Ramzi K. Hemady

Immunosuppressive drugs in immune and inflammatory ocular disease.

Advances in immunology, particularly ocular immunology, have been accompanied by the emergence of safer, more specific immunosuppressive drugs, notably, cyclophosphamide, chlorambucil, methotrexate, azathioprine, cyclosporine A, bromocriptine, dapsone, and colchicine. These drugs have become an important, and often essential, part of the ophthalmologists armamentarium against inflammatory and immune-mediated ocular diseases. In order to better acquaint the ophthalmologist with the properties of the most commonly used immunosuppressive drugs, we review the literature and relate our own experience with these agents.

Phase I clinical trial of all-trans-retinoic acid with correlation of its pharmacokinetics and pharmacodynamics

Abstract A phase I trial of all-trans-retinoic acid (ATRA) was conducted to establish the maximum tolerable dose (MTD) of ATRA given once daily to patients with solid tumors. Cancer patients for whom no standard therapy was available were treated with ATRA once daily. Doses were escalated in cohorts of at least three patients. The pharmacokinetics of ATRA were assessed on day 1 for all patients and weekly for 31 patients who received doses of ≥110 mg/m2 per day. Patients were followed for toxicity and response. Correlations of toxicity frequency and grade with pharmacokinetic parameters were sought. In addition, correlation of changes in ATRA pharmacokinetics with the concentration of ATRA metabolites in plasma were sought. A total of 49 patients received ATRA at doses ranging from 45 to 309 mg/m2 per day. Hypertriglyceridemia was dose-limiting at 269 mg/m2 per day. Other frequent toxicities included mucocutaneous dryness and headache. With chronic dosing, plasma ATRA concentrations fell in 59% of patients. Stable, low, or variable [ATRA] were seen in 16%, 6%, and 16% of patients respectively. Age, gender, smoking, or concurrent medication did not correlate with the pharmacokinetic pattern. Severe toxicities tended to occur with initial peak [ATRA] of ≥0.5 μg/ml (1.7 μM), and the toxicity frequency did not change if [ATRA] decreased with continued dosing. No consistent change in 4-oxo-ATRA or retinoid glucuronide concentrations was observed with decreases in plasma [ATRA]. The recommended once-daily ATRA dose is 215 mg/m2, although significant interpatient variability is observed in toxicity and plasma retinoid concentrations. Although not statistically significant, more frequent and severe toxicity tended to occur in patients with higher plasma peak ATRA concentrations. Other factors, such as responses at target tissues, may be at least as important as the plasma ATRA concentration in predicting toxicity and/or response.

Bacillus-induced endophthalmitis: new series of 10 cases and review of the literature.

We reviewed the charts of 10 patients who were admitted to the Massachusetts Eye and Ear Infirmary over a 10-year period with the diagnosis of Bacillus species endophthalmitis. To our knowledge this is the largest single series in the literature and includes the first two reported cases of Bacillus endophthalmitis following glaucoma filtering procedures. Seven cases developed following penetrating ocular trauma. One occurred in an intravenous drug abuser. Five eyes ultimately underwent enucleation; only the two eyes that developed endophthalmitis after elective surgery retained useful vision. Review of the literature indicates that parenteral and intravitreal antibiotic prophylaxis against endophthalmitis after penetrating ocular trauma should include gentamicin, in combination with vancomycin or clindamycin, to provide adequate coverage against infection with Bacillus spp., as prognosis is poor once infection is established. Bacillus spp. cultured from ocular tissues or fluids should not be dismissed as contaminants.

Six Cases of Scleritis Associated With Systemic Infection

Isolated scleritis (without keratitis) associated with infections is uncommon, and correct diagnosis and appropriate therapy for it are often delayed. Six patients with infection-associated scleritis were seen at our institution between May 1983 and May 1990 (these patients represented 4.6% of all patients with scleritis [six of 130 patients] in that period). Three of these cases were associated with systemic infections. One was associated with syphilis, one was associated with tuberculosis, and one was associated with toxocariasis. Three cases resulted from local infections. One was associated with infection with Proteus mirabilis, one was associated with infection with herpes zoster virus, and one was associated with infection with Aspergillus. The Aspergillus infection developed after trauma and the P. mirabilis-induced infection developed after strabismus surgical procedures. Four of the six cases were initially misdiagnosed and inappropriately managed. Correct diagnosis was made seven days to four years after onset of symptoms. Review of systems, scleral biopsy, culture, and laboratory investigation were used to make the diagnosis. Differential diagnosis of scleritis must include infective agents.

Microbial Keratitis in Patients Infected with the Human Immunodeficiency Virus

BACKGROUND Posterior segment complications of systemic infection with the human immunodeficiency virus (HIV) are well recognized. The anterior segment complications often are, however, overlooked. The author treated 20 episodes of nonherpetic infectious keratitis in 17 eyes of 13 patients infected with HIV who presented between August 1990 and May 1994. METHODS Review of records. RESULTS Nine patients were women, and four were men. Mean age was 35.2 years. The keratitis was bilateral in four patients, polymicrobial in four, and recurrent in two. The most common infecting organism was Candida albicans (5 eyes), a rare cause of keratitis in immunocompetent individuals. Other organisms included Staphylococcus aureus in four eyes, Staphylococcus epidermidis in four, Bacillus sp in two, and one each Pseudomonas aeruginosa, alpha-hemolytic Streptococcus, Micrococcus sp, and Capnocytophaga sp. Seven eyes retained 20/30 or better visual acuity after treatment, eight had visual acuity of 20/50 or worse, and two were eviscerated. Classic predisposing factors for infectious keratitis were found in only two patients and included contact lens wear and atopy in one patient each. Twelve patients had a history of intravenous drug abuse. CONCLUSION Infectious keratitis should be recognized as a complication of systemic HIV infection, especially in the context of drug abuse. The prognosis for recovery of vision in these patients often is poor.

Endogenous Fusarium Endophthalmitis in a Patient With Acute Lymphocytic Leukemia

Endogenous fungal endophalmitis is an uncommon complication of systemic mycosis. Only a few cases involving Fusarium have been reported, most with unfavorable visual outcomes. We examined a 31-year-old woman with acute lymphocytic leukemia who developed sudden visual loss in her right eye. A dense, white placoid infiltrate was present in the right macula extending into the vitreous. An iris nodule and hypopyon were present in the left eye. A vitreous aspirate of the right eye was positive for Fusarium species. The patient progressively lost vision despite amphotericin B and 5-fluorocytosine therapy. She died from bronchopneumonia, fungemia, and multisystem failure. Histopathologic study disclosed a panophthalmitis with Fusarium organisms invading all the ocular coats in the right eye. Leukemic infiltrates were present in the left iris, anterior chamber, and trabecular meshwork. The ocular destructiveness of Fusarium may be caused by marked mycotic vascular invasion and occlusion with consequent infarction and necrosis of ocular tissues.

Keratoconjunctivitis Sicca and Corneal Ulcers

We reviewed the records of 56 patients (109 eyes) who satisfied our criteria for keratoconjunctivitis sicca (KCS) to determine factors associated with the development of sterile corneal ulcers. The patients age, sex, and associated local ocular surface and/or systemic disease were studied. We found a statistically significant association between the development of corneal ulceration and the presence of an underlying condition or disease state, especially chronic rheumatoid arthritis. Patient sex and age were not significantly associated with the development of corneal ulceration. We present three case histories that illustrate the complications that arise in managing KCS plus an associated disease and methods of management.

Spontaneous ulcerative keratitis in immunocompromised patients

We studied the occurrence of ulcerative keratitis in five eyes of four patients who were examined at the University of Maryland Hospital ophthalmology clinic over a 12-month period. All were young women who were intravenous drug abusers, with no known predisposing factors for ulcerative keratitis. Two patients had acquired immunodeficiency syndrome (AIDS), one was human immunodeficiency virus (HIV)-positive, and the fourth refused HIV testing. One had a corneoscleral limbus to corneoscleral limbus keratitis; three had inferiorly located corneal ulcers (bilateral in one patient with AIDS). Corneal cultures disclosed Capnocytophaga species in the corneoscleral limbus to corneoscleral limbus keratitis. The remaining ulcers were polymicrobial; cultures of three grew Candida albicans, cultures of two grew alpha-hemolytic streptococci, cultures of two grew Staphylococcus aureus, and culture of one grew Pseudomonas aeruginosa. Treatment with topical fortified antibiotics and antifungal agents resulted in complete healing in all four inferiorly located ulcers. The corneal ulcer became perforated and the eye was eviscerated. Histopathologic analysis of the eviscerated specimen disclosed acute keratitis with necrosis and no microorganisms.

Intraocular penetration of ketoconazole in rabbits.

We studied penetration of the antifungal agent ketoconazole into the cornea, aqueous humor, and vitreous of rabbits after topical, subconjunctival, and oral administration. The effect of debridement of corneal epithelium on penetration was also investigated. Ketoconazole levels in the cornea and aqueous humor were high after topical or subconjunctival administration, and increased markedly (especially in the cornea) if the corneal epithelium had been debrided before administration of the drug. For example, concentration of ketoconazole in the cornea 1 h after topical drug administration with or without complete corneal epithelial debridement was 44.0 ± 10.1 and 1,391.5 ± 130.0 (µg/g, respectively. Drug levels in the vitreous were not detectable after topical or subconjunctival drug administration, but were improved slightly by prior epithelial debridement (8.3 and 0.12 µg/mL after 1 h, respectively). Orally administered ketoconazole resulted in high corneal concentrations (45.0 ± 7.6 µg/g after 1 h) that were still substantial 24 h later (55.0 ± 7.0 µg/g); levels in the aqueous were low.

Blindness and eye disease in Cambodia.

Purpose: To assess the prevalence and etiology of blindness and low vision and to assess the prevalence of common eye diseases in central Cambodia. Methods: In this cross-sectional, population-based study, 6,558 residents of Kandal Province, Cambodia were registered, and 5,803 (88.5%) were interviewed and examined. This house-to-house survey was conducted by a team consisting of a senior ophthalmologist, a Cambodian eye doctor, and eight Cambodian eyecare workers. Results: The prevalence of bilateral blindness (visual acuity <3/60) is 1.1% (95% confidence interval [CI], 0.9–1.4), and an additional 4.4% (95% CI, 3.9–5.0) have low vision (visual acuity < 6/18, ≥3/60 in the better eye). The major causes of bilateral blindness are cataract (67.4%), phthisis (6.1%), uncorrected refractive error (6.1%), corneal scar (5.3%), uncorrected aphakia (3.0%), trachoma corneal scar (3.0%), optic atrophy (3.0%), and others (6.1%). The major causes of low vision are uncorrected refractive error (49.8%) and cataract (42.7%). The prevalence of unilateral blindness is 1.2% (95% CI, 0.9–1.4), often caused by cataract, corneal scar, or phthisis. Trauma due to landmine explosions and war-related injuries was frequently the underlying etiology in subjects with phthisis, corneal scarring, or other pathology.Conclusions: The prevalence of blindness and low vision in Cambodia is relatively high compared to other developing countries. Most of the causes of blindness and low vision are treatable or preventable. Landmines and other war-related injuries are an important cause of ocular injury. These results will assist in developing a national plan for the prevention of blindness in Cambodia.