Marisa Flores-Aguilar

Pathophysiology and Treatment of Clinically Resistant Cytomegalovirus Retinitis

PURPOSE To determine the incidence, pathophysiology, clinical outcome, and survival in patients with clinically resistant retinitis. METHODS Cytomegalovirus (CMV) retinitis was prospectively studied in 100 patients with acquired immune deficiency syndrome (AIDS). In 11 of these patients, clinically resistant retinitis developed, defined as new activity or progression, despite at least 8 consecutive weeks of induction doses of either foscarnet or ganciclovir. Fundus photography, pharmacokinetics, CMV cultures and sensitivities, and survival analyses were studied. The therapeutic interventions attempted after clinically resistant retinitis was identified included continuing a high dose (induction level) of the same antiviral drug, changing the antiviral drug, and combining antiviral therapy with foscarnet and ganciclovir. RESULTS Clinically resistant retinitis occurred in 11 (11%) of 100 patients with CMV retinitis and appeared to be a manifestation of acquired CMV antiviral drug resistance. Drug metabolism and pharmacokinetics in these patients were normal. The use of combination therapy with foscarnet and ganciclovir was effective in halting the progression of retinitis in three (75%) of four patients (6 of 7 eyes able to be evaluated) receiving combination therapy. CONCLUSION Clinically resistant retinitis is a manifestation of infection by CMV that has acquired drug resistance. In these patients, combination antiviral drug treatment should be considered. It is likely that clinically resistant retinitis will become more frequent as patients with CMV retinitis and AIDS survive longer.

Results of Rhegmatogenous Retinal Detachment Repair in Cytomegalovirus Retinitis with and without Scleral Buckling

Purpose: To determine if scleral buckling is of any benefit in surgical repair of cytomegalovirus (CMV)-associated retinal detachment if combined with vitrectomy, silicone oil, and inferior midperipheral endolaser. Materials and Methods: Twenty-two consecutive eyes with CMV-associated retinal detachments were repaired with vitrectomy and endolaser to all breaks and to the inferior midperipheral retina using silicone oil without scleral buckling (group 1, control group) between July 1987 and May 1992. Results were compared with another series of 56 consecutive eyes undergoing vitrectomy, silicone oil injection, endolaser to all breaks, and 360° encircling scleral buckling (group 2, study group) between June 1992 and July 1993. Results: Total retinal reattachment rates were 84% for group 1 and 86% for group 2. Rates of macular reattachment were 91 % for group 1 and 91 % for group 2. Mean best postoperative refracted visual acuity was 20/66 for group 1 and 20/67 for group 2. Median best postoperative refracted visual acuity was 20/74 for group 1 and 20/80 for group 2. These differences in results between the two groups were not statistically significant. Mean postoperative refractive error was +3.95 for group 1 and +4.92 for group 2. Patients who underwent surgery with the macula attached had a better postoperative visual outcome. Conclusion: Scleral buckling may not be necessary in CMV-related retinal detachment if repaired with vitrectomy, silicone oil, and inferior midperipheral endolaser. Elimination of scleral buckling may reduce intraoperative time, patient morbidity, and the risk of an accidental needle stick. Patients with macula-on retinal detachments also should be considered for surgery before macular detachment.

A Masked Prospective Evaluation of Outcome Parameters for Cytomegalovirus-related Retinal Detachment Surgery in Patients with Acquired Immune Deficiency Syndrome

PURPOSE The management of cytomegalovirus (CMV)-related rhegmatogenous retinal detachments in patients with acquired immune deficiency syndrome (AIDS) has been the subject of recent attention and controversy because of the high degree of variability in visual outcome, as well as significant differences in the reported incidence of profound postoperative optic atrophy. This study was designed to evaluate the various parameters affecting postoperative visual outcome, and to quantitate the degree of postoperative optic disc pallor. METHODS The results of 65 consecutive surgeries for CMV-related retinal detachments in 51 patients with AIDS were prospectively studied. Postoperative vision, survival, optic disc pallor, and retinitis extent were analyzed. Serial photographs of optic discs underwent masked evaluation. RESULTS Mean postoperative survival was 30 weeks (range, 2-146 weeks). Mean best postoperative visual acuity was 20/66 (range, 20/20-2/200) and mean final postoperative visual acuity was 20/100 (range, 20/25-no light perception). Analysis of visual outcome for eyes with no macular or papillo-macular retinitis showed a best postoperative visual acuity of 20/60 (range, 20/25-2/200) and mean final postoperative visual acuity of 20/80 (range, 20/25-no light perception). Postoperative vision was not affected by the presence of a preoperative macular detachment, with both groups (macula on or off detachments), achieving a best postoperative visual acuity of 20/60 in the absence of macular retinitis. Mild postoperative optic disc pallor was observed in 30% of surgical eyes at the final postoperative visit, and moderate pallor was noted in 13%. The mean degree of optic disc pallor was not different from the degree of optic disc pallor seen in fellow, nonsurgical eyes with CMV retinitis (surgical versus fellow nonsurgical eyes, 29% +/- 23% versus 26% +/- 30%; P = 0.64). CONCLUSION In this largest reported series of reattachment surgery for CMV-related retinal detachments, patients are experiencing increased postoperative survival, good vision, and relative optic nerve health.

Evaluation of a novel lipid prodrug for intraocular drug delivery: effect of acyclovir diphosphate dimyristoylglycerol in a rabbit model with herpes simplex virus-1 retinitis.

BACKGROUND Acyclovir diphosphate dimyristoylglycerol is a lipid prodrug of acyclovir that forms liposomes and provides substantial activity against herpes simplex virus, acyclovir-resistant strains of herpes simplex virus, and human cytomegalovirus. We therefore tested this promising new drug in a rabbit model of herpes simplex retinitis. METHODS A total of 22 pigmented rabbits were pretreated with either acyclovir diphosphate dimyristoylglycerol, ganciclovir, acyclovir, or buffer. Retinae then were inoculated with herpes simplex virus-1 or buffer 1 week after the injection of drug. In another experiment we compared the effects of acyclovir diphosphate dimyristoylglycerol and acyclovir diphosphate dioleoylglycerol on the optical clarity of vitreous. RESULTS Animals injected intravitreally with acyclovir diphosphate dimyristoylglycerol showed retinitis that was less severe than that in animals injected with ganciclovir, acyclovir, and buffer; differences in grading scores of the retinitis between animals injected with acyclovir diphosphate dimyristoylglycerol and those injected with buffer were statistically significant (P = 0.0015). Vitreous and optical media became clear 4 days after acyclovir diphosphate dioleoylglycerol injection compared with 10 days after with acyclovir diphosphate dimyristoylglycerol injections. CONCLUSION Acyclovir diphosphate dimyristoylglycerol had prolonged antiviral activity against herpes simplex virus-1 retinitis in a rabbit model. This drug delivery system, modified to improve optical clarity, may allow long-acting intravitreal treatment of cytomegalovirus retinitis and other retinal diseases.

Intraocular Tolerance Of Perfluorooctylbromide (perflubron)

Purpose To determine the intraocular tolerance of perfluorooctylbromide (perflubron) in vitrectomized rabbit and pig eyes and evaluated its use as a vitreous substitute in vitreoretinal surgery. Methods Pars plana vitrectomy was performed on 33 Dutch pigmented rabbits and 11 micro mini pigs. After vitrectomy the eyes were filled with perflubron for 2 hours, 1 week, 2 weeks, 1 month, and up to 6 months. Results No clinical, electroretinographic, or light and electron microscopic evidence of adverse effects on the retina and lens were observed. Perflubron emulsified and dispersed into small bubbles after 2–3 weeks. The lens showed mild posterior subcapsular cataracts in pig eyes after long-term retention of perflubron. Conclusion These findings indicate that perflubron is safe for intraoperative and for longterm use intravitreally. However, emulsification and the breakdown into small bubbles limits the view of the retina when perflubron is used as a long-term tamponade.

Use of perflubron as a new temporary vitreous substitute and manipulation agent for vitreoretinal surgery

PURPOSE The authors determine the intraocular tolerance of a new widely used liquid perfluorocarbon, perfluoroctylbromide (perflubron). METHODS Pars plana vitrectomy was performed on 54 eyes of 54 patients with vitreoretinal disorders at three centers. Diagnoses included giant retinal tears, proliferative vitreoretinopathy, and dislocated intraocular and crystalline lenses. At the conclusion of the vitrectomy, perflubron was removed. RESULTS Perflubron was efficacious for vitreoretinal manipulation. Of the 45 eyes with retinal detachment, 23 (51.1%) of the retinas were reattached after a single surgery; redetachment occurred in 22 (48.9%) after the initial procedure, and further surgery was necessary to reattach the retina. Final retinal reattachment was achieved in 40 (88.9%) eyes. Mean visual acuity improvement was six lines (P < 0.0019). Visualization of the water/perfluorocarbon interface was good. There was no evidence of adverse effects from perflubron on the retina, lens, or anterior segment. CONCLUSION Findings indicate that perflubron is safe for temporary intraoperative use intravitreally. The absence of adverse effects is consistent with the properties of perflubron that our group has studied in the eyes of animals and in other uses in human patients.

Evaluation of Cytologic Specimens Obtained During Experimental Vitreous Biopsy

Vitreous specimens can be useful for diagnosis of intraocular infection, inflammation, and neoplasms. Concern has been raised that obtaining vitreous specimens through a guillotine cutter might result in suboptimal cytologic changes. To determine if aspiration yields better cytologic information than vitrectomy, the authors performed experimental vitreous biopsies on rabbit eyes with vitritis to compare specimens taken by aspiration or vitrectomy with cutting rates of 100, 300, 600 per minute. The specimens were processed by cytospin preparations and stained with Papanicolaou and May-Grünwald-Giemsa stain. There was no difference in the adequacy of the specimens. Cell loss or damage to cell morphologic features when obtaining specimens through aspiration or vitrectomy at different cutting rates could not be differentiated by a blinded cytologic evaluation. A theoretical model of shear stress on cells passing through a guillotine cutter was also developed. The experimental and theoretical data show that vitrectomy with a cutting rate as fast as 600 per minute yields an adequate specimen with a sufficient number of well preserved cells to make definite cytologic interpretations, and that vitreous aspiration is not necessary.

Clinical versus fundus photographic evaluation of the status of cytomegalovirus retinitis in AIDS patients.

Purpose: To evaluate the accuracy of clinical examinations and serial fundus photographic readings in determining the response of cytomegalovirus retinitis to antiviral therapy in patients with acquired immune deficiency syndrome. Methods: Fifty two consecutive patients with cytomegalovirus retinitis who were prospectively evaluated over a 30-month period for a minimum of 6 months (or until death) were included in this study. There was a total of 708 patient visits. The clinical evaluations included indirect ophthalmoscopy, fundus drawings, 60° fundus photographs, and a comparison of the photographs with those of the previous visit. The fundus photographs were reevaluated in a blinded fashion. Cytomegalovirus retinitis was classified as active (progression of border since last examination), intermediate (border activity without progression), healed (no activity since last visit), or normal (no retinitis). Results: Using the photographic data as the measure of cytomegalovirus retinitis activity, the sensitivity and specificity of clinical assessments were determined. The sensitivity and specificity of clinical versus photographic evaluations varied with retinitis status. In healed retinitis the sensitivity of the clinical examination was 98%, and the specificity was 83%. In cases of border opacification without progression the sensitivity was 80%, and the specificity was 96%. In cases of clinically active retinitis the sensitivity was 63% with a specificity of 100%. Clinical detection of active retinitis and border opacification without progression was reduced when potential problems were present that made visualization of the retinitis border difficult, such as smoldering retinitis, progressive retinal destruction without border opacification, poor media, or fundus pigmentation. Conclusions: Progressive retinal destruction and visual loss can occur in patients with cytomegalovirus retinitis despite antiviral therapy. Examining the patient through indirect ophthalmoscopy only can result in failure to detect subtle changes.

Evaluation of retinal toxicity of acetylcholine in rabbit eyes.

Purpose: In vitreoretinal surgery, pupillary constriction may be required at the termination of a procedure especially if mechanical pupillary dilation was used in eyes filled with gas or silicone oil. A miotic agent instilled into the anterior chamber will sink and come into direct contact with retina in the aphakic or pseudophakic vitrectomized eye. Therefore, the retinal toxicity of acetylcholine, a miotic used for pupillary constriction, was studied. Methods: Eight Dutch pigmented rabbit eyes were vitrectomized, had air-fluid exchange, and were injected with a 20% mixture of SF6. Subsequently eyes were randomly selected to have injections of 0.75 ml of 10 mg/ml acetylcholine (Miochol, lolab Corp., Claremont CA) versus 0.75 ml of lactated Ringers solution. Short-term (2 weeks) and long-term (6 weeks) retinal toxicity was assessed by ophthalmoscopy, electroretinogram, and histology by light and electron microscopy at both times. Results: Ophthalmoscopy, electroretinographic tracings, histology, and electron microscopy disclosed no significant abnormalities. Conclusions: Acetylcholine does not appear to have significant retinal toxicity even when undiluted solutions are in direct contact with the retina. We therefore postulate that intraoperative use of acetylcholine in previously vitrectomized eyes filled with gas or silicone is safe.

Results of Rhegmatogenous Retinal Detachment Repair in Cytomegalovirus Retinitis With and Without Scleral Buckling

PURPOSE To determine if scleral buckling is of any benefit in surgical repair of cytomegalovirus (CMV)-associated retinal detachment if combined with vitrectomy, silicone oil, and inferior midperipheral endolaser. MATERIALS AND METHODS Twenty-two consecutive eyes with CMV-associated retinal detachments were repaired with vitrectomy and endolaser to all breaks and to the inferior midperipheral retina using silicone oil without scleral buckling (group 1, control group) between July 1987 and May 1992. Results were compared with another series of 56 consecutive eyes undergoing vitrectomy, silicone oil injection, endolaser to all breaks, and 360 degrees encircling scleral buckling (group 2, study group) between June 1992 and July 1993. RESULTS Total retinal reattachment rates were 84% for group 1 and 86% for group 2. Rates of macular reattachment were 91% for group 1 and 91% for group 2. Mean best postoperative refracted visual acuity was 20/66 for group 1 and 20/67 for group 2. Median best postoperative refracted visual acuity was 20/74 for group 1 and 20/80 for group 2. These differences in results between the two groups were not statistically significant. Mean postoperative refractive error was +3.95 for group 1 and +4.92 for group 2. Patients who underwent surgery with the macula attached had a better postoperative visual outcome. CONCLUSION Scleral buckling may not be necessary in CMV-related retinal detachment if repaired with vitrectomy, silicone oil, and inferior midperipheral endolaser. Elimination of scleral buckling may reduce intraoperative time, patient morbidity, and the risk of an accidental needle stick. Patients with macula-on retinal detachments also should be considered for surgery before macular detachment.