David V. Weinberg

Improvement in Visual Acuity in Chronic Aphakic and Pseudophakic Cystoid Macular Edema After Treatment With Topical 0.5% Ketorolac Tromethamine

Ketorolac tromethamine 0.5% ophthalmic solution treatment was compared to placebo treatment in 120 patients with chronic aphakic or pseudophakic cystoid macular edema (six-month or more duration of distance visual acuity of 20/40 or less and angiographic evidence of cystoid changes) during a four- to five-month double-masked, multicenter study in which patients were randomly assigned. A statistically significant improvement in distance visual acuity (two lines or more) was observed in the ketorolac-treated group as compared to the placebo-treated group after 30 days (P = .038), 60 days (P = .017), and 90 days (P = .008) of treatment. This improvement in visual acuity remained statistically significant one month after cessation of treatment (P = .001). Nine ketorolac-treated patients and two placebo-treated patients demonstrated a decrease in visual acuity one month after treatment was discontinued. Seven of the nine ketorolac-treated patients experienced an improvement in visual acuity after retreatment as compared to none of the placebo-treated patients. This study offers evidence for a more optimistic outlook in the medical treatment of chronic aphakic and pseudophakic cystoid macular edema.

Mutations Conferring Ganciclovir Resistance in a Cohort of Patients with Acquired Immunodeficiency Syndrome and Cytomegalovirus Retinitis

Cytomegalovirus (CMV) retinitis is among the most common opportunistic infections in patients with acquired immunodeficiency syndrome. In a prospective study of 210 patients with CMV retinitis, 26 were identified as having either a phenotypic or a genotypic ganciclovir-resistant isolate from either blood or urine cultures. For blood culture isolates with an IC(50) >6.0 microm for ganciclovir, the sensitivity and specificity for detecting a UL97 mutation were 95% and 98%, respectively, whereas for an IC(50) >8.0 microM they were 79% and 99%, respectively. Although there were trade-offs between the 2 thresholds for blood culture isolates, for urine culture isolates an IC(50) >8.0 microM appeared to be better at identifying genotypic resistance. UL97 mutations identified in both the blood and urine cultures of individual patients were identical in 87.5% of cases. High-level ganciclovir resistance (IC(50), >30 microM) typically, but not invariably, was associated with a mutation in both the UL97 and UL54 genes.

Anatomy of Arteriovenous Crossings in Branch Retinal Vein Occlusion

We studied the photographic records of 292 eyes, including 103 eyes with branch retinal vein occlusion, 90 fellow eyes, and 99 control eyes without branch retinal vein occlusion. All arteriovenous crossings within three disk diameters of the optic disk, including the crossings at the sites of branch retinal vein occlusions, were studied. The relative positions of the crossing artery and vein could be determined at 1,939 crossings in all eyes. Crossings at which a vein crossed over an artery were a common finding (22.3% to 33.0% of crossings), but were rare at the crossings where branch retinal vein occlusions were found (2.4%). A greater proportion of arterial overcrossings was found in eyes with branch retinal vein occlusions (77.7%) compared to fellow eyes (70.6%) or control eyes (67.0%). Our data indicate that arterial overcrossings are at relatively higher risk of branch retinal vein occlusion than venous overcrossings, and that the risk of branch vein occlusion in an eye is proportional to the number of arterial overcrossings in the eye.

Randomized, controlled study of the safety and efficacy of intravenous cidofovir for the treatment of relapsing cytomegalovirus retinitis in patients with AIDS

To assess the effect of intravenous cidofovir on delaying progression of previously treated, relapsing cytomegalovirus (CMV) retinitis, we conducted a randomized, controlled comparison of two maintenance dose levels of cidofovir. One hundred and fifty patients with AIDS and CMV retinitis that had progressed or was persistently active despite treatment with ganciclovir, foscarnet, or both were randomized to receive induction cidofovir, 5 mg/kg once weekly for 2 weeks, then maintenance therapy with either 5 mg/kg or 3 mg/kg once every other week. Concomitant probenecid and intravenous hydration were administered with each cidofovir dose. Retinitis progression was assessed in the first 100 patients by bilateral, full-field retinal photographs read at a central reading center by an ophthalmologist masked to treatment assignment. Incidence of side effects, changes in visual acuity, and mortality were also assessed. Median time to retinitis progression as assessed by retinal photography was not reached (95% confidence interval [CI], 115 days-upper limit not reached) in the 5-mg/kg group, and was 49 days (95% CI, 35-52 days) in the 3-mg/kg group (p = .0006). Dose-dependent asymptomatic proteinuria (39%) and serum creatinine elevation (24%) were the most common adverse events thought to be related to cidofovir. Reversible probenecid reactions including constitutional symptoms and nausea occurred in 65 of 150 (43%) patients. Cidofovir therapy is effective in delaying progression of CMV retinitis that had previously progressed using other anti-CMV therapies.

Evaluation of the safety and performance of an applicator for a novel intravitreal dexamethasone drug delivery system for the treatment of macular edema.

Purpose: Evaluation of safety and performance of an applicator-inserted dexamethasone drug delivery system. Methods: Patients with clinically observable macular edema were randomized to receive 700 μg dexamethasone drug delivery system via a pars plana incisional placement (n = 10) or a 22-gauge applicator insertion (n = 20). Outcome measures included assessment of procedure duration, the postinsertion wound, adverse events, intraocular pressure, and best-corrected visual acuity at baseline and days 1, 7, 14, 30, 60, 90, and 180. Results: Both procedures were well tolerated and none of the patients in the applicator group required sutures to close the insertion wound. The overall incidence of ocular adverse events was less in the applicator group (13/19; 68.4%) than the incisional group (9/10; 90%), although the difference was not statistically significant in this pilot study. Vitreous hemorrhage occurred in two patients in the incisional group and none in the applicator group. Increases in intraocular pressure were less frequent in the applicator group (3/19; 15.8%) than the incisional group (3/10; 30%). No cases of endophthalmitis or retinal detachment occurred in either group. The percentage of patients achieving improvement in visual acuity of ≥15-letters at Day 90 was similar in both groups; 40% (8/20) in the applicator group and 30% (3/10) in the incisional group. Conclusion: The dexamethasone drug delivery system applicator system performed well, allowing safe, effective, and sutureless intravitreal placement of 700 μg dexamethasone drug delivery system.

Management of varicella zoster virus retinitis in AIDS

AIMS/BACKGROUND Varicella zoster virus retinitis (VZVR) in patients with AIDS, also called progressive outer retinal necrosis (PORN), is a necrotising viral retinitis which has resulted in blindness in most patients. The purposes of this study were to investigate the clinical course and visual outcome, and to determine if the choice of a systemic antiviral therapy affected the final visual outcome in patients with VZVR and AIDS. METHODS A review of the clinical records of 20 patients with VZVR from six centres was performed. Analysis of the clinical characteristics at presentation was performed. Kruskall–Wallis non-parametric one way analysis of variance (KWAOV) of the final visual acuities of patients treated with acyclovir, ganciclovir, foscarnet, or a combination of foscarnet and ganciclovir was carried out. RESULTS Median follow up was 6 months (range 1.3–26 months). On presentation, 14 of 20 patients (70%) had bilateral disease, and 75% (15 of 20 patients) had previous or concurrent extraocular manifestations of VZV infection. Median initial and final visual acuities were 20/40 and hand movements, respectively. Of 39 eyes involved, 19 eyes (49%) were no light perception at last follow up; 27 eyes (69%) developed rhegmatogenous retinal detachments. Patients treated with combination ganciclovir and foscarnet therapy or ganciclovir alone had significantly better final visual acuity than those treated with either acyclovir or foscarnet (KWAOV: p = 0.0051). CONCLUSIONS This study represents the second largest series, the longest follow up, and the first analysis of visual outcomes based on medical therapy for AIDS patients with VZVR. Aggressive medical treatment with appropriate systemic antivirals may improve long term visual outcome in patients with VZVR. Acyclovir appears to be relatively ineffective in treating this disease.

Rhegmatogenous retinal detachments in children ☆: Risk factors and surgical outcomes

PURPOSE To describe the presenting features and surgical outcomes in a series of children with rhegmatogenous retinal detachments. DESIGN Retrospective, noncomparative, interventional case series. PARTICIPANTS Thirty-nine eyes of 34 children 18 years of age or younger undergoing surgery for rhegmatogenous retinal detachment. METHODS Patients were identified by chart review at two affiliated tertiary care centers. Risk factors for retinal detachment were classified into four categories: (1). congenital or developmental structural ocular abnormalities, (2). trauma, (3). previous ophthalmologic surgery, and (4). preceding uveitis. RESULTS Median age was 10 years, and 79% of patients were boys. Nine patients (26%) had bilateral retinal detachment at presentation, or experienced a detachment in their second eye before their nineteenth birthday. Every eye had at least one risk factor for retinal detachment, and more than half had risk factors in two or more categories. Structural abnormalities were most common (56%). Fifty-one percent of eyes underwent previous surgery, 36% experienced trauma, and 15% had uveitis. Detachments tended to be complex. Median follow-up was 24 months. Retinal reattachment was achieved in 79% of eyes; however, visual recovery was modest. Median preoperative and postoperative visual acuities were counting fingers and 20/400, respectively. Predictors of a poor visual outcome were: unmeasurable or light perception-only preoperative vision (P = 0.0001), macula-off retinal detachment (P = 0.01), the need for vitrectomy surgery (P = 0.01), the presence of proliferative vitreoretinopathy grade C or worse (P = 0.02), and the use of silicone oil (P = 0.02). CONCLUSIONS Predisposing factors in pediatric retinal detachments, particularly congenital and developmental structural abnormalities, may be more common than previously reported. Modern vitreoretinal surgical techniques can help achieve retinal reattachment in most cases. Many factors contribute to the limited visual recovery in this patient population. Predictors of visual outcomes are similar to those observed in adults. Inability of the clinician to determine confidently the preoperative visual acuity is a newly identified predictor of poor visual outcomes.

Cytomegalovirus resistance to ganciclovir and clinical outcomes of patients with cytomegalovirus retinitis

PURPOSE To evaluate whether cytomegalovirus resistant to ganciclovir, detected in either the blood or urine, correlates with adverse ocular outcomes. DESIGN Prospective cohort study. METHODS Patients with cytomegalovirus and AIDS were enrolled in a study of the occurrence and clinical correlates of resistant cytomegalovirus. Blood and urine cultures for cytomegalovirus were performed at the time of diagnosis of retinitis, 1 and 3 months after the initiation of therapy, and every 3 months thereafter. Patients were seen monthly, at which time fundus photographs were obtained and forwarded to the Fundus Photograph Reading Center for evaluation of retinitis progression (movement of a border of a cytomegalovirus lesion > or = 750 microm, or the occurrence of a new lesion > or = 0.25 disk area in size) and the amount of retinal area affected by cytomegalovirus retinitis. Visual acuity was measured using logarithmic visual acuity charts. Phenotypic resistance to ganciclovir was defined as an IC50 > 6.0 micromol/l, and genotypic resistance to ganciclovir was defined as the occurrence of a cytomegalovirus UL97 gene mutation known to confer ganciclovir resistance. Time-dependent analyses were performed and included viral resistance, highly active antiretroviral therapy, and treatment variables as predictors of clinical outcomes. RESULTS One hundred ninety-seven patients received ganciclovir therapy. Nineteen patients developed phenotypic resistance to ganciclovir, and 18 developed genotypic resistance. The detection of cytomegalovirus resistant to ganciclovir was associated with a 4.17- to 5.61-fold increase in the odds of retinitis progression (P values all < or = .0002), depending upon the definition of resistance and the culture sources analyzed. Resistance was associated with a greater increase in retinal area involved by cytomegalovirus by 3-month interval (1.10% vs 0.05% to 0.10%), which was significant for phenotypic resistance and for genotypic resistance in the blood or urine (P =.012 to.021). There was a suggestion that resistance was associated with a greater loss of visual acuity (P =.009 to.096). Highly active antiretroviral therapy was associated with an approximate 50% reduction in the odds of retinitis progression, and the ganciclovir implant was associated with an approximate 60% reduction. CONCLUSIONS The detection of cytomegalovirus resistant to ganciclovir in either the blood or urine of a patient with cytomegalovirus retinitis is associated with an increased risk of adverse ocular outcomes.

Comparison of Cytomegalovirus (CMV) UL97 Gene Sequences in the Blood and Vitreous of Patients with Acquired Immunodeficiency Syndrome and CMV Retinitis

Cytomegalovirus (CMV) resistance to ganciclovir occurs via mutations in the UL97 gene. CMV DNA, from vitreous and blood specimens and from culture isolates from 87 patients with acquired immunodeficiency syndrome and CMV retinitis who received a ganciclovir implant, was sequenced to identify the relationship between the UL97 DNA sequences in the eye and peripheral blood. There was 93.5% agreement between the UL97 gene sequences from paired vitreous specimens and blood specimens. Sequence analysis of vitreous specimens showed that 15% (13/87) of the patients had either a ganciclovir resistance-conferring mutation or a polymorphism in the CMV UL97 gene. Eleven of the 13 mutations or polymorphisms in the vitreous also were identified in blood. Although the number of mutations limits definitive interpretation, these data suggest that blood specimens may reflect the events occurring in the eyes of patients with CMV retinitis.

NOVEL MUTATIONS IN XLRS1 CAUSING RETINOSCHISIS, INCLUDING FIRST EVIDENCE OF PUTATIVE LEADER SEQUENCE CHANGE

Juvenile retinoschisis is an X‐linked recessive disease caused by mutations in the XLRS1 gene. We screened 31 new unrelated patients and families for XLRS1 mutations in addition to previously reported mutations for 60 of our families (Retinoschisis Consortium, Hum Mol Genet 1998;7:1185–1192). Twenty‐three different mutations including 12 novel ones were identified in 28 patients. Mutations identified in this study include 19 missense mutations, two nonsense mutations, one intragenic deletion, four microdeletions, one insertion, and one intronic sequence substitution that is likely to result in a splice site defect. Two novel mutations, c.38T→C (L13P) and c.667T→C (C223R), respectively, present the first genetic evidence for the functional significance of the putative leader peptide sequence and for the functional significance at the carboxyl terminal of the XLRS1 protein beyond the discoidin domain. Mutations in 25 of the families were localized to exons 4–6, emphasizing the critical functional significance of the discoidin domain of the XLRS1 protein. Hum Mutat 14:423–427, 1999.