High-dose intravitreal ganciclovir and foscarnet for cytomegalovirus retinitis.

PURPOSE: To describe the chronic use of high doses of intravitreal ganciclovir, in combination with foscarnet, for the treatment of cytomegalovirus retinitis. METHODS: A 31-year-old man with human immunodeficiency virus (HIV) infection and unilateral active cytomegalovirus retinitis was treated with escalating intravitreal injections of ganciclovir (up to 3.0 mg twice a week) in combination with foscarnet (up to 2.4 mg twice a week) over the course of approximately 1 year. RESULTS: Complete regression of the retinitis was obtained with high doses of intravitreal ganciclovir and foscarnet. Visual acuity in the affected eye remained 20/20 throughout the course of therapy. No ganciclovir retinal toxicity was identified. CONCLUSION: High doses of intravitreal ganciclovir in combination with foscarnet can be well tolerated and may be required to successfully control cytomegalovirus retinitis in some patients.

Characterization of native pathogenic antigens of Onchocerca volvulus: identification of high molecular mass protein antigens eliciting interstitial keratitis in a guinea pig model.

Sclerosing keratitis is the predominant cause of blindness due to onchocerciasis which is a major human parasitic disease caused by the filarial parasite Onchocerca volvulus. In the present investigation, native pathogenic antigens of O. volvulus which are particularly potent in causing interstitial keratitis were characterized utilizing a guinea pig model. Following demonstration of the protein nature of these antigens using pronase digestion, the crude O. volvulus antigen extract was subjected to stepwise procedures of protein purification. At each stage of purification, pooled antigen fractions were injected into one cornea of presensitized guinea pigs followed by clinical evaluation of stromal inflammation and vascularization at different intervals of time after intrastromal challenge. Initial purification of the pathogenic antigens was carried out in the following order: molecular sieve chromatography on Bio-gel A-5m. anion exchange chromatography on Mono Q followed by DEAE-Sepharose CL-6B and cation exchange chromatography on Mono S. Two out of six different pools from the Mono S column (pool a eluted unbound at 10 mM-NaCl and pool e eluted between 130 mM and 475 mM-NaCl) were found to be most pathogenic. Further purification of Mono S pool a and pool e separately by gel filtration chromatography using Superose 12 demonstrated that the fractions which were most potent in inducing interstitial keratitis contained proteins with approximate molecular masses between 100 and 200 kDa. These results show that minor subfractions of total crude antigens of O. volvulus are largely responsible for induction of experimental interstitial keratitis. We have demonstrated the presence of these antigens in O. volvulus microfilariae by their cross-reactivities with anti-microfilarial antibodies, and hence the relevance of the purified antigens to ocular onchocerciasis in man since sclerosing keratitis is associated with invasion of the cornea by O. volvulus microfilariae. Isolation of these two pathogenic antigen pools represents the practical limits of purification and subsequent animal experiments possible with the available amounts of native parasite material obtained from infected human individuals in the absence of a suitable non-human host or of an in vitro culture system for O. volvulus.

Immune-mediated Onchocerca volvulus sclerosing keratitis in the mouse.

Sclerosing keratitis is the major cause of blindness due to onchocerciasis; its pathogenesis is poorly understood. We have previously reported an immune-mediated model of experimental interstitial keratitis in guinea pigs following intrastromal challenge with soluble antigens from Onchocerca volvulus. This model system is ideal for evaluation of pathogenicity of multiple purified antigen preparations; however, reagents necessary for detailed immunologic analysis of the inflammatory cellular infiltrate are not yet available for guinea pigs. Because of the ready availability of these reagents for mice, a mouse model has been developed. The inflammatory response observed in this model was analogous to that seen in human onchocercal sclerosing keratitis as well as in the guinea pig model of onchocercal sclerosing keratitis. Granulocytes were present in the acute inflammatory response, whereas the chronic response showed lymphocytes, plasma cells, and histiocytes. Neovascularization and scarring of the corneal stroma was also observed. This model will be helpful in examining the mechanisms of immunopathogenesis and the contribution of the host genetic background to the disease.

Precocious retinal adhesion is affected by furosemide and ouabain.

A "precocious" adhesive force develops between the neurosensory retina (NSR) and the retinal pigment epithelium (RPE) 15-30 minutes after eyes are removed from day 15 embryonic chickens and incubated at 37 degrees C. Precocious adhesion has been reported to be blocked by exposure to cold but to be unaffected by exposure to furosemide and ouabain. Since RPE transport is thought to play a major role in the adhesion between the RPE and NSR of adult mammals, and since ouabain and furosemide block RPE transport in embryonic chickens, it has been thought that precocious adhesion in embryonic chickens is not a good model for studying adhesion between the RPE and the NSR of adult mammals. We have found, however, that when steps are taken to ensure that ouabain and furosemide reach the transport sites on RPE apical membrane before precocious adhesion develops, that ouabain and furosemide do affect precocious adhesion.

Digoxin cannot account for the reported association of EKG abnormalities and rhegmatogenous retinal detachment.

The prevalence of cardiovascular disease (by EKG criteria) in patients with rhegmatogenous retinal detachments has been reported to be more than four times that found in age-matched controls. Adhesion between the retinal pigment epithelium (RPE) and the photoreceptors is facilitated by RPE transport. Because RPE transport is driven by a Na-K ATPase, it has been suggested that the correlation of EKG abnormalities and retinal detachment may be due to clinical use of digoxin, a Na-K ATPase inhibitor frequently given to patients with cardiovascular disease. The prevalence of EKG abnormalities in 299 consecutive patients with primary retinal detachment is about the same as that reported previously. However, 92% of these patients with EKG abnormalities did not take digoxin. Therefore, clinical use of digoxin cannot account for the reported association of EKG abnormalities and rhegmatogenous retinal detachment.