David Munguia

Longitudinal Study of Cytomegalovirus Retinitis in Acquired Immune Deficiency Syndrome

The authors prospectively evaluated 67 consecutive patients with the acquired immune deficiency syndrome (AIDS) and cytomegalovirus (CMV) retinitis during a 33-month period to assess the clinical patterns of retinal infection, efficacy of treatment, long-term survival, and relationship of retinitis to immune function. Immediately sight-threatening retinitis presented in six patients (9%) with peripapillary disease; primary foveal infection was not observed. Eighty-seven percent of patients were treated with ganciclovir. Thirty-nine patients (58%) presented with unilateral disease and contralateral infection developed in 15% of those while on ganciclovir. Smoldering (incompletely responsive) retinitis was seen in 33% of the 21 patients whose retinitis progressed while receiving ganciclovir. Progression of treated retinitis was associated with a lower lymphocyte count (P = 0.04). Median survival after diagnosis of CMV retinitis was 8 months. This represents the largest reported prospective study of CMV retinitis and indicates that (1) CMV infrequently poses an immediate threat to vision on presentation, (2) response to therapy may be related to immune function, and (3) smoldering retinitis should be recognized as an important clinical entity associated with treatment failure.

Vision-threatening Complications of Surgery for Full-thickness Macular Holes

OBJECTIVE To study complications of vitrectomy surgery for full-thickness macular holes. DESIGN A multicentered, randomized, controlled clinical trial. PARTICIPANTS Community and university-based ophthalmology clinics. INTERVENTION Standardized macular hole surgery versus observation. MAIN OUTCOME MEASURES Assessment of anatomic and visual outcomes and determination of postoperative complications at 12 months after randomization. RESULTS Posterior segment complications were noted in 39 eyes (41%). The incidence of retinal pigment epithelium (RPE) alteration and retinal detachment (RD) were 33% and 11%, respectively. One RD due to a giant retinal tear resulted in a visual acuity of light perception. Other complications included a reopening of the macular hole in 2 eyes (2%), cystoid macular edema in 1 eye (1%), a choroidal neovascular membrane in 1 eye (1%) and endophthalmitis in 1 eye (1%). Eyes with complications had significantly worse visual acuity outcomes as determined by the Early Treatment Diabetic Retinopathy Study, Word Reading, and Potential Acuity Meter charts (P < 0.01 for all comparisons). Eyes with macular holes greater than 475 microns were more than twice as likely to have complications than eyes with holes less than 475 microns (odds ratio [OR] = 2.2, P = 0.07). Before surgery, the stage of the hole was related to postoperative RPE changes (P < 0.0001) and the occurrence of postoperative RD (P = 0.0002). Intraoperative trauma was related to the occurrence of these complications (P < 0.0001 for RPE changes, P = 0.02 for RDs). Epiretinal membrane removal was related to RPE changes (P = 0.02) but not RDs. CONCLUSIONS The RPE alterations and RDs are common after macular hole surgery and result in significantly reduced postoperative visual acuity. The RPE changes may be related to surgical trauma or light toxicity. Further efforts to reduce complications associated with macular hole surgery are indicated.

Risk Factors for Development of Rhegmatogenous Retinal Detachment in Patients with Cytomegalovirus Retinitis

We studied 259 patients to determine the time-dependent risk and risk factors for the development of retinal detachment in patients with cytomegalovirus retinitis. The six-month and one-year retinal detachment rates (by eye) were 11% and 24%, respectively. Increasing retinal surface involvement outside of the posterior pole and the presence of retinitis activity were found to be the two covariates that best predicted retinal detachment. Eyes with peripheral involvement greater than 25% had a fivefold risk for detachment, compared to eyes with 10% involvement. If there was retinitis activity and more than 25% peripheral (external to major vascular arcades) involvement, the risk increased to 24-fold. The presence of a fellow eye with retinal detachment was not an independent risk factor. These observations should help in the design of a prophylactic trial intended to prevent retinal detachment and should also help ophthalmologists counsel patients with cytomegalovirus retinitis.

Visual Dysfunction Without Retinitis in Patients With Acquired Immunodeficiency Syndrome

Patients with human immunodeficiency virus infection may have noninfectious and infectious retinopathies, as well as clinical symptoms consistent with optic nerve dysfunction. Noninfectious acquired immunodeficiency syndrome-related retinopathy is seen in most patients with AIDS. Morphologic studies have shown that the number of retrobulbar optic nerve fibers in patients with AIDS is decreased compared to the number of optic nerve fibers in normal control eyes. To determine whether these patients had a visual dysfunction consistent with damage to the macula and optic nerve, 78 subjects (156 eyes) were studied using color-vision and contrast-sensitivity testing. The Farnsworth-Munsell 100-Hue color-vision test was performed on all subjects and age-corrected color-vision scores for all groups were compared. A significant decrease in color discrimination was found in the patients with AIDS (P less than .001). Contrast-sensitivity testing disclosed a deficit of contrast threshold in patients with AIDS at four of five spatial frequencies and in patients with AIDS-related complex at three of the five spatial frequencies examined. This study demonstrated a functional visual deficit in eyes without retinitis consistent with dysfunction of the macula or optic nerve in patients with AIDS.

Phase I/II Study of Intravitreal Cidofovir for the Treatment of Cytomegalovirus Retinitis in Patients With the Acquired Immunodeficiency Syndrome

PURPOSE In this study we evaluated the safety and efficacy of the nucleoside phosphonate analogue intravitreal cidofovir to treat cytomegalovirus retinitis in humans. METHODS We conducted a phase I/II unmasked consecutive case series in a single-center institutional referral practice. Eligible patients with the acquired immunodeficiency syndrome had active cytomegalovirus retinitis in at least one eye, despite adequate intravenous therapy with ganciclovir or foscarnet, were intolerant to intravenous therapy, were noncompliant with intravenous therapy, or refused intravenous therapy. In a preliminary safety study (Group 1), ten eyes of nine patients received 14 injections of cidofovir while being treated concurrently with intravenous ganciclovir. In a dose-escalating efficacy study (Group 2), eight eyes of seven patients received 11 injections of cidofovir as sole treatment for cytomegalovirus retinitis. The primary outcome was time to retinitis progression. RESULTS In the Group 1 eyes receiving 20 micrograms of cidofovir, the median time to retinitis progression was between 49 and 92 days (mean, 78 days). In Group 2 eyes treated with 20 micrograms cidofovir, the median time to retinitis progression was 64 days (mean, 63 days). Hypotony occurred in the two eyes treated with a 100-micrograms dose of cidofovir and in one of three eyes receiving a 40-micrograms dose. No adverse effects resulted from the remaining 20 cidofovir injections. CONCLUSIONS Cidofovir (also known as HPMPC) appears to be safe and effective for the local treatment of cytomegalovirus retinitis, providing a long duration of antiviral effect. These preliminary results indicate that additional studies should be performed to investigate more fully this promising medication.

Surgical Repair of Rhegmatogenous Retinal Detachment in Immunosuppressed Patients with Clytomegalovirus Retinitis

The authors performed retinal reattachment surgery in 29 eyes of 24 patients with acquired immune deficiency syndrome virus with retinal detachment associated with cytomegalovirus (CMV) retinitis and documented the course of eight additional untreated eyes. Retinal detachment repair using vitrectomy, posterior hyaloid removal, and intraocular tamponade with silicone oil or SF-6 gas resulted in a total retinal reattachment rate of 76% and a macular attachment rate of 90% in one operation. The mean postoperative visual acuity (best corrected) was 20/60, but, in some patients, the visual acuity decreased because of progressive retinitis. Prophylactic laser photocoagulation of fellow eyes to surround CMV lesions did not appear to prevent retinal detachment. The mean postoperative survival was 37 weeks (range, 8 to 127 weeks). The surgical techniques used and pathophysiology of these retinal detachments are discussed.

Intravitreal cidofovir for the maintenance treatment of cytomegalovirus retinitis

PURPOSE To evaluate the efficacy and safety of multiple intravitreal cidofovir (HPMPC) injections given every 5 to 6 weeks for the maintenance treatment of cytomegalovirus (CMV) retinitis. METHODS A prospective consecutive case series of 53 eyes in 35 patients with acquired immune deficiency syndrome and CMV retinitis was treated with maintenance intravitreal injections of cidofovir (20 micrograms) at one referral center between April 1994 and September 1995. Twenty-four eyes received intravitreal cidofovir as their initial treatment for CMV retinitis (group A), and 29 eyes previously had received systemic therapy (group B). None of the patients in either group received systemic anti-CMV therapy at any time during the study period. Progression of retinitis was the primary end point. RESULTS All eyes with active retinitis healed in response to treatment. None of the 24 eyes in group A demonstrated any progression during the study period. Four (14%) of the 29 eyes in group B had one episode each of retinitis progression (mean follow-up, 15 weeks; range, 0-58 weeks). In 1 (1.9%) of the 53 eyes, a retinal detachment developed. A mild iritis was observed after 14% of injections, which were prophylaxed with oral probenecid. Irreversible visually significant hypotony developed in two eyes (3.8%). CONCLUSION Treatment and subsequent maintenance therapy of CMV retinitis with 20 micrograms intravitreally injected cidofovir, given at 5- to 6-week intervals, is highly effective, with only rare episodes of re-activation and progression.

Anterior nongranulomatous uveitis after intravitreal HPMPC (cidofovir) for the treatment of cytomegalovirus retinitis. Analysis and prevention

BACKGROUND AND OBJECTIVE The authors characterize and analyze the incidence of a previously reported mild anterior nongranulomatous uveitis associated with intravitreal injections of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC), also termed cidofovir (Vistide, Gilead Sciences, Foster City, CA). This is an acyclic nucleoside phosphonate analogue with a potent anticytomegalovirus effect. The authors also analyzed the effects of probenecid therapy, as well as prophylaxis with probenecid plus topical corticosteroids and cycloplegics on the course and outcome of the uveitis. METHODS Prospective case series from a tertiary referral center, which included 46 consecutive patients with acquired immune deficiency syndrome (AIDS) and cytomegalovirus (CMV) retinitis. There was a total of 130 injections in 69 eyes treated with 20 micrograms of intravitreal HPMPC. Forty-one patients (119 injections) received oral probenecid, 5 patients (11 injections) did not, and 21 patients (53 injections) received topical corticosteroids and cycloplegics as an adjuvant to probenecid in the prophylaxis of iritis. RESULTS Mild to moderate nongranulomatous iritis was seen in 26% of patients after their first injection (n = 12). Patients receiving probenecid prophylaxis after first injection had a significantly lower frequency of iritis versus patients who did not receive probenecid at the time of first injection (P = 0.0089). In contrast, treatment with topical corticosteroid and cycloplegics after injection did not statistically significantly affect the frequency of iritis in patients (P = 0.44). The development of iritis after a second injection of HPMPC was more likely if it had occurred after the initial injection (P = 0.015; Fishers exact test). All cases of iritis were treated with topical corticosteroids and cycloplegics, and there was no permanent impairment of vision secondary to iritis after HPMPC injection in any eyes. CONCLUSIONS Anterior uveitis was seen in 26% of patients after first-time HPMPC injection. Concomitant use of probenecid appears to decrease the frequency of the iritis from 71% to 18% in patients with AIDS and CMV retinitis after the first intravitreal injection of HPMPC. Topical corticosteroid administration after injection (before iritis) was ineffective in preventing iritis treatment with topical corticosteroids and cycloplegics resulted in resolution of all iritis cases.

Intraocular Pressure and Aqueous Humor Dynamics in Patients With AIDS Treated With Intravitreal Cidofovir (HPMPC) for Cytomegalovirus Retinitis

PURPOSE To evaluate the decrease in intraocular pressure associated with cidofovir (1-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]cytosine dihydrate; HPMPC) intravitreal injections. METHODS We followed up 97 eyes of 63 patients with acquired immunodeficiency syndrome (AIDS) who had cytomegalovirus retinitis and had been treated with up to nine 20-microgram intravitreal cidofovir injections. Measurements were taken at baseline, between 2 and 3 weeks, and at 5 to 6 weeks after injections. Anterior chamber fluorophotometry was studied in seven eyes (four patients) before and after injections. Ciliary body anatomy was evaluated in two patients. RESULTS After the first intravitreal injection, mean intraocular pressure was 2.2 mm Hg lower than that at baseline at 2 to 3 weeks (P < .001) and 1.3 mm Hg lower than at baseline at 5 to 6 weeks (P = .0025). After the second injection, mean pressure was 2.6 mm Hg lower at 2 to 3 weeks (P = .0013) and 1.5 mm Hg lower at 5 to 6 weeks (P = .043). After subsequent injections, however, the decrease was less than 1 mm Hg, suggesting that a plateau had been reached. Pressure in eyes with anterior uveitis after the first injection was lower than that in eyes without anterior uveitis (P < .0001). The mean rate of aqueous flow decreased from 2.8 to 1.9 microliters per minute 2 to 4 weeks after injection (P < .015). Ultrasound biomicroscopy disclosed that severe hypotony after cidofovir injections is associated with ciliary body atrophy. CONCLUSIONS Intraocular pressure decreases after the initial 20-microgram cidofovir intravitreal injection. However, eyes stabilize (pressure plateaus) after three injections. Effects on the ciliary body are the main cause of the decrease after cidofovir injections.

Evaluation of Retinal Toxicity and Efficacy of Anti-Cytomegalovirus and Anti-Herpes Simplex Virus Antiviral Phosphorothioate Oligonucleotides ISIS 2922 and ISIS 4015

Retinal toxicity of ISIS 2922 and ISIS 4015, phosphorothioate oligonucleotides complementary to human cytomegalovirus (CMV) and herpes simplex virus (HSV) RNA, were evaluated. The intravitreal concentration of ISIS 2922 found not to cause permanent toxic changes in the rabbit retina was 10 microM and in the pig retina, 5 microM. The 3 microM concentration was associated with a transient inflammatory response, and 1 microM caused no retinal toxicity or inflammation. ISIS 4015 showed very mild toxicity with no permanent retinal changes and very mild inflammation at doses of 10 microM; this dose was effective in ameliorating or preventing HSV-1 retinitis when injected 1 day and 1 week prior to virus inoculation. These oligonucleotides have a low intraocular therapeutic index. Attempts to improve the therapeutic index of these compounds are indicated. Only a clinical trial can determine the toxicity profile of ISIS 2922 for the treatment of CMV retinitis.