Ron P. Gallemore

Intravitreal sustained-release cyclosporine in the treatment of experimental uveitis

OBJECTIVE Uveitis often is a chronic disease requiring long-term medical therapy. Despite treatment, the disease may be difficult to control and may produce serious, vision-threatening ocular complications. In this study, the authors determined whether an intravitreal cyclosporine-sustained delivery device was effective in the treatment of ocular inflammation in a rabbit model of uveitis. METHODS New Zealand White rabbits were immunized subcutaneously with Mycobacterium tuberculosis H37Ra antigen. Fourteen days later, sustained-release cyclosporine devices were implanted into the vitreous cavity of the right eye of experimental rabbits. Control animals received sham devices. Seven days after device implantation, rabbits were challenged with an intravitreal injection of tuberculin antigen. To simulate chronic inflammation with exacerbations, some animals were rechallenged with intravitreal antigen on day 21 after device implantation. Inflammation was assessed clinically by a masked observer who graded anterior chamber cells, flare, corneal neovascularization, iris congestion, and vitreous opacity daily until day 7 and on day 13 after the initial intravitreous challenge, and on days 1 and 2 after the rechallenge. Retinal function was evaluated by electroretinography. Animals were killed 3, 6, 8, and 14 days after the initial intravitreal challenge and on the second day after rechallenge for aqueous leukocyte count, protein measurement, and histologic examination. The number of aqueous and peripheral blood proliferating lymphocytes and the subset of CD4+ T cells were determined by flow cytometry. High-performance liquid chromatography was used to measure cyclosporine A levels in vitreous and peripheral blood. Light microscopy was used to evaluate the eyes histopathologically. RESULTS By clinical criteria, treated eyes had significantly less inflammation than untreated eyes. The number of aqueous cells and protein concentration determined quantitatively paralleled the clinical assessment of anterior chamber cells and flare. The electroretinography B-wave was depressed significantly in untreated eyes compared with that of treated eyes (P < 0.02). Histopathologic examination results showed marked inflammation and tissue disorganization in untreated eyes, whereas cyclosporine-treated eyes had preserved architecture and greatly reduced inflammatory cells. Intravitreal cyclosporine remained at therapeutic levels for at least 6 months after intravitreal device implantation, whereas blood levels were low to nondetectable. CONCLUSIONS The intravitreal cyclosporine A device effectively suppresses ocular inflammation in a rabbit model of uveitis. This device may be useful in the treatment of patients with severe chronic uveitis who are intolerant to currently available therapies.

Retinal pigment epithelial transport mechanisms and their contributions to the electroretinogram

Abstract The translocation of ions, fluid and macromolecules across epithelia is made possible by the asymmetric distribution of transport proteins, enzymes and receptors in two physically distinct plasma membrane domains that form the apical and basolateral sides of the cell. Each side faces a different extracellular environment. In the back of the vertebrate eye, the retinal pigment epithelium (RPE) apical membrane receives a continuous stream of paracrine signals that are generated by a variety of retinal neurons in the light and dark. These signals help regulate RPE function, and conversely, alterations in RPE function can modify the activity of retinal neurons. At the basolateral surface, there is a continual exchange of nutrients and waste products, along with a flow of hormonal signals from the choroidal blood supply, all of which serve to maintain the health and integrity of the distal retina and in particular, the photoreceptors. This review provides an integrated summary of the apical and basolateral membrane and intracellular signaling mechanisms that mediate the vectorial traffic of ions and fluid across the RPE. These same mechanisms help regulate the chemical milieu within the cell and in the extracellular spaces that surround the cell. They also generate specific components of the electrical signals that are recorded clinically across the intact human eye, the electroretinogram (ERG) and the electrooculogram (EOG). The last part of this review is focused on the light-induced photoreceptor-dependent decrease in subretinal potassium concentration ([K] 0 ) that occurs in the intact eye and serves as a paracrine signal for the RPE. This signal plays a central role in regulating RPE physiology and in mediating retina/RPE interactions, following transitions between light and dark; it is mimicked in vitro by a small (3 m m ) change in [K] 0 on the apical side of the epithelium. The clinical implications are discussed in terms of the transport mechanisms that regulate hydration of the subretinal space and that potentially mediate fluid absorption out of the retina.

Exudative retinal detachment and retinitis associated with acquired syphilitic uveitis.

Purpose: To describe three cases of exudative retinal detachment and focal retinitis associated with acquired syphilitic uveitis. Methods: Three patients who were referred for evaluation of uveitis were examined. Slit‐lamp examination, ophthalmoscopy, B‐scan ultrasonography, fundus photography, and fluorescein angiography were performed before and after therapy. Results: Each patient had uveitis with exudative retinal detachment, periphlebitis, and focal retinitis. Laboratory testing (fluorescent treponemal antibody absorption) revealed positive serology for active syphilis in all cases. Human immunodeficiency virus antibody testing was negative in all patients. Retinal detachment resolved in all cases after treatment with intravenous penicillin. Despite resolution of subretinal fluid, visual acuity remained poor in eyes in which the macula was detached. Conclusion: Syphilis is a cause of exudative retinal detachment. Antibiotic therapy can lead to retinal reattachment. Early recognition and treatment may prevent severe vision loss.

Efficacy of verteporfin photodynamic therapy on laser-induced choroidal neovascularization and the ancillary effect on diabetic microvasculopathy

Purpose. To demonstrate the efficacy of photodynamic therapy (PDT) in treating choroidal neovascularization (CNV) induced by laser photocoagulation for diabetic macular edema and its ancillary effect on surrounding diabetic microvascular abnormalities. Methods. A retrospective interventional case series study in a clinical practice setting of four patients with proliferative diabetic retinopathy and clinically significant macular edema who had developed classic CNV in proximity to the area of previous laser photocoagulation. The lesions were treated with verteporfin PDT and followed with serial fluorescein angiography. Results. Compared to the pre-treatment angiogram, an acute reduction in leakage from CNV was noted as soon as 5 days post-PDT and persisted in some areas up to three months post-treatment within the zone of the typical dark choroid pattern. No evidence of any closure of microaneurysms was noted. Conclusions. Serial fluorescein angiograms demonstrate that PDT appears to have a beneficial effect on CNV induced by laser photocoagulation for diabetic macular edema without any tangible beneficial effect on diabetic microvasculopathy. PDT had no effect on existing microaneurysms.