Papilledema in two patients with acromegaly and intrasellar pituitary tumors.

Two patients had bilateral papilledema complicating acromegaly. Both patients had enlarged blind spots, but otherwise visual fields were normal. Suprasellar extension of the pituitary tumors was diligently sought with the use of visual field examination, pneumoencephalography, internal carotid arteriography, and computed axial tomography, and tumor extension did not exist. Transphenoidal and transethmoidal routes were used to perform partial hypophysectomies in these patients. The procedure was completely successful in one patient and partially successful in the other patient. After hypophysectomy, papilledema resolved in both patients. This beneficial effect may be the result of anatomical changes, the reduction in growth hormone levels, or both. These observations suggest that the acromegaly may be different from papilledema that occurs secondary to suprasellar expansion of pituitary tumors.

Statistical analysis of multi-eye data in ophthalmic research.

An apparently common error in statistical analysis of ophthalmic data is to perform statistical tests that do not account for the correlation generally present between observations made for the right and left eyes of a subject. This error has as a consequence an overstatement of the precision of the study, resulting in incorrect P values which indicate a greater measure of statistical significance than the data warrant. As measures to reduce the occurrence of this serious error in statistical analyses, the authors recommend increased emphasis on educational programs for investigators, stimulation of nontechnical articles reviewing statistical methods, and a sharper focus upon statistical analysis in the peer review process.

Efficacy of antifungal agents in the cornea. I. A comparative study.

A standardized model of Candida albicans keratitis was developed in pigmented rabbits using a quantitative mycologic technique to evaluate the disease at intervals throughout the course. In this model, using two different infecting strains, the efficacy of five antifungal agents was compared. Amphotericin B, in concentrations of 0.5% to 0.075%, was superior to all other agents tested. Natamycin 5% ranked next, followed by 1% flucytosine, and 1% miconazole. Ketoconazole 1% was ineffective.

In vitro and in vivo susceptibility of Candida keratitis to topical polyenes.

The susceptibility of Candida albicans to topical amphotericin B and natamycin was evaluated in a model of stromal keratitis in Dutch-belted rabbits and compared with minimal inhibitory concentrations in vitro. Treatment was delayed 24 hr to allow invasive disease to occur and was then continued for 5 days. Ten strains of Candida albicans comprised the test panel. For amphotericin B, the minimal inhibitory concentration (MIC) by tube dilution classified the same strains as resistant or susceptible as did the in vivo response. A dose-response was observed with different concentrations of the drug. For natamycin, the MIC misclassified two strains. The rate of administration of natamycin required in this model was much higher than for amphotericin B, a therapeutic effect being observed with natamycin only when the drug was administered every 30 min during the in vivo efficacy and in vitro susceptibility with these strains is in agreement with that observed in the authors' previous studies using a model of immediate treatment.

Correlation of in vitro and in vivo susceptibility of Candida albicans to amphotericin B and natamycin.

The efficacy of topical 0.15% amphotericin B and 5% natamycin was examined in a model of Candida keratitis in rabbits and correlated with three tests of in vitro susceptibility: tube dilution minimal inhibitory concentration (MIC), minimal fungicidal concentration (MFC) and agar diffusion zones of inhibition. For a panel of 17 strains, the MIC classified precisely the same strains as resistant or susceptible to amphotericin B as did the in vivo response. Several strains were misclassified using the MFC and the zone of inhibition. For natamycin the MIC misclassified two strains but it was still superior to the other two tests. For all strains, amphotericin B was equal or superior in efficacy to natamycin in vivo. The tube dilution MIC for amphotericin B was a reliable indicator for natamycin efficacy in vivo.

Differences in response in vivo to amphotericin B among Candida albicans strains.

A group of ten Candida albicans strains previously determined to be resistant or susceptible to topical amphotericin B in vivo and in vitro were exposed to treatment with different concentrations of the drug in a quantitative model of candidal keratitis in Dutch-belted rabbits. After 5 days of topical treatment with amphotericin B eye drops in concentrations of 0.3%, 0.03%, or 0.003%, quantitative isolate recovery in treated animals was compared with that of untreated controls. A dose response was observed for all five susceptible strains. The two strains that were most sensitive to amphotericin B in vitro also were the most susceptible in vivo. At each dose level there was a two- to eightfold reduction in isolate recovery among highly susceptible strains compared with less susceptible strains (P less than 0.05). The five resistant strains remained so even when the 0.3% concentration was used. Among strains of C. albicans susceptible to amphotericin B, there appeared to be a variation in degree of susceptibility in vivo that correlated with the minimum inhibitory concentration.

Efficacy of antifungal agents in the cornea. IV. Amphotericin B methyl ester.

Quantitative mycologic techniques were used to evaluate the efficacy of topical amphotericin B methyl ester in two models of yeast infection in rabbit eyes. Doses of 1%, 0.5%, and 0.15% were used in a model of superficial Candida albicans infection. The 1% dose of drug was highly efficacious, abolishing the disease after 2 days of treatment. With doses of 0.5% and 0.15%, decreasing efficacy was observed. Antifungal activity did not deteriorate when 1% prednisolone acetate was administered concomitantly with the 1% dose. In a model of deep stromal infection, the administration of topical 1% amphotericin B methyl ester was highly efficacious when the corneal epithelium was absent. Even in corneas with intact epithelium, a reduced though still significant effect was noted.

Efficacy of antifungal agents in the cornea. II. Influence of corticosteroids.

The influence of topical corticosteroid on the efficacy of five topical antifungal agents was evaluated in a standardized rabbit model of Candida keratitis using a quantitative mycologic technique. Topical 1% prednisolone acetate worsened the disease when given alone and adversely influenced the efficacy of 5% natamycin, 1% flucytosine, and 1% miconazole when given in combination. The efficacy of amphotericin B appeared unaffected when the antifungal agent was administered in concentrations of 0.5% and 0.15%. The adverse effect of the topical corticosteroid appeared to be inversely related to the efficacy of the antifungal agent in vivo.

Influence of the corneal epithelium on the efficacy of topical antifungal agents.

A model of deep stromal Candida albicans infection was established by injecting 25 microliters of a suspension containing 5 X 10(9) colony forming units/ml of the yeast into corneas of pigmented rabbits. In this model, the infection lasts for more than 8 days. Using quantitative techniques, the authors compared the efficacy of six topical antifungal agents in the presence of an intact epithelium and in corneas debrided of epithelium. In corneas debrided on a daily basis, the polyenes (amphotericin B 0.15% and 0.075% and natamycin 5%) exhibited a significant antifungal effect. When the epithelium was left intact, 5% natamycin and 0.075% amphotericin B were without effect, while the efficacy of the 0.15% preparation of amphotericin B was much reduced. Removal of the epithelium appeared to affect adversely the efficacy of flucytosine. The imidazoles were not efficacious in this model.

Contact lens-induced infection--a new model of Candida albicans keratitis.

PURPOSE: A model of experimental keratomycosis was established that mimics human disease in which the only fungi present are those that are actively growing within the cornea. METHODS: Dutch-belted rabbits received a subconjunctival injection of triamcinolone acetonide to one eye. One day later the epithelium was removed from the central cornea and a standardized inoculum of Candida albicans blastoconidia was placed on the corneal surface and covered with a contact lens. The lids were closed with a lateral tarsorrhaphy. After 24 hours, the lid sutures and contact lens were removed. Five days later the animals were killed, and their corneas were subjected to separate isolate recovery and histology studies. A group of similarly infected rabbits without corticosteroid injection served as controls. RESULTS: Both groups developed invasive corneal disease. Although isolate recovery was not significantly different from corticosteroid-treated rabbits compared with controls, fungal biomass was increased. Hyphal invasion was limited to the anterior cornea in control eyes, but penetrated deep stroma in most of the corticosteroid-treated rabbits. CONCLUSIONS: Invasive corneal disease can be established with a surface inoculum. Corticosteroid administration increased corneal penetration of hyphae. Quantitative isolate recovery is not a reliable measure of the fungal load within the cornea.

Differences in virulence between two Candida albicans strains in experimental keratitis.

PURPOSE: To study the differences in disease caused by two wild-type strains of Candida albicans in a model of contact lens-facilitated keratitis in rabbits. METHODS: Two strains, SC5314 and VE175, were examined. Standardized inocula were placed on the debrided corneal surface of one eye in Dutch belted rabbits and covered with a contact lens. A temporary tarsorrhaphy was opened after 24 hours with removal of the contact lens. Six days later, corneas were photographed and animals killed. Corneas were bisected with one half for quantitative isolate recovery and the other for stromal penetration by hyphae. RESULTS: Strain SC5314 was significantly more virulent. The mean hyphal penetration into the cornea was 24.4% +/- 8.5% of the corneal thickness, and in three of six corneas hyphae penetrated through the entire cornea. In contrast, for VE175, the mean hyphal penetration was 2.6% +/- 1.2%. The difference between these two strains was statistically significant (P = 0.0297). Hyphae did not penetrate into the deep layers of the cornea in any of the six rabbits infected with VE175. The grading of clinical disease was consistent with histology, in that strain SC5314 caused more severe infection than VE175 and the difference was statistically significant (P = 0.0048). There was no difference in isolate recovery. CONCLUSIONS: Wild-type strains of C. albicans can differ significantly in virulence as measured by depth of fungal invasion into corneas and clinical evaluation of infection. Further characterization of the intrinsic genetic differences between such strains may help identify factors responsible for fungal virulence.

Socioeconomics viewpoint: the need for an update of the clinical practice guideline on cataract.

In June 1994, the Agency for Health Care Policy and Research (AHCPR), Washington, DC, called a meeting to hear opinions on the need for a reconstituted panel to revise the recently published clinical practice guideline Cataract in Adults: Management of Functional Impairment. The need and timing of a revision depend essentially on the answer to two questions: (1) Are there serious flaws in the previous panel's work that would necessitate a re-review? or (2) Is there new scientific information that can be critically assessed that would substantially alter the recommendations of the guideline? It is important to consider these questions with care because any revision is likely to be both costly and time-consuming.

Brown tumor of the orbit. Case report and review of the literature.

Brown tumors, focal bony lesions of hyperparathyroidism, result from the direct effect of parathyroid hormone on bone. While such lesions are not uncommon in primary hyperparathyroidism, brown tumors have been associated less frequently with secondary hyperparathyroidism and have rarely been described as involving the orbital bones. We have found only four such cases previously reported in the ophthalmic literature. We report a case of orbital involvement by brown tumor in a child with chronic renal failure and secondary hyperparathyroidism. Use of long-term hemodialysis has increased the life span of individuals with chronic renal failure and produced an increased population of patients with secondary hyperparathyroidism and resultant bony changes. The ophthalmologist should consider brown tumor in the differential diagnosis of a patient with chronic renal failure and ocular symptomatology.

Melanotic neuroectodermal tumor of infancy. An ophthalmic appearance.

Fullness developed in the left side of a 5-month-old male infant's face in the region of the zygoma. An incisional biopsy specimen showed the mass to be a melanotic neuroectodermal tumor, and radical excision was performed. There has been no recurrence of the tumor one year later. Tumors of this type occur in the face, particularly in the maxilla, and have only rarely been reported around the orbit.

Corneal toxicity of propamidine.

Two patients with Acanthamoeba keratitis developed a corneal abnormality following prolonged treatment with topical 0.1% [corrected] propamidine isethionate. In both instances, withdrawal of drug therapy resulted in a gradual clearing of the keratopathy, with no permanent sequelae. The changes we observed may be confused with those of active Acanthamoeba infection.

Hereditary sclerocornea.

Sclerocornea is a primary anomaly in which scleralization of a peripheral part of the cornea, or the entire corneal tissue, occurs. In the peripheral type of sclerocornea, the affected area is vascularized with regular arcades of superficial scleral vessels. In total sclerocornea, the entire cornea is opaque and vascularized. To our knowledge, 97 cases of all types of sclerocornea have been reported in the world literature, either as a primary anomaly or in association with cornea plana. Peripheral sclerocornea in association with cornea plana was found in nine members of one family, in four of five generations studied. To our knowledge, this is the largest pedigree of hereditary peripheral sclerocornea identified. Our pedigree suggests the autosomal-dominant transmission of this entity but doesn't rule out phenocopies or other modes of inheritance in other cases of sclerocornea. Chromosomal analyses of representative family members revealed normal karyotypes.

Influence of corticosteroid on experimentally induced keratomycosis.

To assess the effect of corticosteroid on the establishment of experimentally induced keratomycoses, rabbits were injected subconjunctivally with triamcinolone acetonide on two successive days before inoculation with Candida albicans, Aspergillus fumigatus, or Fusarium solanae. Whereas isolate recovery rates declined steadily in normal control corneas, they remained stable over 15 days in corticosteroid-treated corneas. Clinically, inflammation was equivalent (A fumigatus and F solanae) or significantly less (C albicans; P = .001) until the 10th day. At 15 days, inflammation in corticosteroid-treated corneas was significantly worse in animals infected with A fumigatus (P = .003) or F solanae (P = .02). Inflammatory signs correlated inconsistently with isolate recovery. Pathogenicity of the infecting organism appears to be important in determining the degree to which corticosteroid is able to mask clinical signs of infection while enhancing fungal replication.

Ocular pharmacokinetics of saperconazole in rabbits. A potential agent against keratomycoses.

The ocular pharmacokinetics of saperconazole, an experimental lipophilic triazole with activity against filamentous fungi, including Aspergillus and Candida species, were evaluated in rabbits by radioassay. The drug was administered by topical, subconjunctival, and oral routes. Following a single 20-microL drop of 0.25% saperconazole in normal corneas, a mean (+/- SEM) peak level of 2.32 +/- 0.06 micrograms/g was achieved in 10 minutes. In débrided corneas, a peak level of 13.09 +/- 2.87 micrograms/g was achieved in 2 minutes. The drug was rapidly cleared from the cornea within 2 hours. The administration of 13 drops during 1 hour resulted in a threefold increase in normal corneal levels and in a sixfold increase in débrided cornea levels. Peak levels following subconjunctival injection in normal corneas (12.91 +/- 2.02 micrograms/g) were approximately twofold greater than those following sustained topical administration (6.19 +/- 0.16 micrograms/g) and, in débrided corneas, were a third higher than those following topical therapy in débrided corneas. Clearance was virtually complete by 8 hours. Levels following oral administration were low and probably subtherapeutic in all ocular tissues that were evaluated. Bioassay studies revealed that 44.17% of the drug in the cornea following topical administration was bioactive.

The relationship of corneal epithelial defect size to drug penetration.

OBJECTIVE: To determine the relationship between corneal epithelial defect size and corneal penetration of a triazole antifungal drug in an animal model. METHODS: Corneas of adult rabbits were débrided of epithelium 25%, 50%, 75%, or 100% of surface area; the untreated fellow eye served as a control. Tritiated saperconazole was applied to each cornea every 5 minutes for 1 hour. The animals were killed and the cornea and aqueous of each eye were assayed for radiolabel activity. RESULTS: Removal of 25% of the corneal epithelium produced an increase in corneal saperconazole concentration compared with eyes with intact epithelium. Increasing epithelial defect size from 25% to 50% produced a ninefold increase in mean corneal drug concentration (P = .0001). There was no further increase in corneal drug levels in eyes with 75% or 100% epithelial defects. A similar threshold effect was observed in aqueous drug concentration between 25% and 50% débridement (P = .0001). CONCLUSION: In this experimental model, an apparent threshold was noted between 25% and 50% epithelial defect area, beyond which larger defects did not significantly increase drug penetration into the cornea or aqueous. This may be of clinical benefit in circumstances in which epithelial débridement is considered to enhance drug penetration.

Ocular uptake of fluconazole following oral administration.

The ocular penetration and distribution of oral fluconazole was studied in Dutch-belted rabbits. Measured by high-pressure liquid chromatography, fluconazole readily penetrated all ocular tissues and fluids. No difference was observed between the levels obtained in phakic and aphakic eyes. Four hours after a single oral dose of 20 mg/kg, the mean levels and SEs were as follows: cornea, 13.3 +/- 1.4 micrograms/g; aqueous, 7.4 +/- 0.3 mg/L; vitreous, 9.8 +/- 0.9 mg/L; and choroid/retina, 5.2 +/- 0.4 micrograms/g. These levels were approximately twice those obtained with a 10-mg/kg dose. The corneal concentrations correlated highly with serum levels (r = .89). A steady accumulation in both normal corneas and corneas infected with Candida albicans was noted when 17.5 mg/kg of fluconazole was administered twice daily over a 5-day period. Drug levels did not increase in the cornea when fluconazole was administered as a single daily dose of 35 mg/kg. In view of its excellent ocular pharmacokinetic profile, fluconazole merits further attention as an orally administered agent for ocular fungal infections.