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Biomechanics of echothiophate-induced anatomic changes in monkey aqueous outflow system.

Cynomolgus monkeys underwent long-term topical treatment with echothiophate, echothiophate + atropine, or control solution. Echothiophate-treated eyes exhibited increased intraocular pressure, collapse and densification of the trabecular meshwork with accumulation of extracellular material in the cribriform region, alterations in the shape and orientation of Schlemm's canal and the ciliary muscle, and discontinuity between ciliary muscle bundles and trabecular beams. Atropine or ciliary muscle disinsertion with subsequent scar formation supporting the mesh posteriorly at least partially prevented these alterations. Only sometimes did discontinuing echothiophate treatment restore normal anatomy. Collectively, these findings indicate that the pathophysiology of structural alterations in the outflow apparatus induced by echothiophate is mediated at least in part by an anterior segment muscarinic receptor, involves mechanical factors and underperfusion of the meshwork, and does not involve any direct toxic effect of echothiophate.

Animals↗

New developments in the drug treatment of glaucoma.

This article reviews standard treatment modalities for patients with glaucoma and describes 3 classes of drugs which are undergoing development: apraclonidine (aplonidine, ALO 2145), an alpha 2-adrenergic agonist which has been released for clinical use; topical carbonic anhydrase inhibitors, a modification of the systemic carbonic anhydrase inhibitors currently in use; and prostaglandins (PGs), a new class of drugs with topical ocular hypotensive activity. Standard treatment modalities include parasympathomimetic agents such as pilocarpine, carbachol, and phospholine iodide, which lower intraocular pressure (IOP) by increasing aqueous outflow through the trabecular meshwork. A newer form of pilocarpine as a gel produces a longer action. Adrenergic agonist medications, such as epinephrine (adrenaline) and its prodrug dipivefrine (dipivalyl epinephrine), function by increasing uveoscleral outflow and trabecular outflow facility. A decrease in aqueous formation by the ciliary processes is thought to be the mechanism of action of beta-adrenoceptor antagonists, but the physiological basis for this action has not been clearly demonstrated. A newer beta-blocker, betaxolol, has relatively selective beta 1-blocking activity. Carbonic anhydrase inhibitors are nonbacteriostatic sulphonamide derivatives which decrease aqueous formation by the ciliary body. Almost 50% of patients taking these medications are unable to tolerate them because of their adverse effects, and there is thus much interest in the development of a topical carbonic anhydrase inhibitor with the potential for fewer adverse effects. MK 507 is the most recent and most potent compound in the series of topically active carbonic anhydrase inhibitors. Apraclonidine hydrochloride is a derivative of clonidine hydrochloride, an alpha 2-adrenergic agonist. Clonidine has previously been shown to lower IOP significantly, but has the potential to produce marked lowering of both systolic and diastolic blood pressures. Its major ocular effect appears to be a decrease in aqueous production. The structural modification to apraclonidine decreases corneal absorption and the drug's ability to cross the blood-brain barrier, minimising the risk of centrally mediated cardiovascular side effects. Apraclonidine may also influence secondary avenues of aqueous outflow, such as uveoscleral outflow, and may also affect conjunctival and episcleral vascular flow. It produces a mean decrease in IOP of 25% for as long as 12 hours. Adverse effects include blanching of the conjunctiva, minimal mydriasis and eyelid retraction. This drug has been approved in the US for use in prevention of elevated IOP after argon laser trabeculoplasty and iridotomy, and has potential uses in preventing an IOP rise after YAG laser posterior capsulotomy and cataract surgery in patients already on other antiglaucomatous medications.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenergic alpha-Agonists↗

Primary argon laser trabeculoplasty vs. pilocarpine. Short-term effects.

This is a prospective study of 82 newly discovered patients with simplex or capsular glaucoma from two centres, collected between 1984 and 1989 and selected at random for primary treatment by either laser or pilocarpine. Preliminary two-year follow-up shows that primary laser treatment gives a significantly higher number of patients where the intraocular pressure is successfully controlled. Primary argon laser trabeculoplasty has been carried out in 40 patients. The first treatment was given to either the upper or to the lower half of the trabecular meshwork. In the second treatment after one month the other half was treated. In both groups the first treatment gave the highest pressure reduction. The somewhat higher pressure reduction after upper treatment versus lower was insignificant. The degree of trabecular pigmentation did not influence the two month follow-up result, neither did the type of glaucoma. Of the eyes treated with laser, peripheral anterior synechiae could be seen in 18%. Acute intraocular pressure rises greater than 5 mmHg occurred in 21% of the eyes after the first treatment and in 37% after the second treatment. Pressure rises greater than 10 mmHg occurred in 5% after the first and in 10% after the second treatment. No pressure-lowering substances were given. Considering that 16% of the eyes had an intraocular pressure that was higher than baseline pressure even 6 h after either first or second treatment, it is recommended that a pressure-lowering medication on the day of treatment should be administered.

Follow-Up Studies↗

[Laser trabeculopuncture. III Experiments with rhesus monkeys].

Argon-laser trabeculopuncture was carried out on 7 rhesus monkeys. Perforation of the trabecular meshwork was possible with laser impacts of 100 msec, 4,200 mW and a beam diameter of 50 mum. Clinical and histological observations covered an interval of up to 15 weeks after coagulation. They revealed an obliteration of both the trabecular holes and the canal of Schlemm after a few days. Shorter pulse durations and higher energies might be helpful to improve the effectiveness, possibly assisted by a therapy with anti-inflammatory agents.

Animals↗

Familial amyloidotic polyneuropathy: ocular manifestations with clinicopathological observation.

Clinical findings of ocular involvement in two patients with familial amyloidotic polyneuropathy are described. Both cases revealed irregular pupillary margin, white membranous material on the pupillary border and on the lens surface. Open-angle glaucoma was found in one case, and ocular hypertension in the other. Histopathological examination of the tissues obtained during trabeculectomy in Case 1 revealed a large amount of amyloid substance around the vessels of the conjunctiva and the iris and in the endothelial meshwork of the chamber angle. Electron microscopic observation revealed that amyloid fibrils had formed in the basement membrane of the endothelial cells of the blood vessels in the conjunctiva and the iris. However, no amyloid fibrils were observed in the endothelial cells of the trabecular meshwork. Crossed immunoelectrophoresis of the aqueous humor of Case 1 showed a high-protein content, especially of alpha 1-lipoprotein and ceruloplasmin. The findings described above suggest that glaucoma or ocular hypertension in association with familial amyloidotic polyneuropathy is a result of the accumulation of amyloid substance in the endothelial meshwork.

Adult↗

[Long-term results of laser-trabecular-puncture (author's transl)].

A report on 38 eyes with glaucoma simplex that were treated by laser-trabecular-puncture 2 years ago is given. By this method one attempts to perforate the trabecular meshwork by means of a laser beam. Gonioscopy revealed that the pores had become occluded by scar tissue and goniosynechiae. In only 3 eyes (7.9%) was the intraocular tension lowered. The hypothesis is made, that in these cases contracture of scar tissue in the iris tissue led to a pull on the trabecular network and hence to an improvement of liquor drainage.

Aged↗

Distribution of thrombospondin-4 in the bovine eye.

PURPOSE: The purpose of this study was to analyze the distribution of thrombospondin-4 (TSP-4) in the bovine eye. METHODS: Anterior and posterior segments of the bovine eyes were sectioned and stained by the indirect immunofluorescence method with an anti-TSP-4 antibody. The tissues were analyzed by reverse-transcription-polymerase chain reaction (RT-PCR) to determine where the TSP-4 mRNA is produced. RESULTS: Immunohistochemical staining for TSP-4 indicated the presence of TSP-4 in the cornea (epithelium, basement membrane, and keratocytes), conjunctiva (epithelium and stroma), aqueous ducts, sclera, iris (stroma), ciliary processes and muscle, trabecular meshwork, Bruch's membrane, retina, lamina cribrosa, and optic nerve, and in all blood vessel walls. TSP-4 mRNA was expressed by the cells in all structures. CONCLUSIONS: TSP-4 is widely distributed in the bovine eye where it may play a role in the functions of basement membranes in various tissues. It is abundant in the trabecular and uveo-scleral pathways and may play a role in the regulation of aqueous outflow resistance.

Animals↗

Age related changes in extracellular materials in the inner wall of Schlemm's canal.

An electron microscopic investigation was conducted to study the extracellular materials of the endothelial meshwork in the human outflow apparatus. A quantitative analysis was made to determine the changes which occur with age. Tissue from 20 cases, ages 4 months to 80 years, was examined. A morphometric technique which utilised a grid of 100 random points was used to estimate the percentage area of extracellular components in the endothelial meshwork. It was found that while the percentage area occupied by amorphous ground substance and fibrillar material decreased with age, the percentage area occupied by the electron-dense component increased. Variation in distribution of these components was noted both between cases of similar age and also within one section. A qualitative description of other changes in the trabecular meshwork is given, and the limitations of the technique are discussed.

Adolescent↗

Mediation of laser trabeculoplasty-induced matrix metalloproteinase expression by IL-1beta and TNFalpha.

PURPOSE: Laser trabeculoplasty of the anterior uveal region of the trabecular meshwork induces sustained matrix metafloproteinase expression within the juxtacanalicular region of the meshwork. Studies were conducted to test the hypothesis that a factor mediates this response and to identify the factor. METHODS: Human anterior segment organ cultures were subjected to laser treatment using standard clinical parameters and were returned to culture for 8 hours. The resultant 8-hour-conditioned culture medium was then tested for factor activity by evaluating its ability to produce two typical trabecular responses to laser treatment, that is, to induce stromelysin expression or to trigger cell division, when applied to fresh organ cultures or to cell cultures. Confocal immunohistochemistry of the laser-treated organ cultures and western immunoblot analysis of the conditioned medium were used to evaluate changes in potential candidates for the factor activity. The ability of the interleukin (IL)-1 receptor antagonist (IL-1ra)- and of tumor necrosis factor alpha (TNFalpha)- blocking antibodies to eliminate the stromelysin induction was evaluated. RESULTS: Medium conditioned for 8 hours induced typical trabecular cell division in anterior segment organ cultures. Medium conditioned for 8 hours, but not for 30 minutes, induced typical increases in stromelysin expression in these organ cultures and in cell cultures. After 8 hours, both trabecular cells in laser-treated organ cultures and in the conditioned medium contained elevated levels of IL-1beta and TNFalpha. The laser-treated organ cultures contained elevated levels of IL-1alpha, but it was not secreted into the medium. The ability of conditioned media to induce stromelysin expression was partially blocked by either the IL-1ra- or the TNFalpha-blocking antibody. CONCLUSIONS: Laser trabeculoplasty induces the expression and secretion of both IL-1beta and TNFalpha within the first 8 hours after treatment. These cytokines then mediate increased trabecular stromelysin expression. Putatively, this initiates remodeling of the juxtacanalicular extracellular matrix, a likely site for the aqueous outflow resistance, and thus restores normal outflow facility.

Animals↗

[Non-penetrating filtering surgery: concept, technique and results].

Recently, many discussions occurred concerning non-penetrating filtering surgery. Viscocanalostomy and deep sclerectomy with external trabeculectomy are the most practiced techniques. Their goal is to reduce intraocular pressure by enhancing the natural aqueous outflow, while reducing its resistance. Both techniques involve the removal of a deep scleral flap, the external wall of Schlemm's canal and corneal stroma behind the anterior trabecular meshwork and Descemet membrane, thus creating a scleral lake, where the aqueous humor remains until it is absorbed in many different ways. In viscocanalostomy, a high-molecular viscoelastic substance is injected into the ostia of Schlemm's canal in order to enlarge it and its collectors channels. In deep sclerectomy with external trabeculectomy, the inner wall of Schlemm's canal is removed with adjacent trabecular layers. Studies, both retrospective and prospective, demonstrated similar tensional results when compared to classical trabeculectomy, with fewer complications and better visual recovery after non-penetrating procedure. The aim of this study is to expose the non-penetrating surgery techniques, mechanism of action and results based on the analysis of published literature.

Clinical Trials as Topic↗

An ultrastructural study of DNA precipitation in the anterior segment of eyes with retinoblastoma.

The anterior segment of six infant eyes enucleated for retinoblastoma were studied by light and electron microscopy in an attempt to describe the pattern of DNA precipitation. In only one of these cases was extracellular deposition of DNA in the iris and aqueous outflow pathways detectable by routine light microscopy and Feulgen staining. In two cases, ultrastructural examination was necessary to resolve the presence of small discrete electron-dense DNA granules (60-200 nm). In three cases, the DNA deposits were found on the anterior surface of the iris, in the mid-iris stroma around blood vessels, and in the outer layers of the trabecular meshwork around Schlemm's canal. Although the quantity of the material varied in the three cases, the similar pattern of distribution appeared to reflect routes of fluid movement within the eye and sites of permeability barriers at which the passage of larger particulate matter is obstructed. The DNA deposits had an affinity for collagen and basal lamina, especially in the iris. Interestingly, they were not phagocytosed by the trabecular endothelial cells. No DNA could be detected ultrastructurally in the anterior segment of the three remaining eyes also enucleated for retinoblastoma. The authors' findings suggest that DNA deposition in the anterior segment may be a more common phenomenon in retinoblastoma than has been suspected previously from routine histopathologic studies. The findings are discussed in relation to other types of tumor in which DNA coating around blood vessels has been observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Anterior Eye Segment↗

Ab-interno trabeculo-canalectomy: surgical approach and histological examination.

PURPOSE: To evaluate, on eye bank eyes, a new surgical approach aimed at removing a quadrant of the trabecular meshwork (TM), with an ab interno approach. METHODS: Gonioscopically controlled ab interno removal of the TM was done with a subretinal forcep on six human bank eyes. Serial histological sections were obtained from the treated and untreated part of each globe to assess the effect of the technique on intraocular tissues. RESULTS: Under the gonioscope, the TM was easily removed in strings of varying length. Histological examination showed, unexpectedly, that this resulted in a well-defined deep furrow in the middle of the trabecular region involving both the TM and the inner wall of Schlemm's canal. The operation created a direct communication between the anterior chamber and Schlemm's canal lumen without any evident damage to the outer canal wall and adjacent ocular structures such as the iris base and corneal endothelium. CONCLUSIONS: Our small series on human bank eyes showed that the procedure involves both the TM and the inner wall of Schlemm's canal and is therefore called ab interno trabeculocanalectomy (AITC). The intraoperative findings and the histological evidence are encouraging, and suggest that the procecedure could have potential clinical application.

Cornea↗

Glycosaminoglycans and outflow pathways of the eye and brain.

The etiology of the majority of defects of the outflow pathways of aqueous humor (glaucoma) and cerebrospinal fluid absorption (hydrocephalus) is unknown. A considerable amount of evidence indicates that glycosaminoglycans have a role in regulating fluid movement through connective tissues such as the trabecular meshwork of the eye and the arachnoid of the brain. Both the eye and the brain outflow pathways have hyaluronic acid and chondroitin sulfate within the filtration barrier. The physiological significance of glycosaminoglycans in the outflow pathways may be their ability to form highly viscous and elastic gel-like solutions that function as a selective biological gel filtration system, which maintains normal intraocular and intracranial pressure. We suggest that glycosaminoglycans may act to maintain the unidirectional character, low-flow fluid movement, and pressure gradient between the trabecular lamellae and the drainage channels of the eye and the brain. This review of the outflow pathways of the eye and the brain discusses the cell biology of glycosaminoglycans in regulating normal aqueous outflow and cerebrospinal fluid absorption.

Animals↗

Early glial responses after acute elevated intraocular pressure in rats.

PURPOSE: To study the responses of glial cells to a short-term elevation in intraocular pressure (IOP) in rats. METHODS: Adult Sprague-Dawley albino rats, 45 to 55 days old, were given India ink intracamerally. After 7 days, 200 spots of laser burn over 360 degrees were delivered by an Argon laser (620-637 nm; 200 mW; 200 mm; 0.2 seconds) aimed at the ink deposits in the trabecular meshwork. IOP was recorded and eye tissues at 12 hours and 1, 3, 5, 7, or 14 days after laser were examined by immunohistochemistry with antibodies against glial fibrillary acidic protein (GFAP), vimentin, S-100, ED1, and OX42. To evaluate neuronal loss, the number of cells in the retinal ganglion cell layer (RGCL) was counted on flat preparations of retinas at various times after elevation of IOP. RESULTS: Significant elevation of IOP from 1 to 7 days and loss of cells in the RGCL from 3 days onward were noted after trabecular laser photocoagulation. In the inner retina, there was a gradual and sustained increase in GFAP and S-100 immunoreactivity, but only a transient increase in vimentin immunoreactivity. No remarkable changes in GFAP, vimentin, and S-100 immunoreactivity were noted at the optic nerve head (ONH). ED1- and OX42-labeled cells were noted in the choroidal plexus, the parapapillary region of the optic nerve, and the ONH from 3 days onward, whereas expression in the retina was unremarkable. CONCLUSIONS: There is differential expression of glial cell markers in the retina and the ONH, with early loss of cells in the RGCL in response to the elevation of IOP. Macroglia such as astrocytes and Müller cells may be involved in the pathophysiology of retinal ganglion cell death or retinal repair, and activated microglial/phagocytic cells may play an important role in modulating the changes in the ONH that occur with the elevation of IOP.

Acute Disease↗

[Argon laser trabeculoplasty].

There is currently a general consensus to perform argon laser trabeculoplasty (ALT) onto the 360 degrees of the trabecular ring to obtain the best long term results; but in two sessions a month apart with, during each session, 50 burns of a true 50 mu laser spot on 180 degrees, a 0.1 sec exposure time and a power high enough to create a tiny but visible trabecular reaction on the anterior edge of the posterior trabecular meshwork. During the first three hours after treatment, the main complication is raised intraocular pressure (IOP) which occurs in between 14% and 33% of the cases with a 10 mmHg rise above the initial IOP. In end stage glaucomas, a very close monitoring is mandatory during these first hours. Pretreatment with apraclonidine drops can dramatically reduce this complication. Our results and those of the literature with the same follow-up show that ALT seems effective in phakic chronic open-angle glaucomas (COAG) in half of the cases for about five years with a 10% new failure rate per year. The youngest patients, the aphakic patients and all the cases with trabecular severe disorganisation display the worst results. ALT must be considered to be a physical treatment - initially powerful but with decreasing efficacy in the long term. It should be used in presurgical glaucomas when IOP does not exceed 30 mmHg with intensive medical treatment and in intermediate stages of the disease where it is more effective.

Humans↗

Nd:YAG laser trabeculopuncture in angle-recession glaucoma.

Nd:YAG laser trabeculopuncture (YLT) was performed in 12 eyes of 12 patients with angle-recession glaucoma. Confluent, 1-clock-hour trabeculotomy was attempted in all eyes. The calculated average laser energy was 181 +/- 86 mJ. Where possible, the midtrabecular meshwork was treated, preferably at the superior half. After a mean follow up of 12.0 +/- 5.6 months, intraocular pressure (IOP) was controlled (less than or equal to 19 mm Hg) in five eyes (41.7%). YLT was associated with blood reflux during or after treatment in all successfully treated eyes. In eyes that failed, blood reflux could be detected in only two of seven eyes (28.6%). YLT failed to control IOP in all five eyes that had angle-recession for 360 degrees. Following YLT, IOP rose in two eyes (16.6%), minimal hyphema occurred in one eye, and temporary flare and cells developed in the anterior chamber in all eyes. Six eyes (50%) required glaucoma surgery (four had trabeculectomy and two had Molteno implant surgery). We recommend YLT only for selected cases of uncontrolled angle-recession glaucoma in which at least part of the trabecular meshwork by gonioscopy appears to maintain its anatomical structure, permitting penetration into Schlemm's canal.

Adolescent↗

[Non penetrating filtering surgery, evolution and results].

Trabeculectomy is currently the standard filtration procedure for glaucoma surgical treatment. Despite several advantages over full-thickness procedures, trabeculectomy can be responsible for early postoperative complications related to sudden ocular decompression that can lead to hypotony with its sight-threatening complications. Nonpenetrating glaucoma surgeries, namely viscocanalostomy and deep sclerectomy with external trabeculectomy, have been developed in recent years in order to improve the safety of conventional filtering procedures. The goal of these procedures is to reduce intraocular pressure (IOP) by enhancing the natural aqueous outflow channels, while reducing outflow resistance, attributed for 75% to the trabecular meshwork and for 25% to the outer wall of Schlemm's canal (SC) or tissue surrounding it. In these procedures, the anterior chamber is not opened so that complications related to full thickness procedures are mainly avoided. In the last few years, viscocanalostomy and deep sclerectomy with external trabeculectomy have become the most popular nonpenetrating filtering procedures. Both involve the removal of a deep scleral flap, the external wall of SC, and corneal stroma behind the anterior trabecula and Descemet membrane, thus creating a scleral lake. The aqueous humor leaves the anterior chamber through the intact trabeculodescemetic membrane and reaches the scleral lake, from where it will egress into different pathways. In viscocanalostomy, a high-molecular viscoelastic substance is injected into the ostia of the SC in order to enlarge the SC and its collector channels. In deep sclerectomy with external trabeculectomy, the main goal is to remove the inner wall of the SC and the adjacent trabecular layers involved in aqueous outflow resistance, while leaving the innermost trabecular layers intact so that the anterior chamber does not open during operation. Different surgical adjuvants designed to maintain the scleral lake open are commercially available. Retrospective and prospective published studies have reported similar midterm results with trabeculectomy and nonpenetrating filtering procedures in terms of IOP control, with fewer postoperative complications and better visual acuity recovery with the nonpenetrating procedures. This article reviews the current nonpenetrating surgical procedure techniques, their mechanism of action, and their outcome.

Filtering Surgery↗

Familial Axenfeld-Rieger anomaly, atrial septal defect, and sensorineural hearing loss: a possible new genetic syndrome.

OBJECTIVE: To describe the clinical and ocular histopathological findings in multiple members of a family with congenital Axenfeld-Rieger anomaly, atrial septal defect, and sensorineural hearing loss. METHODS: We performed a retrospective review of the medical charts and the ocular histopathological material of multiple members of a family. RESULTS: Congenital Axenfeld-Rieger anomaly and glaucoma were inherited by both the proband and her male half-sibling from a phenotypically positive father and 2 different phenotypically negative mothers, suggesting an autosomal dominant inheritance. The proband's male half-sibling and her father also had atrial septal defects and sensorineural hearing loss. The proband's paternal grandmother had severe glaucoma. Histopathological analysis of blind, painful eyes removed from the proband's father and paternal grandmother showed incomplete development of the anterior chamber angle with iris stromal hypoplasia, prominent posterior embryotoxon with iris adhesions, and abnormal position and insertion of the ciliary muscles. CONCLUSIONS: This is the first description of coexisting Axenfeld-Rieger anomaly, atrial septal defect, and sensorineural hearing loss in multiple members of a single family. The iris, trabecular meshwork, and large portions of the cardiac intraventricular septum all arise from neural crest anlagen, thus supporting the notion that anterior segment dysgenesis represents a developmental disorder of the neural crest.

Abnormalities, Multiple↗