Howard M. Leibowitz

Changes in the corneal endothelium as a function of age

Abstract In vivo photomicrography has been used to examine the corneal endothelium of humans as a function of age. Sixty-one normal volunteers of both sexes ranging in age from 20 to 89 years of age were photographed. The endothelial photographs were analyzed to determine mean endothelial cell area for the central cornea and the frequency distribution of cell areas for each subject. The mean endothelial cell area was found approximately to double from age 20 to age 80. The increase in mean endothelial cell area with age was found to be statistically significant to better than the 0·1% level. The frequency distribution of cell area and cellular pleomorphism were also found to change with age. There was a statistically significant variability in the values of the difference in mean endothelial cell area between the two eyes of the population studied with age.

Prevalence of Senile Cataract, Diabetic Retinopathy, Senile Macular Degeneration, and Open-Angle Glaucoma In The Framingham Eye Study

Of the Framingham, Massachusetts Heart Study population, 2,675 individuals underwent an ophthalmologic evaluation that stressed detection of senile cataract, diabetic retinopathy, open-angle glaucoma, and senile macular degeneration. Those examined were 52 to 85 years old at the time this study was initiated. The prevalence rate of each of these ocular conditions increased with age. Prevalence of senile cataracts ranged from 4.6% for those between the ages of 52 to 64 years to 46% for those 75 to 85 years of age. Diabetic retinopathy was present in 2% of those between 52 and 64 years of age or older. Overall prevalence of senile macular degeneration was 9%, with a prevalence rate of 2% in our youngest age group and 28% in the oldest age group. Open-angle glaucoma had an overall prevalence of approximately 3%. This disease also showed a statistically significant (P less than .01) increase with age from 1.4% (52 to 64 years old) to 7.2% (75 to 85 years old).

Morphological Changes in Corneal Endothelial Cells After Penetrating Keratoplasty

Fifteen patients who had had a successful penetrating keratoplasty were photographed with the clinical specular microscope and the resulting endothelial photomicrographs were analyzed. The average endothelial cell area was one to six times larger and the average endothelial cell perimeter was one to 2 1/2 times larger than that of a normal cornea of a subject the same age as the donor. In each corneal graft, endothelial cell areas and perimeters clustered tightly around a mean value, although the mean value for different corneas varied significantly. The thickness and transparency of each graft was normal, indicating that within the observed limits the success of the transplantation procedure did not depend on final endothelial cell size or perimeter.

Evidence for Mitosis in the Adult Corneal Endothelium

Intracellular structures probably representative of mitotic figures were seen by specular microscopy in the endothelium of a corneal graft following a rejection reaction. Serial measurements over an eight month period initially showed grossly enlarged cells and apparent mitotic figures. Subsequently, clusters of cells smaller than any cells previously seen were observed. Measurements of endothelial cell area over this period demonstrated a highly significant (P less than 0.0001) decrease in cell area, or increase in cell density, with time. These observations indicate that at least under some circumstances mitosis occurs in the endothelium of the adult human cornea.

Evaluation of Dexamethasone Acetate as a Topical Ophthalmic Formulation

Penetration of an ophthalmic suspension of 0.1% dexamethasone acetate into the rabbit cornea and aqueous humor was unaffected by the status of the corneal epithelium or by the presence or absence of intraocular inflammation. However, the total quantity of this corticosteroid that could be measured in the cornea or aqueous humor was significantly less than that produced by either dexamethason alcohol or dexamethasone sodium phosphate. Despite this, dexamethasone acetate was the most effective of the three dexamethasone derivatives in suppressing inflammation in the cornea, which indicates that following topical administration to the eye it is the most potent of the dexamethasone derivatives studied. This greater therapeutic effect does not seem to be accompanied by a greater propensity to increase intraocular pressure. Comparison of the intraocular pressureincreasing effect in known corticosteroid responders of dexamethasone acetate with that of dexamethasone sodium phosphate, the least effective of the dexamethasone products studied, demonstrated no difference between the two drugs. These data support the conclusion that dexamethasone acetate is superior to the commercially available dexamethasone derivatives for use as a topical ocular anti-inflammatory agent.

Management of Inflammation in the Cornea and Conjunctiva

The ability of the cornea to react to inflammatory stimuli is limited, and in most instances the polymorphonuclear leukocyte is primarily responsible for corneal damage. Of currently available drugs, corticosteroids are the most effective for the non-specific control of these inflammatory cells. Principles for obtaining maximal therapeutic effect from minimal amounts of the drug are presented. The use of corticosteroids in the treatment of a keratitis caused by various types of replicating microbial agents is discussed. The response to therapy of inflammatory processes in the conjunctiva seemingly differs from the response in the cornea. Suggestions are offered for corticosteroid use in conjunctivitis.

Advances in polyvinyl alcohol hydrogel keratoprostheses: Protection against ultraviolet light and fabrication by a molding process

Our goal was to: 1) modify poly(vinyl alcohol) hydrogels intended for use in a synthetic cornea to absorb ultraviolet light and 2) develop molding procedures for the fabrication of the device. Two ultraviolet light-absorbing monomers were incorporated by copolymerization. The resulting hydrogels protected against ultraviolet light, were not toxic to corneal fibroblasts, and the protection did not diminish during prolonged aqueous exposure. A novel keratoprosthesis molding procedure was developed that made use of the phase transition properties of mixtures of poly(vinyl-trifluoroacetate) and acetonitrile. In this procedure the keratoprosthesis was shaped and a fibrous skirt was bonded to it in a single operation. Composite keratoprostheses were designed and prepared for in vivo testing.

Gel Tears: A New Medication for the Treatment of Dry Eyes

Gel Tears, a clear, semisolid formulation of synthetic, high molecular weight, cross-linked polymers of acrylic acid, persists in the conjunctival sac for hours after topical instillation, slowly melting while absorbing fluid and retaining it locally. In the present study of 55 patients (106 eyes) with severe dry eyes, who were unable to obtain ocular comfort with frequent administration of a wide variety of commercially available artificial tear preparations, 78% were improved by Gel Tear therapy. Subjective symptoms such as burning, stinging, foreign body sensation, dryness, and photophobia were significantly (P less than 0.001) alleviated, while objective signs concurrently improved but to a lesser degree. No patient required Gel Tears more often than four times daily. Most maintained optimal comfort on a dose of twice daily or less, and several patients previously unable to obtain ocular comfort with hourly administered conventional artificial tears required Gel Tears less than once a day.

Penetration of Fluorometholone Into the Cornea and Aqueous Humor

In each of the experimental conditions studied, fluorometholone penetrated into the cornea and aqueous humor following topical administration of a standard drop. The amount of drug measured in each location was less than that previously documented for dexamethasone and prednisolone preparations. In contrast to these more conventional steroids, the ocular penetration of fluorometholone appeared to be unaffected by the presence or absence of the corneal epithelium or of intraocular inflammation.

Penetration of topically administered prednisolone acetate into the human aqueous humor.

A single standardized drop of 1.0% prednisolone acetate labeled with tritiated thymidine was administered topically to one eye of 58 patients shortly before elective cataract extraction. An aqueous humor sample was aspirated at varying intervals and its corticosteroid content was determined. Peak drug concentration in aqueous humor was 1.13 mug/ml, which occurred 30 to 45 minutes after instillation of the medication. Substantial quantitites of corticosteroid were found in the aqueous humor five minutes after drug administration. The area under the drug concentration in aqueous humor-vs-time curve (a measure of the drugs bioavailability in aqueous humor) was 88 mug min/ml, and its half-life in human aqueous humor was 28 minutes. None of these values were significantly different from the comparable values in rabbit eyes.