Alan G. Palestine

ORAL GANCICLOVIR FOR PATIENTS WITH CYTOMEGALOVIRUS RETINITIS TREATED WITH A GANCICLOVIR IMPLANT

BACKGROUND The intraocular ganciclovir implant is effective for local treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome (AIDS), but it does not treat or prevent other systemic manifestations of cytomegalovirus infection. METHODS Three hundred seventy-seven patients with AIDS and unilateral cytomegalovirus retinitis were randomly assigned to one of three treatments: a ganciclovir implant plus oral ganciclovir (4.5 g daily), a ganciclovir implant plus oral placebo, or intravenous ganciclovir alone. The primary outcome measure was the development of new cytomegalovirus disease, either contralateral retinitis or biopsy-proved extraocular disease. RESULTS The incidence of new cytomegalovirus disease at six months was 44.3 percent in the group assigned to the ganciclovir implant plus placebo, as compared with 24.3 percent in the group assigned to the ganciclovir implant plus oral ganciclovir (P=0.002) and 19.6 percent in the group assigned to intravenous ganciclovir alone (P<0.001). As compared with placebo, oral ganciclovir reduced the overall risk of new cytomegalovirus disease by 37.6 percent over the one-year period of the study (P=0.02). However, in the subgroup of 103 patients who took protease inhibitors, the rates of new cytomegalovirus disease were low and of similar magnitude, regardless of treatment assignment. Progression of retinitis in the eye that initially received an implant was delayed by the addition of oral ganciclovir, as compared with placebo (P=0.03). Treatment with oral or intravenous ganciclovir reduced the risk of Kaposis sarcoma by 75 percent (P=0.008) and 93 percent (P<0.001), respectively, as compared with placebo. CONCLUSIONS In patients with AIDS and cytomegalovirus retinitis, oral ganciclovir in conjunction with a ganciclovir implant reduces the incidence of new cytomegalovirus disease and delays progression of the retinitis. Treatment with oral or intravenous ganciclovir also reduces the risk of Kaposis sarcoma.

Standardizatlon of Vitreal inflammatory Activity in Intermediate and Posterior Uveitis

Standardization of observations is recognized as fundamental to clinical research. The methodology for the evaluation of anterior segment inflammatory disease has become well accepted, while the ocular inflammatory standardization of the posterior segment has not been so well described or accepted. A system for the evaluation of vitreal inflammatory activity in patients with intermediate and posterior uveitis is presented. A series of photographs representing various degrees of fundus vitreal haze is depicted. The observer examines the eye with an indirect ophthalmoscope, then chooses the photograph which most closely simulates what is being seen. This technique is rapid and its reproducibility is helpful in standardizing clinical observations.

Renal Histopathologic Alterations in Patients Treated with Cyclosporine for Uveitis

To evaluate abnormalities of renal morphology associated with long-term cyclosporine therapy, we obtained percutaneous renal biopsy specimens from 17 patients who had been treated for autoimmune uveitis with cyclosporine for an average of two years. For comparison, we also analyzed renal biopsy specimens from patients with idiopathic hematuria who had not received cyclosporine. The atrophic and sclerosing glomerular and tubulointerstitial lesions in the specimens were assessed to derive a chronicity index. The specimens from the patients treated with cyclosporine showed a significantly higher chronicity index than those from the controls (P less than 0.00005). All patients who had received cyclosporine had interstitial fibrosis, tubular atrophy, or both. A good functional predictor of the abnormalities in renal morphology was the length of time that a patients serum creatinine had exceeded the base-line value by more than 50 percent. Chronic pathologic alterations were seen even in patients who had normal renal function at the time of the biopsy. In conjunction with sequential measurements of renal function, renal biopsy may have an important role in defining the type and degree of nephrotoxicity that can develop in patients receiving long-term cyclosporine therapy for autoimmune disease.

A randomized, controlled trial of foscarnet in the treatment of cytomegalovirus retinitis in patients with AIDS

OBJECTIVE To evaluate foscarnet sodium in treating cytomegalovirus retinitis in patients with AIDS. PATIENTS Twenty-four previously untreated persons with AIDS and cytomegalovirus retinitis who were at low risk for loss of their visual acuity. INTERVENTION PATIENTS were randomly assigned to receive either no therapy (delayed treatment, control group) or immediate treatment with intravenous foscarnet at a dose of 60 mg/kg body weight three times a day for 3 weeks (induction regimen) followed by a maintenance regimen of 90 mg/kg once a day. MEASUREMENTS PATIENTS were examined weekly until they reached the primary clinical end point, defined as progression of their retinitis border by 750 microns or the development of a new retinal lesion due to cytomegalovirus. Progression was evaluated using retinal photographs by masked readers. Secondary evaluations included changes in visual acuity, cytomegalovirus shedding in the blood and urine, serum levels of human immunodeficiency virus type 1 (HIV-1) p24 antigen, and total CD4 T lymphocyte counts. RESULTS The mean time to progression of retinitis was 3.2 weeks in the control group (n = 11) compared with 13.3 weeks in the treatment group (n = 13) (P less than 0.001). Nine of 13 patients in the treatment group had positive blood cultures for cytomegalovirus at entry and all nine cleared their blood of cytomegalovirus by the end of the induction period (P = 0.004) compared with one of six patients in the control group. No reductions in p24 levels were seen in the control patients compared with a reduction of more than 50% in p24 levels for all four patients on treatment for whom follow-up levels were available. The main adverse effects of foscarnet treatment were seizures (2 of 13 patients), hypomagnesemia (9 of 13), hypocalcemia (11 of 13), and elevations in serum creatinine above 176.8 mumol/L (2.0 mg/dL) (3 of 13). The control patients received an average of 0.2 units of blood per week compared with an average of 0.6 units of blood per week for the patients on treatment. CONCLUSIONS The administration of foscarnet decreases the rate of progression of cytomegalovirus retinitis in persons with AIDS. Its judicious use is likely to prevent loss of vision in these patients. In this study, however, there was little change in visual acuity in patients in either the immediate or delayed treatment group because only patients with non-sight-threatening disease were selected.

Cyclosporin a Therapy in the Treatment of Intraocular Inflammatory Disease Resistant to Systemic Corticosteroids and Cytotoxic Agents

Sixteen patients (ten women and six men, ranging in age from 20 to 67 years) with active bilateral posterior uveitis of noninfectious origin were treated with cyclosporin A, a specific anti-T-cell medication. All had previously received systemic corticosteroids or cytotoxic agents or both and had responded poorly or had intolerable side effects. Fifteen of 16 patients had positive responses to oral cyclosporin A therapy (initially 10 mg/kg of body weight/day), measured by a decrease in inflammatory activity, with a concomitant improvement in visual acuity in most patients. Fluorescein angiographic findings varied considerably with some patients showing an improvement with continued cystoid macular edema. Renal toxicity occurred in five patients, but renal function reverted toward normal with a decrease in cyclosporin A dosage.

Side effects of systemic cyclosporine in patients not undergoing transplantation

Twenty-six patients with ocular inflammatory disorders of presumed autoimmune origin were treated with oral cyclosporine. Cyclosporine is a potent T cell regulatory agent that has been utilized extensively in organ transplantation. In general, the patients in this study did not have chronic debilitating illnesses that are observed in organ transplant recipients, did not receive corticosteroids in addition to cyclosporine, and did not undergo any surgical procedure during their treatment. This study describes the observed adverse reactions in this group of patients not undergoing transplantation. The reported side effects of cyclosporine in organ transplant recipients have included nephrotoxicity, hepatotoxicity, infections, lymphoma, hirsutism, gingivitis, and central nervous system toxicity. Side effects were observed that were similar to those in previous reports, but the severity of the nephrotoxicity and hepatotoxicity appeared to be less. Nephrotoxicity occurred in eight patients and hepatotoxicity occurred in one patient. No lymphomas were seen. Hypertension and anemia each were observed in six patients. In addition, previously unreported effects of hyperuricemia, elevated sedimentation rate, and hidradenitis were observed. However, the overall severity of the side effects did not seriously affect the usage of cyclosporine in the patients in this study. Cyclosporine may be useful in the treatment of other autoimmune diseases.

Intraocular lymphoma : clinical and histopathologic diagnosis

BACKGROUND Intraocular lymphoma is associated with significant morbidity and mortality, but early diagnosis and treatment may improve prognosis. METHODS The diagnostic features of 12 cases of intraocular lymphoma diagnosed at the National Eye Institute between 1984 and 1992 were retrospectively reviewed. RESULTS A pathologic diagnosis of large B-cell lymphoma was made on vitrectomy specimens in ten patients, cerebral spinal fluid in one, and on an enucleation specimen in one. The mean time from onset of symptoms to diagnosis was 21.4 months (range, 1-66 months). All 12 patients were given a final diagnosis of non-Hodgkins lymphoma of the central nervous system (NHL-CNS), based on the epidemiology, pathology, and clinical course of their tumors. Although an initial vitrectomy was negative for malignant cells in three of ten patients, a repeat vitrectomy specimen subsequently showed intraocular lymphoma. Results of examination of the cerebrospinal fluid (CSF) showed malignant cells in 5 of 11 patients, although malignant cells were only identified after repeat examination of additional samples of CSF in three of these patients. Malignant cells often are difficult to identify, and an experienced cytopathologist was critical in making the correct diagnosis. In addition, corticosteroids are lympholytic to the lymphoma cells, and they appeared to decrease the viability of tumor cells obtained in samples of vitreous and CSF. CONCLUSION The prompt, appropriate handling of specimens and review by an experienced cytopathologist are critical to the diagnosis of intraocular lymphoma. Malignant cells often are present in the cerebral spinal fluid at the time that ocular lymphoma is diagnosed. Nevertheless, multiple vitrectomies and lumbar punctures may be necessary before the correct diagnosis is made.

Macular Thickening and Visual Acuity: Measurement in Patients with Cystoid Macular Edema

Cystoid macular edema (CME) is commonly associated with many ocular conditions. The presence of CME on fluorescein angiographic examination need not, however, preclude good visual acuity. The hypothesis that the degree of macular thickening is associated with visual acuity was tested. Ten consecutive stereoscopic fluorescein angiograms were graded by 13 ophthalmologists using a set of four standards. Linear regression showed a significant relationship between mean macular thickening and the visual acuity recorded at the time of angiography. However, no significant relationship could be made between the estimation of visual acuity and the amount of fluorescein staining measured in the posterior pole. Although the observation of fluorescein leakage is indispensable for documenting a breakdown in the blood-retinal barrier, the observation of retinal thickening is important for identifying the sites of edema accumulation, and may be the useful parameter to follow when trying to assess improvement or worsening of retinal edema and in cases of uveitis when the cause of poor vision may be multifactorial.

Cyclosporine: Immunology, pharmacology and therapeutic uses

Human and animal investigations since the mid-1970s have demonstrated the effectiveness of cyclosporine (CsA) as an immunosuppressive agent. In the area of transplantation immunity, it has been shown to enhance success of renal, bone marrow, and liver transplantation. Moreover, certain models of autoimmune disease have been effectively treated with CsA, and a number of studies have reported encouraging results with CsA therapy for ocular inflammatory disorders, notably Behçets disease. The most serious side effects of CsA are nephrotoxicity and hypertension; thus, conservative dosages of the drug and careful monitoring of renal function during treatment are recommended. The purpose of this review is to provide clinicians and researchers with a clear perspective of both the potential benefits and shortcomings of this agent.

Chronic Propionibacterium Endophthalmitis After Extracapsular Cataract Extraction and Intraocular Lens Implantation

We studied six cases of chronic, indolent intraocular inflammation that occurred after extracapsular cataract extraction and posterior chamber intraocular lens implantation. The inflammation was characterized by a delayed onset, and in three cases had the clinical appearance of a granulomatous iridocyclitis. Cultures of intraocular specimens obtained from six eyes yielded Propionibacterium; five yielded P. acnes. Pleomorphic gram-positive bacilli consistent with Propionibacterium were identified in cytologic or histopathologic studies in four of the six culture-positive cases. After surgical and medical therapy, the inflammation resolved. Postoperative Propionibacterium endophthalmitis may masquerade as a chronic iridocyclitis.