Famciclovir for ophthalmic zoster: a randomised aciclovir controlled study.

AIMS: To compare the efficacy and safety of famciclovir with aciclovir for the treatment of ophthalmic zoster. METHODS: Randomised, double masked, aciclovir controlled, parallel group in 87 centres worldwide including 454 patients with ophthalmic zoster of trigeminal nerve (V(1)) comprised the intent to treat population. Oral famciclovir 500 mg three times daily or oral aciclovir 800 mg five times daily for 7 days. Assessments included day 0 (screening), days 3 and 7 (during treatment), days 10, 14, 21, 28 and monthly thereafter, up to 6 months (follow up). Proportion of patients who experienced ocular manifestations, severe manifestations and non-severe manifestations; loss of visual acuity was the main outcome measure. RESULTS: The percentage of patients who experienced one or more ocular manifestations was similar for famciclovir (142/245, 58.0%) and aciclovir (114/196, 58.2%) recipients, with no significant difference between groups (OR 0.99; 95% CI 0.68, 1.45). The percentage of patients who experienced severe and non-severe manifestations was similar between groups, with no significant difference. The prevalence of individual ocular manifestations was comparable between groups. There was no significant difference between groups for visual acuity loss. CONCLUSION: Famciclovir 500 mg three times daily was well tolerated and demonstrated efficacy similar to aciclovir 800 mg five times daily.

Oral ganciclovir for patients with cytomegalovirus retinitis treated with a ganciclovir implant. Roche Ganciclovir Study Group.

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 Kaposi's 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 Kaposi's sarcoma.

Discontinuing anticytomegalovirus therapy in patients with immune reconstitution after combination antiretroviral therapy.

PURPOSE: To describe our experience with discontinuation of anticytomegalovirus maintenance therapy in patients who have had immune reconstitution after initiation of highly active antiretroviral therapy. METHODS: Fifteen patients with treated cytomegalovirus retinitis, who had immune reconstitution after initiation of highly active retroviral therapy, had anticytomegalovirus maintenance therapy discontinued. Patients were followed closely for relapse of retinitis. RESULTS: Median nadir CD4+ T-cell count, before institution of highly active antiretroviral therapy, was 20 cells/microl. At the time of discontinuation of anticytomegalovirus therapy, median CD4+ T-cell count was 297 cells/microl. Patients were followed for a median of 8 months off anticytomegalovirus therapy (range, 3 to 16 months). The median CD4+ T-cell count at last follow-up was 267 cells/microl. No patient off anticytomegalovirus therapy relapsed. CONCLUSION: In selected patients with immune reconstitution after initiation of highly active antiretroviral therapy, anticytomegalovirus therapy may be safely discontinued, at least temporarily. Longer follow-up of these patients is needed to determine how long such therapy may be interrupted, and when anticytomegalovirus therapy should be reinstituted.

Intraocular therapy for cytomegalovirus retinitis.

AIDS: Cytomegalovirus (CMV) retinitis, a sight-threatening infection common in AIDS patients, can be treated systemically with intravenous ganciclovir, intravenous foscarnet, or oral ganciclovir. These treatments are subject to resistance and become less effective with time. A retinal detachment also occurs in 25 percent to 30 percent of patients with the condition. Intravitreal treatment for CMV retinitis is increasingly effective. It does not have the disadvantage of systemic toxicity, and it allows higher drug levels to be delivered to the retina. A disadvantage is that it does not treat the infection throughout the body. Eye diseases are often treated locally with topical agents because they are isolated, but CMV retinitis cannot be treated topically. Local treatment for CMV involves direct delivery of the drug into the vitreous so it can diffuse into the retina, where CMV replicates. Intravitreal CMV therapy can be delivered either through ganciclovir implantation, ganciclovir injection, foscarnet injection, cidofovir injection, or Isis 2922 injection. Each option has its advantages and disadvantages, and using more than one of the treatments may be necessary over the course of infection.^ieng

Kinetics of corneal transplant rejection in the rat penetrating keratoplasty model.

Kinetic changes of inflammatory cells and major histocompatibility (MHC) antigenic markers in syngeneic and allogeneic corneal grafts in rats were studied. Syngeneic grafts demonstrated mild inflammation in the first week with macrophages and T-helper/inducer cells found in a 2:1 ratio. By week 2 fewer macrophages were seen, and by week 4 no inflammatory cells were seen in the central graft. Central keratocytes and endothelium were negative for class II MHC expression. Significant inflammation persisted adjacent to the wound with macrophages and T-helper/inducer cells seen surrounding the sutures. Allogeneic grafts in the first week demonstrated mild inflammation with macrophages and T-helper/inducer cells in a 2:1 ratio. The central graft in week 2 had increased numbers of T-helper/inducer cells and T-suppressor/cytotoxic cells. By the third and fourth week, the T-suppressor/cytotoxic cells had become the major infiltrating cell. MHC class II antigens were seen on inflammatory cells, keratocytes, donor, and recipient endothelium.

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-Hodgkin's 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.

The role of chorioretinal biopsy in the management of posterior uveitis.

BACKGROUND: The ideal management of intraocular inflammation may require a tissue diagnosis. Diagnostic vitrectomy is a well-established method for acquiring such tissue. However, in some patients, the diagnostic pathology is limited to the choroid and retina and vitrectomy may yield no useful information. In such cases, a more aggressive surgical approach to obtain tissue may be useful. METHODS: The authors performed chorioretinal biopsies on seven patients with progressive chorioretinal lesions of unknown etiology. Indications for biopsy included: (1) macular-threatening lesions unresponsive to therapy, (2) suspicion of malignancy, or (3) suspicion of an infectious etiology. In all cases, it was expected that the results would alter therapy or other aspects of clinical care. Preoperative visual acuity was 20/200 or worse in each eye biopsied with one or more peripheral chorioretinal lesions present. Biopsy specimens were divided into three parts and submitted for light and electron microscopy, immunohistochemistry, and tissue culture. RESULTS: On the basis of the biopsy findings, a diagnosis of multifocal choroiditis and subretinal fibrosis was rendered in three eyes, sarcoidosis in two eyes, and viral retinitis in two eyes. Therapy was changed in five patients. Final visual acuity was unchanged or improved in five eyes. Complications included the progression of lens opacity in all eyes and the development of phthisis in one eye that was extensively diseased preoperatively. CONCLUSION: Chorioretinal biopsy may provide useful information for determining the diagnosis and guiding the subsequent management of patients with progressive chorioretinal lesions of unknown etiology.

Increased survival of a cohort of patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis who received sodium phosphonoformate (foscarnet).

PURPOSE: To evaluate the impact of foscarnet on the longevity of persons with human immunodeficiency virus, type 1 (HIV-1) infection and cytomegalovirus (CMV) retinitis. PATIENTS AND METHODS: A cohort of 24 patients with acquired immunodeficiency syndrome (AIDS) and CMV retinitis received sodium phosphonoformate (foscarnet) as part of a controlled efficacy trial at the National Institutes of Health. Foscarnet was continued for as long as it was tolerated. Antiretroviral therapy was given to the patients as tolerated. Long-term follow-up was available on all patients. RESULTS: Seventeen patients received zidovudine during or after receiving foscarnet, 2 patients received dideoxyinosine, 2 patients zidovudine and dideoxyinosine, and 3 patients received no specific antiretroviral agent. Patients received foscarnet for a mean of 6.2 months (median, 4 months; range, 10 days to 22 months). Ten patients required a change to ganciclovir therapy at some time after receiving foscarnet. The median time from the diagnosis of CMV retinitis until death was 13.5 months (range, 3 to 34 months). Patients lived longer than untreated or ganciclovir-treated historical controls with AIDS and CMV retinitis. There was no difference in the survival of patients treated with foscarnet at the time of diagnosis and those patients treated with foscarnet only after progression of their CMV retinitis. CONCLUSIONS: These data suggest that foscarnet may prolong the survival of persons with AIDS and CMV retinitis and should be the initial treatment of choice in these patients.

Immunocytochemical staining of vitreous cells. Indications, techniques, and results.

Diagnostic vitrectomy is often performed because of suspected infection or malignancy. Giemsa, Gram, and Papanicolaou stains are used routinely to identify the components in the vitreous. Immunocytochemical staining of cellular components of vitreous specimens has the potential to significantly increase the amount of useful information that can be gained from histopathologic study. Vitreous specimens from 14 patients undergoing diagnostic or therapeutic vitrectomy for infection, suspected primary intraocular lymphoma, or uveitis were examined by immunocytochemical staining using monoclonal antibodies specific for leukocyte subclass antigens and immunoglobulin. The three classes of disorders showed characteristic patterns of staining, which were useful in confirming microbiologic and clinical diagnoses. Infections showed more pronounced neutrophils and macrophages, primary intraocular lymphomas demonstrated light chain restriction of the malignant B lymphocytes, and uveitis was characterized by the predominance of T lymphocytes. The routine use of immunocytochemical staining is recommended to characterize cellular infiltrates and increase the diagnostic yield from vitrectomy specimens.

Analysis of autoantibodies among patients with primary and secondary uveitis: high incidence in patients with sarcoidosis.

The sera of 122 patients with uveitis were examined for the presence of various antinuclear autoantibodies. Overall 21.3% of the patients had antibodies to ribonucleoprotein (RNP) and 18% to Ro (SSA). When subdividing the patients according to primary uveitis versus secondary uveitis, the autoantibodies were detected more frequently in the second group [anti-RNP 13.3 vs. 31.4%, anti-Ro (SSA) 11.8 vs. 27.7%, anti-Sm 10.3 vs. 24% and poly (G) 2.9 vs. 14.8%, respectively]. No differences could be asserted in autoantibody frequencies according to disease location within the uvea. Among uveitis patients afflicted with sarcoidosis a particular high incidence of autoantibodies was detected in comparison with all other subgroups of patients with uveitis. Although the presence of autoantibodies among patients with uveitis appears not to have a major diagnostic value, their assessment may aid to a better understanding of disease pathogenesis.

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.

Clinical and immunohistologic studies of corneal rejection in the rat penetrating keratoplasty model.

We used immunohistologic techniques with a penetrating keratoplasty model in the rat to study the mechanisms of corneal transplant rejection. Thirteen of 14 syngeneic grafts remained clear in contrast to 24 of 26 allogeneic grafts, which had a rejection reaction. Immunohistochemical studies of syngeneic grafts showed only rare inflammatory cells in the central grafts; however, a focal inflammatory reaction made up of macrophages and T-helper/inducer lymphocytes was seen surrounding the sutures and in the wound. In contrast, immunohistochemical studies of allogeneic grafts showed diffuse inflammation throughout the donor and recipient corneas with T-suppressor/cytotoxic cells, T-helper/inducer cells, and macrophages, resulting in destruction of the donor endothelium, neovascularization, and graft failure. Class II antigen expression was seen extensively on Langerhans cells, donor keratocytes, and both the donor and recipient endothelial cells. These findings emphasize the role of early nonspecific inflammation in the wound and around the sutures, and delineate the cellular immune response and class II antigen expression in corneal allograft rejection.

Role of chorioretinal biopsy in inflammatory eye disease.

Two patients who had similar clinical presentations of bilateral multiple chorioretinal lesions and needed a correct diagnosis underwent chorioretinal biopsy. The biopsy from one patient demonstrated mainly a B cell infiltrate in choroidal and subretinal nodules, while the biopsy from the second patient showed mainly macrophages in the retina. These findings directed the therapeutic approach taken in each patient. Although chorioretinal biopsy is an invasive procedure with the potential for serious complications, the resultant finding may aid in the diagnosis and guide the subsequent management of certain patients presenting with serious ocular findings of undefined etiology.

Randomized, double-masked study of cyclosporine compared to prednisolone in the treatment of endogenous uveitis.

Fifty-six patients with bilateral sight-threatening noninfectious intermediate or posterior uveitis participated in a randomized double-masked study of the use of cyclosporine vs prednisolone in their treatment. Applying the end-point definitions, visual acuity or vitreal haze improved in only 13 of 28 (46%) patients in each group. The macular edema resolved in seven of 15 patients of the cyclosporine-treated group, and in ten of 16 patients of the prednisolone-treated group (P = .376). Patients whose therapies failed both cyclosporine and prednisolone trials were treated with both drugs, which resulted in additional patient improvements. Secondary effects were observed in both therapeutic alternatives, the most notable being alterations in serum creatinine concentration and hypertension with the dosage of cyclosporine used.

Immunohistochemistry of the inflammatory response in Propionibacterium acnes endophthalmitis.

Specimens were obtained from two patients with culture-proven Propionibacterium acnes endophthalmitis who had undergone vitrectomy. Wright's and Giemsa stains were performed using cytospin preparations of the dilute vitreous and revealed a predominance of polymorphonuclear leukocytes (80% to 90%). The remaining inflammatory cells in the vitreous were mostly macrophages (10% to 15%); very few lymphocytes were present (less than 5%). Immunohistochemical studies using monoclonal antibodies confirmed the paucity of lymphocytes. Most lymphocytes were CD4+ helper/inducer T cells. Almost no CD8+ suppressor/cytotoxic T lymphocytes or B lymphocytes were found. The inflammatory response in these two patients is most characteristic of acute inflammation and consistent with an underlying bacterial infection, despite a clinical picture of persistent, low-grade inflammation. Infection with P acnes has been shown to inhibit CD8+ T cells and may play a role in the persistent inflammation in cases of P acnes endophthalmitis.