Brenda J. Tripathi

Corticosteroids and glaucoma risk

Corticosteroids (glucocorticoids), used frequently as potent anti-inflammatory agents, increase the risk of glaucoma by raising the intraocular pressure (IOP) when administered exogenously (topically, periocularly or systemically) and in certain conditions of increased endogenous production (e.g. Cushing’s syndrome). Approximately 18 to 36% of the general population are corticosteroid responders. This response is increased to 46 to 92% in patients with primary open-angle glaucoma (POAG). Patients over 40 years of age and with certain systemic diseases (e.g. diabetes mellitus, high myopia) as well as relatives of patients with POAG are more vulnerable to corticosteroid-induced glaucoma. The association of corticosteroid-induced ocular hypertension in other conditions which are considered as risk factors for glaucoma (racial origins, hypertension, migraine, vasospasm) is likely but not fully established.The proposed mechanism of corticosteroid-induced glaucoma includes morphological and functional changes in the trabecular meshwork system and is similar to the pathogenesis of POAG. Trabecular cells exposed to corticosteroids in vitro show endoreplication of nuclei, an increase in cell size and excessive production of an approximately 56kD glycoprotein, identified as myocilin and transcribed by the GLC1A gene. Induction of ocular hypertension after corticosteroid administration depends on the specific drug, the dose, the frequency of administration and the corticosteroid responsiveness of the patient. The risk of corticosteroidinduced glaucoma can be minimised with judicious use of corticosteroids, as well as education of patients and medical practitioners. New treatment modalities include modified steroids and nonsteroidal anti-inflammatory agents that will have less effect on the elevation of IOP.

Drug-Induced Ocular Disorders

While beneficial therapeutically, almost all medications have untoward effects on various body tissues and functions, including the eye in which organ toxic reactions are readily detectable. Every part of the eye and all ocular functions could be affected adversely. In this review, we describe the most commonly recognized drug-induced ocular disorders, their specific clinical features, the medications that can cause the problem, the differential diagnosis and possible mechanisms of action, as well as guidelines for the management of the adverse reactions.The eyelids are most frequently involved in drug toxicity that commonly manifests as inflammation, hypersensitivity reaction or dermatitis. Drug-induced keratoconjunctival disorders present mainly as conjunctival hyperaemia (red eye), with or without superficial corneal involvement. Frequently, drug preservatives in topical ocular medications induce these adverse effects. Treatment of blepharospasm with Botox® may lead to drooping of the eyelids and corneal exposure. Intraoperative floppy iris syndrome is a drug-induced reaction in patients treated with tamsulosin and who undergo cataract surgery. Certain sulfa-based drugs can cause swelling of the ciliary body and lead to the development of angle-closure glaucoma. In addition, adrenergic agents, certain β2-adrenergic agonists and anticholinergic agents may induce pupillary dilation and precipitate angle-closure glaucoma in susceptible patients. Glucocorticoids administered systemically, topically or intravitreally are known to increase intraocular pressure, which can lead to the development of open-angle glaucoma in susceptible patients. This painless form of glaucoma has also been associated with the use of the anticancer agents docetaxel and paclitaxel. The toxic effects of systemic and topically applied drugs may manifest as cloudiness of the lens. Long-term use of glucocorticoids produces a characteristic posterior subcapsular cataract and, although the opacities may remain stationary or progress, they rarely regress upon drug withdrawal. Systemic administration of phenothiazines or busulfan induce cataractous changes in the anterior or posterior cortex, respectively. Many systemic drugs reach the retina through the vascular supply. Aminoquinolines induce a characteristic bull’s eye maculopathy. Phenothiazines bind to melanin granules and can cause a severe phototoxic retinopathy. Typical tamoxifen retinopathy manifests as crytalline deposits in the inner retina. Some patients treated with retinoids have decreased night vision and abnormal dark-adaptation. Patients on long-term treatment with linezolid may develop an optic neuropathy (swollen or pale optic disc), symmetric painless decrease of visual acuity and colour vision, and bilateral visual field defects. A probable link exists between amiodarone and a bilateral optic neuropathy that is very similar to nonarteritic ischaemic optic neuropathy (NAION). The most common adverse effects of cGMP-specific phosphodiesterase type 5 inhibitors (erectile dysfunction drugs) are changes in colour perception, blurry vision and increased light sensitivity; recently these drugs have been also implicated in the development of NAION. A bilateral, retrobulbar optic neuropathy that manifests as loss of visual acuity or colour vision and visual field defect is associated with the use of ethambutol. Many different kinds of medications can cause similar ocular adverse reactions. Conversely, a single medication may affect more than one ocular structure and cause multiple, clinically recognizable disorders. Clinicians should be mindful of drug-induced ocular disorders, whether or not listed in product package inserts and, if in doubt, consult with an ophthalmologist.

Human trabecular endothelium, corneal endothelium, keratocytes, and scleral fibroblasts in primary cell culture. A comparative study of growth characteristics, morphology, and phagocytic activity by light and scanning electron microscopy

To obtain baseline data for our experimental investigations in vitro we established a pure cellline culture model of human trabecular endothelium, corneal endothelium, keratocytes, and scleral fibroblasts, using an identical environment for each cell type. We studied the growth characteristics, morphology and phagocytic activity of live cultures by phase-contrast microscopy and time-lapse cinephotomicrography; fixed preparations were examined by light and scanning electron microscopy. From these observations, we were able to characterize the distinctive features of the cells. By correlated ultrastructural and tissue culture studies, we showed that human cadaver eyes cold-stored (4°C) up to 5 days can be used as a tissue source of trabecular endothelium, keratocytes and scleral fibroblasts. Corneal endothelium, however, rarely survived after 4 days of postmortem storage. Our observations revealed that, in primary confluent culture, the trabecular cells grew in a monolayer. Individual cells had flattened, elongated cell bodies, a centrally located, oval nucleus, and a generally smooth cell surface with occasional microvillous projections; in places, adjacent cells and their processes adhered closely one to another. Corneal endothelium at confluency presented a flattened hexagonal profile of cells arranged in a honeycomb pattern, interdigitating cell borders, a centrally located nucleus, prominent perinuclear microvillous projections, and numerous surface invaginations. The keratocytes and scleral fibroblasts had a thin and elongated, spindle-shaped profile with a remarkably smooth cell surface and an oval to oblong nucleus surrounded laterally by scanty cytoplasm; the cell surfaces and processes frequently overlapped but rarely formed firm attachments. In contrast to the monolayer growth of trabecular and corneal endothelium, these cells characteristically grew in superimposed layers. In primary culture and with latex spheres and carmine particles used as markers, the trabecularendothelial cells showed a greater phagocytic capability than did corneal endothelium, keratocytes and scleral fibroblasts. Our preliminary studies indicate that cytochalasin B markedly inhibits the phagocytic activity of the trabecular cells.

Protein composition of human aqueous humor: SDS-PAGE analysis of surgical and post-mortem samples

We analyzed the protein composition of human aqueous humor. Samples were obtained by paracentesis from 25 human eyes (age range 64-92 years) at elective cataract surgery, and from 20 age-matched post-mortem eyes within 1.5 to 18 hr after death. Individual samples were assayed for total protein, and the polypeptides were separated by qualitative SDS-PAGE into high-, medium- and low-molecular-weight ranges and then silver-stained. The clinical samples showed a remarkable consistency in the total protein values (mean +/- SEM: 12.4 +/- 2.0 mg per 100 ml) and no detectable variations in the profiles of the silver-stained proteins. Twelve major protein fractions, with apparent molecular weights of 140, 80 (doublet), 67, 60 (doublet), 35, 27, 25, 17, 14.6 and 9 kDa, were present. A preliminary analysis showed that the 17 kDa band contained a molecule resembling basic fibroblast growth factor. Two additional samples of aqueous humor from patients whose blood/aqueous barrier was compromised during paracentesis showed a quantitative and qualitative increase in the polypeptides that were present. Compared with the samples of aqueous humor obtained at surgery, the post-mortem samples exhibited a greater variability in total protein content (56.1 +/- 11.6 mg per 100 ml) and an increased number of high- and low-molecular-weight protein fractions. In view of wide differences in the clinical parameters, including ocular and systemic medications, systemic illness, surgical premedications, anesthesia and total serum protein values, the similarity in the protein profiles of the carefully drawn surgical samples is most remarkable. Our results indicate that, in patients who underwent elective cataract surgery, the levels of major proteins in human aqueous humor are not affected by wide individual variations in the clinical parameters. We attribute this finding to the care taken in the collection of aqueous humor samples.

Glaucoma in Sturge-Weber Syndrome

Trabeculectomy specimens from three eyes with Sturge-Weber syndrome were examined histopathologically. Changes in the trabecular meshwork-Schlemms canal system were similar to findings in old age and in primary open-angle glaucoma. Two mechanisms for glaucoma are theorized. In cases with buphthalmos and congenital glaucoma, the chamber angle is often anomalous, as in other types of congenital glaucoma. In later onset juvenile cases, the chamber angle more often appears normal. A premature aging of the trabecular meshwork Schlemms canal complex, as shown by us histopathologically, is a primary cause of juvenile glaucoma. It is suggested that both mechanisms relate to the abnormal hemodynamics of episclera and chamber angle, due to persistence of Streeters primordial vascular plexus.

Drug-induced glaucomas: mechanism and management.

Glaucoma comprises a heterogeneous group of diseases that have in common a characteristic optic neuropathy and visual field defects, for which elevated intraocular pressure is the major risk factor. The level of intraocular pressure within the eye depends on the steady state of formation and drainage of the clear watery fluid, called the aqueous humour, in the anterior chamber of the eye. An obstruction in the circulatory pathway of aqueous humour causes an elevation in intraocular pressure. Because intraocular pressure is the most modifiable parameter, therapeutic measures (medical and surgical) are aimed at reducing the pressure to protect against optic nerve damage. Glaucomatous optic neuropathy results from degeneration of the axonal nerve fibres in the optic nerve and death of their cell bodies, the retinal ganglion cells. Clinical examination of the optic nerve head or disc and the peripapillary nerve fibre layer of the retina reveals specific changes, and the resulting visual field defects can be documented by perimetry.Glaucoma can be classified into four main groups: primary open-angle glaucoma; angle-closure glaucoma; secondary glaucoma; and developmental glaucoma. Drug-induced glaucoma should be considered as a form of secondary glaucoma because it is brought about by specific systemic or topical medications. Although there is a high prevalence of glaucoma worldwide, the incidence of drug-induced glaucoma is uncertain.Drugs that cause or exacerbate open-angle glaucoma are mostly glucocorticoids. Several classes of drugs, including adrenergic agonists, cholinergics, anticholinergics, sulpha-based drugs, selective serotonin reuptake inhibitors, tricyclic and tetracyclic antidepressants, anticoagulants and histamine H1 and H2 receptor antagonists, have been reported to induce or precipitate acute angle-closure glaucoma, especially in individuals predisposed with narrow angles of the anterior chamber. In some instances, bilateral involvement and even blindness have occurred. In this article, the mechanism and management of drug-induced glaucomatous disease of the eye are emphasised. Although the product package insert may mention glaucoma as a contraindication or as an adverse effect, the type of glaucoma is usually not specified. Clinicians should be mindful of the possibility of drug-induced glaucoma, whether or not it is listed as a contraindication and, if in doubt, consult an ophthalmologist.

Morphology of the aqueous outflow pathway

The anterior chamber angle is formed by the approximation of the root of the iris and the peripheral cornea. The importance of the anterior chamber angle lies in the fact that the main drainage pathway of the aqueous humor is located in this region, represented by the trabecular meshwork and Schlemms canal.

Neural Crest Origin of Human Trabecular Meshwork and Its Implications for the Pathogenesis of Glaucoma

We used an immunohistochemical method to examine the distribution of neuronal-specific enolase in the trabecular meshwork of adult normal human eyes, as well as in primary cultures of human trabecular cells maintained in vitro for up to 44 days with or without the addition of nerve growth factor. In tissue sections of the globes, neuronal-specific enolase was present in the cells of the anterior region of the meshwork and those of the inner uveal beams. The cells of the posterior region of the meshwork stained variably with antiserum against neuronal-specific enolase. Cultured trabecular cells were initially neuronal-specific enolase-positive, but became negative after 18 to 21 days in vitro. The addition of nerve growth factor restored the expression of neuronal-specific enolase in these cultured cells. Because the presence of neuronal-specific enolase in normal cells is believed to indicate their differentiation from neuroectoderm, our results provide evidence that the trabecular cells in human eyes are derived from the embryonic neural crest. Our finding also supports the hypothesis that abnormal migration or a defective terminal induction of the neural crest cells has a role in certain ocular diseases that are characterized by chamber angle anomalies or primary glaucoma.

Cataracts induced by microwave and ionizing radiation

Microwaves most commonly cause anterior and/or posterior subcapsular lenticular opacities in experimental animals and, as shown in epidemiologic studies and case reports, in human subjects. The formation of cataracts seems to be related directly to the power of the microwave and the duration of exposure. The mechanism of cataractogenesis includes deformation of heat-labile enzymes, such as glutathione peroxide, that ordinarily protect lens cell proteins and membrane lipids from oxidative damage. Oxidation of protein sulfhydryl groups and the formation of high-molecular-weight aggregates cause local variations in the orderly structure of the lens cells. An alternative mechanism is thermoelastic expansion through which pressure waves in the aqueous humor cause direct physical damage to the lens cells. Cataracts induced by ionizing radiation (e.g., X-rays and gamma rays) usually are observed in the posterior region of the lens, often in the form of a posterior subcapsular cataract. Increasing the dose of ionizing radiation causes increasing opacification of the lens, which appears after a decreasing latency period. Like cataract formation by microwaves, cataractogenesis induced by ionizing radiation is associated with damage to the lens cell membrane. Another possible mechanism is damage to lens cell DNA, with decreases in the production of protective enzymes and in sulfur-sulfur bond formation, and with altered protein concentrations. Until further definitive conclusions about the mechanisms of microwaves and ionizing radiation induced cataracts are reached, and alternative protective measures are found, one can only recommend mechanical shielding from these radiations to minimize the possibility of development of radiation-induced cataracts.

Corneal growth factors: a new generation of ophthalmic pharmaceuticals.

Several of the known growth factors either have an effect on corneal tissues or can be isolated from them. Both epidermal growth factor (EGF) and fibroblast growth factor (FGF) stimulate the proliferation of corneal epithelium, keratocytes, and endothelium. Compared to FGF, EGF is more potent in stimulating the growth of endothelial cells; it also increases the tensile strength of corneal stromal wounds. The corneal epithelium produces an angiogenic growth factor as well as a neuronotrophic growth factor. Insulin-like growth factor stimulates the growth of keratocytes and enhances the effect of EGF on the corneal endothelium. Mesodermal growth factor stimulates the proliferation of keratocytes and increases the rate of healing of damaged corneal endothelial cells. It is evident that growth factors have many potential clinical applications especially in accelerating corneal wound repair after surgery, chemical burns, or ulcers, and in increasing the numbers of corneal endothelial cells in aging and diseased corneas, as well as in donor corneas to be used for transplantation. Several parameters require evaluation, e.g. the dose, concentration, combination and formulation, exposure time, receptor affinity, and tissue interdependence of the growth factor(s), as well as the variability in patient response and severity of disease and/or injury. Investigations are also needed for the development of effective delivery systems and for determining whether growth factors are specific and safe in humans. Growth factors are emerging as a new generation of ophthalmic pharmaceuticals, and they will soon be integrated into the advancing practice of ophthalmic surgery and medicine.