive astrocytes respond to central nervous system (CNS) injury and disease by elaborating a glial scar that is inhibitory to axonal regeneration. To identify genes that may be involved in the astrocytic response to injury, we used differential display polymerase chain reaction and an in vivo model of the CNS glial scar. Expression of the trabecular meshwork inducible glucocorticoid response (TIGR) gene was increased in gliotic tissue compared with the uninjured cerebral cortex. Increased TIGR expression by reactive astrocytes was confirmed by in situ hybridization, quantitative reverse transcriptase-polymerase chain reaction, immunoblot analysis, and immunohistochemistry. Although mutations of the TIGR gene have been implicated in glaucoma, a function for TIGR has not been reported. Since TIGR is secreted, we assessed a possible role in inhibition of neuronal regeneration with an in vitro bioassay and found that this protein is a potent inhibitor of neurite outgrowth. Thus, TIGR is a newly identified component of the CNS glial scar that is likely to contribute to neuronal regenerative failure characteristic of the mammalian CNS.

Animals↗

Postoperative intraocular pressure elevation after the use of Healon GV in pediatric cataract surgery.

Intraocular pressure elevation after the use of viscoelastic agents in uncomplicated cataract surgery has been well documented in adults. However, pediatric patients are thought to clear residual viscoelastic agents from the anterior chamber more easily than adults, presumably because of healthier trabecular meshwork. (1) We report on a series of 4 eyes of 4 children with previously normal intraocular pressure who underwent cataract extraction with primary (3 patients) or secondary (1 patient) intraocular lens implantation with Healon GV, which was complicated by marked postoperative intraocular pressure elevation (greater than 30 mm Hg). The patients, aged 5 to 14 years, had an intraocular pressure ranging from 34 to 50 mm Hg with Tonopen or applanation tonometry 1 day, postoperatively associated with nausea, eye pain, and microcystic corneal edema. Viscoelastic material was not entirely removed during surgery. Each of these cases occurred after a change in our preferred viscoelastic agent from one with less viscosity to Healon GV. Medical management controlled the elevated intraocular pressure in all cases without affecting the visual outcome. However, 1 patient with intractable nausea and vomiting required hospitalization for rehydration. With meticulous removal of all viscoelastic material at the completion of surgery, we have not documented any additional cases of postoperative pressure elevation.

Adolescent↗

Hepatocyte growth factor/scatter factor in the eye.

Hepatocyte growth factor, also known as scatter factor (HGF/SF) is a multipotential cytokine which can produce a range of responses in target cells and its influence in the eye in health and disease is just beginning to be appreciated. Usually HGF/SF is synthesised by mesenchymally derived cells and targets and signals epithelial cells in a paracrine manner via their c-Met surface receptor. However, there is growing evidence for the existence of autocrine loops in a number of cell systems prominent among which are ocular cells such as the corneal endothelium, the lens epithelium, the retinal pigment epithelium (RPE) and others. Marked cellular proliferation is stimulated when activated HGF/SF is exposed to hepatocytes, renal epithelium, melanocytes and vascular endothelial cells but it is often a poor mitogen for other cell types. In target cells the cytokine promotes other bioactions such as junctional breakdown, shape change, cell scattering, directional and nondirectional migration, cell survival, invasive behaviour and/or tubule formation. These activities seem to depend on HGF/SF linking with the c-Met receptor and pathways to stimulate the various types of cytokine/receptor response are being unravelled at the present time. In corneal wound healing, HGF/SF is produced by stromal keratocytes and targets the repairing epithelium. HGF/SF is a constituent of tears, aqueous humour and vitreous humour at levels above that found in plasma although it is not clear how much is activated. Aqueous HGF/SF may well influence lens epithelial, corneal endothelial and trabecular meshwork cell survival. Vitreous levels of HGF/SF are elevated in proliferative vitreoretinopathy (PVR), where a target cell is the RPE and in proliferative diabetic retinopathy (PDR) where HGF/SF has been shown to be a major angiogenesis factor. Finally HGF/SF may be involved in the metastatic spread of tumour cells from uveal melanomata and in the formation of vascular channels in these tumours.

Animals↗

Myocilin and glaucoma: facts and ideas.

Mutations in the MYOC gene that encodes for myocilin are causative for some forms of juvenile and adult-onset primary open-angle glaucoma (POAG). Myocilin is a secreted 55-57kDa glycoprotein that forms dimers and multimers. Characteristic structural motifs include a myosin-like domain, a leucine zipper region and an olfactomedin domain. Most of the mutations that have been identified in patients with POAG are localized in the olfactomedin domain, which is highly conserved among species. In the eye, myocilin is expressed in high amounts in the trabecular meshwork (TM), sclera, ciliary body and iris, and at considerable lower amounts in retina and optic nerve head. Secreted myocilin is present in the aqueous humor. In the TM, myocilin is found within the cytoplasm of TM cells and in the juxtacanalicular region in association with fibrillar extracellular matrix components. Since patients with mutations in myocilin may have high intraocular pressures, the role of myocilin for aqueous humor outflow has been investigated and conflicting results have been obtained. Recombinant myocilin increases outflow resistance in perfused anterior segment organ cultures, while overexpression of myocilin after viral gene transfer appears to reduce outflow resistance. In TM cells, the expression of myocilin is induced upon treatment with dexamethasone at a time course similar to that observed in steroid-induced glaucoma. Other factors that induce myocilin expression are transforming growth factor-beta and mechanical stretch. Promoter elements that are important for the glucocorticoid induction have not been identified, but it has been shown that upstream stimulatory factor is critical for the basal promoter activity of MYOC. Mice with a targeted disruption of the myocilin gene do not express a phenotype, indicating that the glaucomatous phenotype in humans is not because of a loss-of-function effect. Experimental studies show that mutated myocilin is not secreted, but appears to accumulate in the cells. Such an accumulation might interfere with TM function and lead to impaired outflow resistance, but, so far, experimental evidence for such a scenario is lacking. In addition, the normal function(s) of myocilin is (are) still elusive.

Animals↗

Predisposing factors for chronic angle-closure glaucoma.

Chronic angle-closure glaucoma is the commonest form of glaucoma in Sino Mongaloid populations. It is an anatomical disorder of the anterior segment of the eye characterised by permanent closure of part of the filtration angle as a result of iris apposition to the trabecular meshwork. Two pathways lead to this condition: recurrent pupillary block and "creeping" angle closure. East or Southeast Asian ethnic background is an important risk factor for the development of chronic angle-closure glaucoma. Other demographical risk factors include ageing, female gender and a familial tendency. Eyes with chronic angle-closure glaucoma have different anterior segment anatomical relationships when compared to normals. Those eyes at risk tend to be hypermetropic with a shallow anterior chamber, a relatively anteriorly positioned lens and a short axial length. The role of the ciliary body anatomy and ciliary processes in the pathogenesis of this condition requires further investigation.

Chronic Disease↗

Differential gene expression in the human ciliary epithelium.

The generation of expression and subtractive libraries from the ocular ciliary body and cultured ciliary epithelial cells has been instrumental in the cloning, identification and characterization of many genes which, overall reflect a representative profile of transcripts expressed in ciliary nonpigmented, ciliary pigmented and ciliary muscle cells. The cell-specific expression of some of these genes (i.e. a neurotrophic factor, a gene associated with juvenile open glaucoma, and a visual component) reveal a degree of cell differentiation with a diversity of functions and properties higher than previously thought. The protection from light-induced oxidative reactions, free radicals and detoxification, may be partially attributed to the high level of expression in the ciliary epithelium of antioxidative enzymes (i.e., glutathione S-transferase, glutathione peroxidases, selenoprotein-P). The expression of genes encoding plasma proteins (i.e., complement component C4, alpha2-macroglobulin, apolipoprotein D) is in contrast with the view that plasma proteins in aqueous humor are synthesized outside the eye (i.e., liver). The identification of neuropeptide-processing enzymes (i.e., prohormone convertases, carboxypeptidase E, peptidyl-glycine-alpha-amidating monoxigenase), neuropeptides (i.e., secretogranin II, neurotensin) and regulatory peptides (i.e., atrial natriuretic peptide and angiotensinogen) with hypertensive and hypotensive activities provide the molecular basis to support the view that the ciliary epithelium is a neuroepithelium with neuroendocrine functions. We propose a working model to demonstrate that aqueous humor and intraocular pressure are under neuroendocrine control through regulatory peptides synthesized and released by the ciliary epithelium and targeting the peptide producing cells at the inflow system by an autocrine mechanism and/or cells at the outflow system (i.e., trabecular meshwork cells) by a paracrine mechanism. Finally, we hypothesize that these mechanisms could be entrained in the light-dark cycle following the circadian rhythm of aqueous humor and intraocular pressure.

Ciliary Body↗

Pseudoexfoliation syndrome and pseudoexfoliative glaucoma.

BACKGROUND: Pseudoexfoliative glaucoma (PXG) is a common secondary glaucoma that occurs when pigment and abnormal basement membrane material from anterior segment anatomical structures deposit in the trabecular meshwork. This anomaly arises from the predisposing condition, pseudoexfoliation syndrome (PXE). Complications are common, making this one of the most difficult glaucomas to manage. PURPOSE: The literature is reviewed in order to facilitate understanding of this condition.

Antihypertensive Agents↗

Cochlin and glaucoma: a mini-review.

Primary open angle glaucoma (POAG) is a leading cause of late onset, progressive, irreversible blindness and, although its etiology is poorly understood, elevated intraocular pressure (IOP) often appears to be a contributory factor. Proteomic and Western analyses of trabecular meshwork (TM) from patients with POAG and age-matched controls originally implicated cochlin as possibly contributing to glaucoma pathogenesis. Cochlin deposits were subsequently detected in glaucomatous but not in control TM and older glaucomatous TM was found to contain higher levels of cochlin and significantly lower amounts of collagen type II. More recently, similar results were reported in DBA/2J mice, which at older ages develop elevated IOP, retinal ganglion cell degeneration, and optic nerve damage. Notably, cochlin was absent in TM from C57BL/6J, CD1, and BALBc/ByJ mice, which do not exhibit elevated IOP or glaucoma. Cochlin was found in the TM of very young DBA/2J mice, prior to elevated IOP, suggesting that over time the protein may contribute to the events leading to increased IOP and optic nerve damage. Here we review these findings and describe how future studies in DBA/2J mice can help resolve whether cochlin plays a causal role in mechanisms of POAG and elevated IOP.

Animals↗

Pigmented striae of the anterior lens capsule and age-associated pigment dispersion of variable degree in a group of older African-Americans: an age, race, and gender matched study.

PURPOSE: To investigate pigmented striae of the anterior lens capsule in African-Americans, a potential indicator of significant anterior segment pigment dispersion. METHODS: A group of 40 African-American subjects who exhibited pigmented lens striae (PLS) were identified from a non-referred, primary eye care population in Chicago, IL, USA. These subjects were then compared to an age, race, and gender matched control group relative to refractive error and the presence or absence of diabetes and hypertension. RESULTS: The PLS subjects (mean age = 65.4 +/- 8.8 years, range = 50-87 years) consisted of 36 females and 4 males. PLS were bilateral in 36 (85%) of the 40 subjects. Among the eyes with PLS, 21 (55%) of 38 right eyes and 22 (61%) of 36 left eyes also had significant corneal endothelial pigment dusting, commonly in the shape of a Krukenberg's spindle. Ten (25%) of the PLS subjects had either glaucoma or ocular hypertension (7 bilateral, 3 unilateral). The presence of trabecular meshwork pigment varied from minimal to heavy. The mean +/- SD (range) refractive error of the PLS right eyes was +1.61 +/- 1.43D (-1.50 to +5.00D) and +1.77 +/- 1.37D (-1.00 to +5.00D) for the left eyes. Based on these data, the PLS right eyes were +1.63D (Student's t, p = 0.0001; 95% CI = +0.82 to +2.44D) more hyperopic on average than the control right eyes, and the PLS left eyes were +1.77D (p = 0.0001; 95% CI = +0.92 to +2.63D) more hyperopic on average than the control left eyes. Trend analysis showed a gradually increasing likelihood of PLS with increasing magnitude of hyperopia in both eyes (Mantel-Haenszel chi-square, p = 0.001). Among PLS subjects, 24 (60%) of 40 were hypertensive and 9 (23%) of 40 were diabetic. However, these proportions were not significantly different (two-tailed Fisher's exact test; hypertension: p = 0.30; diabetes: p = 0.70) from the randomly selected controls. CONCLUSIONS: Among our African-American group, which consisted predominately of females >50 years of age, the likelihood of PLS increased with increasing hyperopic refractive error. This finding is consistent with the possibility that PLS may, in some circumstances, indicate a significant pigment dispersal process due to iris-lens rubbing that may be associated with crowding of anterior segment structures. Additional study is warranted to further assess the nature of PLS, their precise relationship with an age-related pigment dispersal process, and their true significance as a risk factor for development of glaucoma.

Adolescent↗

Congenital glaucoma associated with Rubinstein-Taybi syndrome.

PURPOSE/METHODS: Rubinstein-Taybi syndrome is a constellation of clinical findings characterized by mental and motor retardation, broad thumbs and broad first toes, marked growth retardation, microcrania, typical facies, high-arched palate, and cryptorchidism in males. Ocular and adnexal abnormalities are quite common and include antimongoloid slant of the palpebral fissures, epicanthal folds, congenital obstruction of the lacrimal excretory system, ptosis, strabismus, and severe ametropia. Macrocornea, microophthalmos, colobomas of the iris and of the optic nerve head, congenital cataract, and optic nerve atrophy have also been described. Congenital glaucoma is a rare complication. We examined a patient with Rubinstein-Taybi syndrome with bilateral congenital glaucoma. RESULTS/CONCLUSIONS: Examination of this patient revealed bilateral antimongoloid slants of the palpebral fissures, and bilateral congenital glaucoma. Gonioscopic examination revealed the iris to be inserted flatly into the trabecular meshwork. This case emphasizes the importance of detailed, complete ocular examinations in patients with Rubinstein-Taybi syndrome, and also highlights the occurrence of ocular abnormalities rarely associated with this disease.

Female↗

The medium and long-term efficacy of primary argon laser trabeculoplasty in avoiding topical medication in open angle glaucoma.

PURPOSE: To study the medium and long-term efficacy of primary argon laser trabeculoplasty in open angle glaucoma with especial emphasis on avoidance of additional medical therapy. METHODS: Records of 168 patients with chronic open angle glaucoma or pseudoexfoliation glaucoma who underwent primary argon laser trabeculoplasty between 1987 and 1995 were studied retrospectively (duration of follow-up 1-8 years, mean 4.1 years). Mean baseline intraocular pressure was 28.7 mmHg (range 22-60 mmHg). Need of additional medical therapy was in each case evaluated at the surgeons' discretion, and the results were analysed by survival analysis. RESULTS: The probability of treatment success (no medication required) was for chronic open angle glaucoma 77% after 2 years, 67% after 5 years and 67% after 8 years Corresponding numbers for pseudoexfoliation glaucoma were 80%, 54% and 36%. Prelaser IOP higher than 31 mmHg, pretreatment visual field defect and sparse pigmentation of the trabecular meshwork were independent predictors of failure. CONCLUSION: Primary argon laser trabeculoplasty gives a long-lasting and favourable effect in chronic open angle glaucoma where 2/3 of the eyes still managed without additional medication for 8 years. The success in pseudoexfoliation glaucoma was even higher the first 3 years, and kept above 50% for 5 years. This makes laser a valuable option as first choice of therapy in glaucoma.

Administration, Topical↗

Activation of a tissue-specific stress response in the aqueous outflow pathway of the eye defines the glaucoma disease phenotype.

The glaucomas are a group of optic neuropathies comprising the leading cause of irreversible blindness worldwide. Elevated intraocular pressure due to a reduction in normal aqueous outflow is a major causal risk factor. We found that endothelial leukocyte adhesion molecule-1 (ELAM-1), the earliest marker for the atherosclerotic plaque in the vasculature, was consistently present on trabecular meshwork (TM) cells in the outflow pathways of eyes with glaucomas of diverse etiology. We determined expression of ELAM-1 to be controlled by activation of an interleukin-1 (IL-1) autocrine feedback loop through transcription factor NF-kappaB, and activity of this signaling pathway was shown to protect TM cells against oxidative stress. These findings characterize a protective stress response specific to the eye's aqueous outflow pathways and provide the first known diagnostic indicator of glaucomatous TM cells. They further indicate that common mechanisms contribute to the pathophysiology of the glaucomas and vascular diseases.

Adolescent↗

Intraocular pressure increases with fenoldopam, but not nitroprusside, in hypertensive humans.

Fenoldopam mesylate stimulates adenyl cyclase in porcine ocular trabecular meshwork and raises intraocular pressure in humans. To clarify whether this results from direct activation of the dopamine-1 receptor or indirectly from baroreflex sympathetic stimulation after blood pressure reduction, intraocular pressure was measured in 14 patients with accelerated/malignant hypertension, randomized between intravenous fenoldopam or sodium nitroprusside. Intraocular pressure was measured with a Perkins tonometer, before and at the twentieth minute of each dose increment. In seven patients with a mean blood pressure of 232/131 mm Hg treated with fenoldopam, intraocular pressure increased in a dose-dependent fashion, from 16 +/- 1 to 20 +/- 2 mm Hg (p less than 0.005). In contrast, seven patients with a mean blood pressure of 225/134 mm Hg treated with sodium nitroprusside exhibited no change in intraocular pressure (15 +/- 1 versus 14 +/- 1 mm Hg) despite similar blood pressure reduction. Increases in heart rate were not significantly different. Rates of urinary excretion of norepinephrine plus epinephrine increased significantly relative to baseline (p less than 0.05) but were not different between groups. These data suggest that the increase in intraocular pressure with fenoldopam results from specific activation of the dopamine-1 receptor and is not caused by baroreflex sympathetic stimulation. Because dopamine-1 receptors may modulate intraocular pressure, dopamine-1 receptor blockers might be useful therapy for glaucoma.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

Pilocarpine to prevent acute pressure increase following primary laser trabeculoplasty.

The effect of pilocarpine pretreatment on the transient pressure elevations immediately following primary laser trabeculoplasty was investigated in a prospective, randomised study. Fifty eyes of 50 patients, 33 with exfoliative and 17 with simple glaucoma, were treated in 360 degrees of the trabecular meshwork. The mean maximum pressure increase was 2.4 (SD = 4.4)mm Hg with pilocarpine pretreatment and 12.8 (SD = 11.2)mm Hg without pretreatment (p less than 0.05). Except in two cases, all peak pressures appeared during the first two hours after treatment. The degree of chamber angle pigmentation was predictive of the magnitude of the post laser hypertensive pressure response in eyes without pretreatment (p less than 0.05).

Aged↗