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To determine classification criteria for acute retinal necrosis (ARN).Machine learning of cases with ARN and 4 other infectious posterior uveitides / panuveitides.Cases of infectious posterior uveitides / panuveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the infectious posterior uveitides / panuveitides. The resulting criteria were evaluated on the validation set.Eight hundred three cases of infectious posterior uveitides / panuveitides, including 186 cases of ARN, were evaluated by machine learning. Key criteria for ARN included (1) peripheral necrotizing retinitis and either (2) polymerase chain reaction assay of an intraocular fluid specimen positive for either herpes simplex virus or varicella zoster virus or (3) a characteristic clinical appearance with circumferential or confluent retinitis, retinal vascular sheathing and/or occlusion, and more than minimal vitritis. Overall accuracy for infectious posterior uveitides / panuveitides was 92.1% in the training set and 93.3% (95% confidence interval 88.2, 96.3) in the validation set. The misclassification rates for ARN were 15% in the training set and 11.5% in the validation set.The criteria for ARN had a reasonably low misclassification rate and seemed to perform sufficiently well for use in clinical and translational research.

Purpose To identify determinants of adverse outcomes in acute retinal necrosis (ARN), presenting characteristics and incidence rates of vision loss and ocular complications in a cohort of polymerase chain reaction (PCR)-positive eyes were analyzed. Design Retrospective observational cohort study. Methods Forty-one eyes of 36 patients with clinically diagnosed ARN, PCR-positive for herpes simplex virus or varicella zoster virus and evaluated between January 2002 and June 2013, were included. Main outcome measures included incidence rates of vision loss and retinal detachment (RD). Results Presenting visual acuity was generally poor (20/50 to >20/200 in 27%; 20/200 or worse in 56%). The incidence rate of ≤20/200 was 0.66/eye-year (EY), (95% confidence interval [CI], 0.32/EY to 1.22/EY); the rate of light perception or no light perception vision was 0.07/EY (95% CI, 0.02/EY to 0.16/EY). During follow-up, 59% of eyes developed at least 1 RD (rate = 0.40/EY, 95% CI, 0.19/EY to 0.58/EY). Eyes with retinitis involving ≥25% of the retina at presentation detached at nearly 12 times the rate, as compared to those with P = .001). Development of an RD was the greatest determinant of adverse visual outcomes, with 4% of eyes, that had experienced at least 1 RD, achieving a best-corrected visual acuity of ≥20/40 compared to 53% of eyes that never detached ( P = .0003). Conclusions Poor outcomes in ARN were common in this cohort. RD confers the greatest risk of incident vision loss, and once 25% or more of the retina is involved the risk of RD and visual loss increases significantly.

Purpose To evaluate the rates of new-onset cytomegalovirus (CMV) retinitis and worsening existing CMV retinitis in patients with AIDS after initiating combination antiretroviral therapy (cART) and the role of an immune recovery inflammatory syndrome (IRIS). Design Cohort study. Methods Immune recovery was defined as an increase in CD4 + T cells to ≥100 cells/μL; rates of new-onset CMV retinitis and of worsening of CMV retinitis (either increasing border activity or retinitis progression) were compared between those with and without immune recovery. Results Among patients without CMV retinitis, 1 of 75 patients with immune recovery developed CMV retinitis in the first 6 months after initiating cART vs 1 of 31 without immune recovery ( P = .14). Among patients with CMV retinitis, the rates of retinitis progression and increasing retinitis border activity among patients during the first 6 months after initiating cART in those with immune recovery were 0.11 per person-year (PY; 95% confidence interval [CI] 0–0.62) and 0.11 per PY (95% CI 0–0.62), respectively, vs 0.67 per PY (95% CI 0.22–1.56) and 0.40 per PY (95% CI 0.08–1.17), respectively, for those without immune recovery ( P = .11 and .47). Conclusions Among persons with AIDS who experience immune recovery, there was neither an increased rate of new-onset CMV retinitis nor worsening of existing CMV retinitis in the first 6 months after initiating cART vs those without immune recovery. These data are consistent with the known 3- to 6-month lag in recovery of specific immunity to CMV after initiating cART and suggest that "immune recovery retinitis," a proposed immune recovery inflammatory syndrome phenomenon, is rare.

To evaluate clinical features and long-term visual outcome of cytomegalovirus (CMV) retinitis in patients without human immunodeficiency virus (HIV) infection, and to determine factors that predict visual outcome.Retrospective cohort study.Consecutive patients with CMV retinitis without HIV infection were reviewed. Main outcome measures included clinical features, proportion of eyes with 6-month and final visual acuity (VA)20/70 and20/400, and odds ratios of factors associated with poor visual outcome.A total of 20 eyes from 13 patients were included with a median follow-up time of 17 months. All had at least 6 months of follow-up except 1 patient who died from sepsis at 1 month. At presentation, 50% of eyes had VA20/70 and 25% had VA20/400. Zone 1 involvement occurred in 55% and vitreous haze ≥grade 2+ occurred in 25%. Recurrence occurred in 33.3% at a mean time of 6.4 ± 3.3 weeks after discontinuation of anti-CMV therapy. The retinal detachment rate was 21.7% per eye-year and mortality rate was 11.7% per person-year. At final visit, 60% had VA20/70 and 35% had VA20/400. Macular involvement was significantly associated with poor final VA20/400 (odds ratio = 25.00, P = .016).CMV retinitis without HIV infection was often aggressive at presentation. Significant intraocular inflammation was not uncommon. The long-term visual outcome was poor, especially in those with macular involvement.

Purpose To describe an approach to diagnosing the uveitides, a collection of about 30 separate diseases characterized by intraocular inflammation. Design Perspective. Methods Integration of clinical approach with a more formal, informatics-derived approach to characterization and a Bayesian approach to laboratory testing. Results The patient's uveitis is characterized along several dimensions: course, laterality, anatomic location of the inflammation, morphology, presence of active infection, and the host (age, presence of a systemic disease). Posterior uveitis can be characterized further by whether it is primarily a retinitis, choroiditis, or retinal vasculitis; by whether it is paucifocal or multifocal; and by the morphology of the lesions. This characterization narrows the differential diagnosis to 1 or, at most, a few diseases. Laboratory screening (ie, testing all patients) should be reserved for those diseases that can present as any type of uveitis, whereas targeted testing (ie, testing a subset with specific features) is used selectively. Laboratory testing should be used to identify an infection (which will alter therapy) or a systemic disease that will affect the patient's health. A uveitis that is not one of the established diagnoses is designated as “undifferentiated” with the course, laterality, and anatomic location (eg, undifferentiated bilateral chronic anterior uveitis). We avoid the term “idiopathic” uveitis as most identified noninfectious uveitic diseases are idiopathic, and most systemic diseases associated with uveitis also are idiopathic (eg, juvenile idiopathic arthritis). Conclusion This approach should lead to the correct diagnosis of the specific uveitic disease in the large majority of cases without overuse of laboratory testing.

Purpose The incidence of cytomegalovirus (CMV) retinitis in the pediatric allogeneic hematopoietic stem cell transplant (HSCT) population is unknown. We report a cluster of 5 pediatric patients with CMV retinitis diagnosed in a 12-month period and compare this to the rate of CMV viremia and retinitis in the 4 years prior. Presented is the ophthalmic screening protocol developed in response to this experience. Design Retrospective cross-sectional study. Methods A retrospective chart review was performed on patients at Children's Hospital of Colorado (CHCO) who received allogeneic HSCT between January 2010 and December 2014. Fisher exact test was used to compare the proportion of CMV viremia and CMV retinitis in patients transplanted between January 2010 and December 2013 with those transplanted in 2014. Results A total of 101 patients underwent allogeneic HSCT from January 2010 to December 2013; 32 (32%) tested positive for CMV viremia. No cases of CMV retinitis were identified. From January 2014 to December 2014, 28 patients underwent allogeneic HSCT; 13 patients (46%) had CMV viremia, not a statistically significant increase ( P = .18). There were 5 cases of CMV retinitis diagnosed in those transplanted in 2014, a statistically significant increase compared with those transplanted in 2010-2013 ( P = .0004). A multidisciplinary team was formed to review the literature and an ophthalmic screening protocol was developed. Conclusion Our recent cluster of CMV retinitis in pediatric allogeneic HSCT patients may suggest a rise in incidence of CMV retinitis. We propose an ophthalmic screening protocol to diagnose retinitis in pediatric HSCT patients in the early, often asymptomatic stage.

Purpose To assess the prevalence of proliferative vitreoretinopathy (PVR) and prognosis of cytomegalovirus (CMV) retinitis–related retinal detachment (RD) surgery in the era of highly active antiretroviral therapy (HAART). Design Retrospective interventional cohort study. Methods Thirty-five human immunodeficiency virus (HIV)-positive patients with CMV retinitis–related RD who underwent surgical repair were assessed for PVR, CD4-positive T cell counts, and use of HAART. Main outcome measures included anatomic and functional outcomes of RD surgery as well as the presence of PVR and CD4-positive T cell counts. Results PVR was present in 10 of 35 patients (29%) at the time of the first surgery. The presence of PVR was associated with worse preoperative and postoperative visual acuity ( P = .017 and P = .009, respectively), with the CD4-positive T cell counts above 200 cells/μL ( P = .054), and with a longer interval between the diagnosis of RD and surgery ( P = .025). The odds ratio for development of PVR in patients with CD4-positive T cells above 200 cells/μL was 11.3 (95% confidence interval 1.01-125). PVR was not associated with age, gender, or duration of HIV infection. Anatomic reattachment was obtained in 31 patients (89%), though the functional outcomes were limited. The central location of CMV retinitis was associated with postoperative visual acuity (VA) of less than 0.1 ( P = .000). Postoperative logMAR VA was associated with preoperative logMAR VA ( P P = .009). Conclusion PVR was present in 29% of CMV retinitis–related RD and was associated with higher CD4-positive T cell counts and longer interval between the diagnosis of RD and surgery.

Purpose To evaluate the risk and risk factors for developing cytomegalovirus (CMV) retinitis in previously uninvolved second eyes among patients with unilateral CMV retinitis. Design Cohort study. Methods settings : Single-center academic AIDS ophthalmology practice. patient population : Three hundred seventy-six consecutive patients with AIDS and unilateral CMV retinitis were followed from the time of CMV retinitis diagnosis for the development of second-eye retinitis. experimental procedures : Demographic and clinical characteristics were noted at baseline. Use of highly active antiretroviral therapy (HAART) and immune recovery in response to HAART were noted prospectively. main outcome measure : Development of CMV retinitis in a previously uninvolved eye. Results Ninety-one percent of subjects received systemic anti-CMV treatment. Second-eye retinitis occurred in 26.1%/person-year (19.6% within the first 6 months), less than half the rate previously reported in untreated groups. Initial CD4+ T cell count >12 cells/μl, use of HAART, and initial posterior pole involvement were associated with 64%, 46%, and 41% reductions in incidence vis-a-vis comparison groups. Benefit from HAART was limited to that subset who developed immune recovery of a degree expected to restore innate control of CMV (a rise in the CD4+ T cell count by >50 cells/μl to a level >100 cells/μl). Conclusions The risk of second-eye retiniti is substantial in patients with unilateral CMV retinitis but appears to be reduced by anti-CMV therapy and by HAART-induced immune recovery. Patients are at highest risk when CD4+ T cell counts are very low and in the months immediately after CMV retinitis diagnosis.

Purpose To compare grading of cytomegalovirus retinitis progression by two different fundus photograph reading centers (FPRCs). Design Patients with AIDS followed in an ophthalmology service were enrolled in a prospective epidemiologic study of the prevalence and incidence of resistant cytomegalovirus in vitro. Methods We compared masked replicate gradings by two different FPRCs of monthly fundus photographs for retinitis progression (onset of a separate new lesion or expansion of an existing lesion by ≥one-half disk diameter). Results For 77 patients, Kaplan-Meier plots of progression over time were similar between FPRCs (median time to progression, 65 vs 69 days). Agreement between FPRCs was 51% (kappa [κ] = .37, “fair”) on exact visit of progression (28 patients) or on absence of progression through follow-up (11 patients) and 62% (κ = .38) on progression visit ± 1 month. Eight of 12 patients with progression graded as more than 1 month apart were only 2 months apart. Considering each monthly visit as a choice point, overall agreement on progression was 78% (κ = .55, “moderate”). Baseline evaluation of retinitis showed 95% agreement on presence/absence and a concordance correlation coefficient of .75 for extent in combined zones 1 and 2. Rates of retinal loss over follow-up were estimated as 2.8%/month vs 2.0%/month (P = .015). Conclusions By adopting similar protocols and procedures, different FPRCs can achieve good agreement on presence and extent of cytomegalovirus retinitis. Further efforts to harmonize evaluation through ongoing comparison of gradings would likely improve agreement on retinitis progression.

Purpose To describe the demographic and clinical features, complications, treatment, and visual results in patients with childhood-onset Behcet uveitis. Design Observational case series. Methods A retrospective study was made of 36 consecutive patients with Behcet disease seen at the Uveitis Service, Department of Ophthalmology, Istanbul Faculty of Medicine, Istanbul University, between January 1975 and January 2002. Inclusion criteria were fulfillment of the classification criteria of the International Study Group for Behcet Disease and onset of uveitis at 16 years of age or younger. The medical records of 36 patients with childhood-onset Behcet uveitis were reviewed. The main outcome measures were sex, age at onset of uveitis, the initial symptom of Behcet disease, clinical ocular features, ocular complications, systemic treatment, complications of treatment, and final visual acuity. Results Twenty-five patients were male, 11 were female. Mean age at onset of uveitis was 13.6 years. The initial symptom was oral ulcer in 63.8% of the patients. The majority of patients (83.3%) had bilateral involvement. Panuveitis was the most common form (86.2%). Retinal vasculitis and retinitis were the most common ocular findings seen in 83.3% and 68.2% of the involved eyes, respectively. Cataract, maculopathy, and optic atrophy were the most common complications seen in 46.9%, 45.4%, and 39.4% of the involved eyes, respectively. Immunosuppressive therapy was administered to 75% of the patients. Response to treatment was variable. The most common complications of systemic treatment were associated with corticosteroid therapy. Final visual acuity was worse than 0.1 in 22.7% of the involved eyes. Conclusions Childhood-onset Behcet uveitis was more common among males. Bilateral panuveitis with retinal vasculitis and retinitis was the most common form of ocular involvement, similar to the adult patient. The treatment is challenging, as the use oral corticosteroids is associated with significant complications and the response to conventional immunosuppressive therapy is variable.

To determine the incidence of and risk factors for cataract and to describe the visual outcomes of cataract surgery in eyes with cytomegalovirus-related retinal detachments repaired with silicone oil.Retrospective cohort study.A prospectively generated database of all patients with cytomegalovirus retinitis examined at a single tertiary care institution was used to identify all cases of retinal detachment between October 1983 and August 1997. Data on retinal detachment repair, development of cataract, and outcomes of cataract surgery were obtained retrospectively.Among 904 eyes of 587 immune-compromised patients diagnosed with cytomegalovirus retinitis, 198 eyes of 155 patients developed retinal detachment. Among these, 106 eyes of 90 patients underwent retinal detachment repair with silicone oil. The Kaplan-Meier estimated median time to cataract was 1.8 months after surgery with silicone oil. The adjusted relative risk of cataract in eyes that underwent retinal detachment repair with silicone oil compared with eyes that did not was 6.74 (P.0001). Eight of the eyes that developed cataract underwent uncomplicated cataract surgery by phacoemulsification and posterior chamber intraocular lens implantation. Among these, six eyes experiencedor=2 lines of improvement in visual acuity. All developed posterior capsule opacification a median of 7 days after cataract surgery. Four of five eyes that that underwent neodymium:yttrium-aluminum-garnet laser capsulotomy experiencedor=2 lines improvement in visual acuity.There is a high incidence of cataract after surgery with silicone oil tamponade for cytomegalovirus-related retinal detachment. Posterior capsule opacification occurs rapidly after cataract surgery in these patients.

Purpose To determine the association between anticytomegalovirus (CMV) maintenance therapy after immune recovery and immune recovery uveitis in acquired immunodeficiency syndrome (AIDS) patients on highly active antiretroviral therapy (HAART). Design Observational cohort study. Methods Data were obtained on AIDS patients with CMV retinitis followed up at the AIDS Ocular Research Unit of University of California San Diego from November 1995 to October 1999. Immune recovery was defined as CD4 count greater than 50 cells/μl for more than 3 months. Patients with immune recovery uveitis presented with vitritis, cystoid macular edema, or epiretinal membrane. Statistical analyses were conducted to determine the risk of continued use of anti-CMV therapy after immune recovery and the relationship of developing immune recovery uveitis with the type of anti-CMV therapy. Results Forty-three patients (64 eyes) had healed CMV retinitis and had achieved immune recovery. Thirty-one patients (48 eyes) received anti-CMV therapy after immune recovery, and 20 patients (29 eyes) developed immune recovery uveitis. Per-eye analyses revealed a 3.8-fold increase in the odds of developing immune recovery uveitis with anti-CMV therapy compared with no treatment ( P = .02). If treated with cidofovir the odds were 3.3 greater than if treated with an alternative regimen ( P = .04), 4.1 greater if treated intravenously ( P = .01), and 5.2 greater than if not treated ( P = .004). If not treated with cidofovir, a nonsignificant increase in the risk (2.4) of immune recovery uveitis was found ( P = .15). Neither the potency nor the use of implants for noncidofovir treatment was related to the risk of recovery uveitis ( P > .62). Conclusions The use of cidofovir is a primary risk factor in the subsequent development of immune recovery uveitis. Ongoing treatment of healed CMV retinitis after immune recovery does not appear to protect against the development of immune recovery uveitis.

Purpose To describe the incidence, clinical course, and outcomes of endophthalmitis in patients treated with a ganciclovir implant. Design Retrospective review of cases identified from a clinical survey. Methods Cases of endophthalmitis were identified from a survey of 30 clinical practices known to treat a large number of patients with cytomegalovirus retinitis. Results Twenty-four cases of endophthalmitis were identified from 5,185 implants performed (incidence, 0.46%). Final visual acuity ranged from 20/20 to no light perception, with 50% (12/24) seeing light perception or worse. Vitreous cultures revealed Staphylococcus epidermidis in 29% (7/24) of patients, whereas other gram-positive organisms were responsible in 42% (10/24) of cases. In the remaining 29% (7/24) of cases, no organisms were cultured; these cases exhibited a better visual outcome ( P = .007). Six of the eight late-onset cases were associated with wound problems such as implant strut or suture exposure. There was no significant relationship between implant removal and final visual acuity. Conclusions Endophthalmitis is an infrequent but potentially devastating complication associated with placement of a ganciclovir implant.

PURPOSE: The accumulation of numerous or confluent drusen, especially in the macula, is a significant risk factor for the development of age-related macular degeneration (AMD). Identifying the origin and molecular composition of these deposits, therefore, has been an important, yet elusive, objective for many decades. Recently, a more complete profile of the molecular composition of drusen has emerged. DESIGN: In this focused review, we discuss these new findings and their implications for the pathogenic events that give rise to drusen and AMD. METHODS: Tissue specimens from one or both eyes of more than 400 human donors were examined by light, confocal or electron microscopy, in conjunction with antibodies to specific drusen-associated proteins, to help characterize the transitional events in drusen biogenesis. Quantification of messenger RNA from the retinal pigment epithelium (RPE)/choroid of donor eyes was used to determine if local ocular sources for drusen-associated molecules exist. RESULTS: The results indicate that cellular remnants and debris derived from degenerate RPE cells become sequestered between the RPE basal lamina and Bruch’s membrane. We propose that this cellular debris constitutes a chronic inflammatory stimulus, and a potential “nucleation” site for drusen formation. The entrapped cellular debris then becomes the target of encapsulation by a variety of inflammatory mediators, some of which are contributed by the RPE and, perhaps, other local cell types; and some of which are extravasated from the choroidal circulation. CONCLUSIONS: The results support a role for local inflammation in drusen biogenesis, and suggest that it is analogous to the process that occurs in other age-related diseases, such as Alzheimer’s disease and atherosclerosis, where accumulation of extracellular plaques and deposits elicits a local chronic inflammatory response that exacerbates the effects of primary pathogenic stimuli.

PURPOSE: To determine the value of aqueous humor analysis for confirming the diagnosis of ocular toxoplasmosis in patients who present with atypical clinical features and to relate the results of local antibody production and polymerase chain reaction (PCR) with the extent of active retinitis and the immune status of the patient. DESIGN: Retrospective case series. METHODS: Sixty-seven consecutive patients with retinitis or retinochoroiditis that was clinically consistent with atypical ocular toxoplasmosis underwent diagnostic anterior chamber paracentesis and serological studies. The aqueous humor was analyzed both by PCR to detect Toxoplasma gondii B1 gene and by the Goldman-Witmer coefficient to determine levels of local anti- T. gondii antibody production. RESULTS: In nine of the 67 cases, PCR was positive for T. gondii ; seven of these were negative for local antibody production. All nine patients had illnesses associated with immunosuppression or advanced old age and all had active retinitis with a mean area of 11.5 disk areas (DA). Twenty-five of the remaining 58 cases were positive for local antibody production. These 25 had a mean area of active retinitis measuring 2.6 DA, and 24 of these patients were immunocompetent. All 34 cases with laboratory evidence of ocular toxoplasmosis diagnosed by either method responded to anti- T. gondii agents. The remaining 33 were negative for T. gondii infection by these two methods; some had laboratory evidence of other infections. CONCLUSIONS: Although in the present study, the sensitivity and specificity of the aqueous humor PCR and Goldman-Witmer coefficient could not be ascertained in the laboratory diagnosis of toxoplasmic retinochoroiditis, the PCR method appears to confirm the diagnosis in immunocompromised individuals with large atypical foci of retinitis. Conversely, determination of local antibody production may be appropriate for proper diagnosis in immunocompetent individuals presenting with small foci of retinitis.

C YTOMEGALOVIRUS (CMV) RETINITIS IS AMONG THE most common opportunistic infections in patients with the acquired immunodeficiency syndrome (AIDS).1 Before the availability of highly active antiretroviral therapy (HAART), CMV retinitis was estimated to affect 30% of patients with AIDS at some time during the course of their disease.2 Although HAART has been reported to result in 55%–95% decreases in the number of new cases of CMV retinitis,3–5 there appears to have been a leveling off of this decline with the incidence of CMV retinitis at 25% to 30% of its peak incidence.3,6 Although the incidence has declined, as survival among patients with AIDS improves, there is an increasing prevalent population of patients alive with opportunistic infections, such as CMV retinitis. Before the advent of HAART

To describe the characteristics of patients with AIDS and cytomegalovirus retinitis in the era of highly active antiretroviral therapy (HAART).Prospective cohort study. Baseline (enrollment) data were compared between patients with newly diagnosed cytomegalovirus retinitis (incident cases) and those with previously diagnosed cytomegalovirus retinitis (prevalent cases).As of December 31, 2000, 45 incident and 200 prevalent cases had been enrolled. Among prevalent cases, the median time from cytomegalovirus retinitis diagnosis was 2.9 years. Incident cases were more likely than prevalent cases to be women (35.4% vs 15.3%, P =.001), African American (45.4% vs 20.4%, P =.002), and uninsured (29.6% vs 7.6%, P.001). Incident cases were less likely than prevalent cases to be on HAART (51.2% vs 77.6%, P =.001) and to have had an immunologic response to HAART (increase in CD4(+) T-cell count to100 cells/microl) (12.2% vs 57.5%, P.001). The median CD4(+) T-cell count at enrollment among incident cases was 17 cells/microl and among prevalent cases was 159 cells/microl (P.001). Immune recovery uveitis had been diagnosed in 15.5% of the prevalent cases. Sixty-three percent of prevalent cases were not on anticytomegalovirus therapy.There is a population of patients with previously diagnosed and longstanding cytomegalovirus retinitis who have experienced immune recovery as a consequence of HAART and are no longer receiving anticytomegalovirus therapy. There are demographic differences between incident and prevalent cases that may reflect the evolution of the AIDS epidemic and differences in utilization of health care services.

PURPOSE: Cytomegalovirus retinitis is the most common intraocular infection in patients with acquired immunodeficiency syndrome (AIDS). With prolonged suppressive anticytomegalovirus maintenance therapy, resistance occurs in over 25% of patients. We evaluated longitudinal changes in the cytomegalovirus genotype in patients with cytomegalovirus retinitis who developed ganciclovir resistance that was demonstrated in either the blood or urine. METHODS: Patients with AIDS and previously untreated cytomegalovirus retinitis were followed prospectively for the occurrence of resistance while on treatment. Blood and urine specimens were obtained periodically for cytomegalovirus culture according to a predetermined schedule. Positive isolates were tested for phenotypic susceptibility and for mutations in the UL97 and UL54 genes. RESULTS: A mutation conferring resistance to ganciclovir in either the UL97 or UL54 gene was detected in 18 patients. In general, patients with a genotypically resistant virus developed increasing phenotypic resistance over time. There was a suggestion that unless therapy was changed, UL97 mutations tended to persist. In seven of eight patients, the mutations identified in isolates from the blood and urine were identical. In selected patients, there was a suggestion that a mixed population of cytomegalovirus might be present. Progression of the retinitis in an involved eye (15 of 18), contralateral eye retinitis (10 of 11), and extraocular cytomegalovirus disease (5 of 18) occurred commonly among patients with resistant virus. CONCLUSION: Resistance-conferring mutations in the cytomegalovirus genome emerge and may persist when the selective pressure for resistance is maintained. Some patients appear to harbor complex subpopulations of virus with different mutations and different levels of phenotypic resistance. Changes in therapy may result in a shift in virus population and changes in the cytomegalovirus genotype identified.

PURPOSE: To describe clinical and/or histopathologic features that could help distinguish endogenous Candida endophthalmitis from endogenous Aspergillus intraocular inflammation and to provide histologic documentation of intraocular spread of these agents. METHODS: Twenty-five patients who underwent enucleation, 13 with morphologic features and/or positive culture for Aspergillus and 12 with histologic evidence and/or positive culture for Candida were included in the study. Clinical information was sought from each case. Patients with AIDS were excluded. The enucleated globes were analyzed to detect location of the fungi, vascular invasion by these agents, and inflammatory response. RESULTS: Candida endophthalmitis was noted in patients with a history of gastrointestinal surgery, hyperalimentation, or diabetes mellitus, whereas aspergillosis was present in patients who had undergone organ transplantation or cardiac surgery. Histopathologically, the vitreous was the primary focus of infection for Candida, whereas subretinal/subretinal pigment epithelium infection was noted in eyes with aspergillosis. Retinal and choroidal vessel wall invasion by fungal elements was noted in cases of aspergillosis but not in cases with candidiasis. Both infectious agents induced suppurative nongranulomatous inflammation. CONCLUSIONS: Unlike Candida endophthalmitis, aspergillosis clinically presents with extensive areas of deep retinitis/choroiditis, and vitreous biopsy may not yield positive results. Histopathologically, it appears that Aspergillus grows preferentially along subretinal pigment epithelium and subretinal space. This intraocular infection is usually associated with a high rate of mortality caused by cerebral and cardiac complications.

PURPOSE: To compare the regimen of the ganciclovir implant plus oral ganciclovir to one of intravenous cidofovir for the treatment of cytomegalovirus retinitis. METHODS: Sixty-one patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis were randomized either to the regimen of the ganciclovir implant plus oral ganciclovir, 1 gm three times daily, or intravenous cidofovir, 5 mg/kg once weekly for two doses, followed by 5 mg/kg every other week. RESULTS: Mortality was similar between the two treatment groups. Mortality rates were 0.41 per person-year in patients assigned to the ganciclovir regimen and 0.49 per person-year in patients assigned to cidofovir (P = .59). Ocular outcomes were similar between the two groups. Retinitis progression occurred at a rate of 0.67 per person-year in the ganciclovir group and 0.71 per person-year in the cidofovir group (P = .72). A loss of visual acuity of 15 letters or more occurred at a rate of 0.78 per person-year in the ganciclovir group and 0.47 per person-year in the cidofovir group (P = .28). The rate of loss of visual field was 7 degrees per month in the ganciclovir group and 2 degrees per month in the cidofovir group (P = .048). Vitreous hemorrhage was more common in the ganciclovir implant group (0.13 per person-year) than in the cidofovir group (no cases, P = .014), whereas uveitis appeared to be more common in the cidofovir group (0.35 per person-year) than in the ganciclovir group (0.09 per person-year, P = .066). Nephrotoxicity (serum creatinine 1.6 mg/dL or greater) occurred at a rate of 0.18 per person-year in the ganciclovir group and 0.48 per person-year in the cidofovir group (P = .10). CONCLUSIONS: Although the small number of patients in this study limits definitive interpretation, these data suggest that in the era of highly active antiretroviral therapy, the regimens of the ganciclovir implant plus oral ganciclovir and of intravenous cidofovir are similar for controlling cytomegalovirus retinitis and preventing visual loss but have different side effects.

PURPOSE: To evaluate the role of first operation anatomic success compared with success after reoperation and preoperative characteristics in achieving ambulatory vision (≥4/200) and good vision (≥20/100) after repair of complex retinal detachment with vitrectomy and silicone oil tamponade. METHODS: A prospective, observational, multicenter study of patients who underwent vitrectomy with silicone oil for retinal detachments associated with cytomegalovirus necrotizing retinitis or a non–cytomegalovirus necrotizing retinitis etiology, including proliferative diabetic retinopathy, giant retinal tear, proliferative vitreoretinopathy, and ocular trauma. RESULTS: A higher rate of ambulatory vision was achieved in the first operation anatomic success cases, compared with the reoperation cases, for eyes with cytomegalovirus necrotizing retinitis (72% vs 50%, P < 0.01) and eyes without cytomegalovirus necrotizing retinitis (51% vs 38%, P = 0.04). For eyes with cytomegalovirus necrotizing retinitis, preoperative ambulatory vision (RR = 2.3, P < 0.0001) and reoperation (RR = 0.4, P = 0.05) were independent predictors of postoperative ambulatory vision. For eyes without cytomegalovirus necrotizing retinitis, preoperative ambulatory vision (RR = 4.0, p < 0.0001) and retinal detachment etiology (P = 0.02) were prognostic factors. Compared to eyes with trauma, eyes with giant retinal tear, proliferative vitreoretinopathy and proliferative diabetic retinopathy were 2.8 (P < 0.003), 2.2 (P = 0.01) and 1.6 (P = 0.17) times as likely to achieve postoperative ambulatory vision, respectively. Within the giant retinal tear group, a higher rate of ambulatory vision was achieved in the first operation anatomic success cases compared with the reoperation cases (66% vs 31%, P = 0.03). Although not statistically significant, similar outcomes occurred in the proliferative diabetic retinopathy (48% vs 25%) and proliferative vitreoretinopathy groups (54% vs 45%). Similar prognostic relationships were found for good visual acuity outcomes. CONCLUSIONS: First operation anatomic success, preoperative visual acuity, and giant retinal tear or proliferative vitreoretinopathy as the retinal detachment etiology are important factors that predict visual outcome.

PURPOSE: To identify and describe long-term posterior and anterior segment complications of immune recovery uveitis in patients with inactive cytomegalovirus retinitis who are undergoing highly active antiretroviral therapy–mediated recovery of immune function. METHODS: A prospective cohort study at a university medical center. Twenty-nine eyes of 21 patients with immune recovery uveitis and inactive cytomegalovirus retinitis were followed for 14.5 to 116 weeks (median, 43 weeks) after diagnosis of immune recovery uveitis. RESULTS: Nine eyes of nine patients developed visually important complications involving the posterior segment, anterior segment, or a combination of both. Posterior segment complications included severe proliferative vitreoretinopathy in three eyes and spontaneous vitreous hemorrhage from avulsion of a blood vessel secondary to contraction of the inflamed vitreous in one eye. Proliferative vitreoretinopathy recurred in all cases after surgery, severely compromising the visual outcome. Anterior segment complications included posterior subcapsular cataracts with vision decrease in five eyes and persistent anterior chamber inflammation after cataract extraction, resulting in posterior synechiae and large visually important lens deposits in three eyes. CONCLUSION: Persistent inflammation in immune recovery uveitis may lead to vision-threatening complications, such as proliferative vitreoretinopathy, posterior subcapsular cataracts, and severe postoperative inflammation. Immune recovery uveitis is a chronic inflammatory syndrome that may result in complications months to years after the onset of inflammation.

PURPOSE: To document the ocular disorders seen in patients known to be infected with human immunodeficiency (HIV) virus at a referral eye clinic in India. METHODS: The first 100 individuals known to be HIV-positive at a referral eye clinic between 1993 and 1998 were enrolled in a prospective study. They underwent complete ocular and systemic evaluation. RESULTS: Most of the patients (76%) were in the 20- to 40-year age group. Heterosexual exposure to commercial sex workers was the most common risk factor. See also pp. 1–8. (70%) for HIV infection. Cytomegalovirus (CMV) retinitis (17%) and HIV retinopathy (15%) were the most common HIV-associated ophthalmic lesions. Pulmonary tuberculosis (67%) and oropharyngeal candidiasis (66%) were the most commonly associated systemic infections. Ocular involvement was most common in children who contracted the disease through perinatal transmission (66.7%) and in homosexual patients (60%). Ocular involvement was comparatively less common in patients who contracted the disease through blood transfusions (33%) or exposure to commercial sex workers (24.3%). CONCLUSIONS: This study shows that the spectrum of ocular lesions associated with HIV infection in India is different from that seen elsewhere in the world. The prevalence of CMV retinitis and HIV retinopathy is lower in India, and there have been no cases of ocular Kaposi sarcoma. Adnexal infections, albeit rare, were seen in our series. The nonavailability and cost of therapy influenced the visual prognosis in these patients.

PURPOSE: To describe the occurrence of intraocular inflammatory reactions as the sole ophthalmic manifestation of acquired systemic toxoplasmosis. METHODS: Review of medical records for 10 patients with uveitis and evidence of recent Toxoplasma gondii infection. RESULTS: Patient ages ranged from 3 to 51 years. Ocular symptoms were present in each of eight adult patients. Inflammation was unilateral in nine patients; it manifested as vitreous humor cells and haze (10 patients), anterior chamber cells (seven patients), and retinal vasculitis (seven patients). No patient had necrotizing retinochoroiditis upon initial examination. Inflammation resolved in each of nine patients who had follow-up examinations. Foci of retinitis or inactive retinochoroidal scars were seen in four of these nine patients during follow-up examinations, at intervals of 2.0 weeks to 2.5 years after initial examination. CONCLUSIONS: Retinal vasculitis and associated inflammatory reactions may be the only ophthalmic disorder during the early stages of a newly acquired T. gondii infection. Later development of retinitis or scars consistent with toxoplasmic retinochoroiditis in the same eyes suggests that the initial, isolated inflammation may be caused by the presence of parasites in retinal tissue. These cases may have implications for understanding the original source of retinal infection in patients who have recurrent toxoplasmic retinochoroiditis and for treatment of newly acquired T gondii infection.

PURPOSE: To describe the ocular and systemic features of children with cytomegalovirus retinitis and their disease outcomes. METHODS: Review of all cases of cytomegalovirus retinitis diagnosed or treated at a tertiary care pediatric hospital during a 10-year period. RESULTS: Nine immunocompromised children younger than 16 years were diagnosed as having cytomegalovirus retinitis. The underlying causes of immunocompromise were severe combined immunodeficiency syndrome (n = 2), severe combined immunodeficiency syndrome after bone marrow transplantation (n = 1), acquired immunodeficiency syndrome (AIDS) (n = 2), AIDS and previous bone marrow transplantation for leukemia (n = 1), immunosuppressive therapy after renal transplantation (n = 1), chemotherapy for leukemia (n = 1), and congenital cytomegalovirus infection (n = 1). Five children (56%) had symptomatic extraocular cytomegalovirus infection. Only two children reported visual symptoms with cytomegalovirus retinitis at initial examination. Cytomegalovirus retinitis was bilateral in eight children (89%) and involved the posterior pole in at least one eye of all nine children. Four children (44%) died within 10 months of being diagnosed with cytomegalovirus retinitis. The remaining five children were alive, with follow-up ranging from 14 to 70 months. Successful bone marrow transplantation in one child and discontinuation of immunosuppressive medications in two children improved systemic immune function and permitted discontinuation of anticytomegaloviral therapy. CONCLUSION: Pediatric cytomegalovirus retinitis is often asymptomatic and bilateral and involves the posterior pole at initial examination. Recovery of systemic immune function may occur in some children. Evaluation of children at risk and prompt treatment of cytomegalovirus retinitis are important to prevent long-term visual morbidity.

PURPOSE: To determine the effect of highly active antiretroviral therapy on cytomegalovirus (CMV) retinitis treated with ganciclovir implants. METHODS: A retrospective cohort study was performed of 15 patients with recurrent CMV retinitis treated with the ganciclovir implant and highly active antiretroviral therapy (cases) and 38 patients with recurrent retinitis treated with ganciclovir implants before availability of improved antiretroviral therapy (controls). Progression was defined as occurrence of new lesions in the treated eye or advancement of the retinitis border by more than 750 μm. RESULTS: Cases and controls were statistically similar in age, ethnicity, and duration of acquired immunodeficiency syndrome (AIDS). Controls had received intravenous ganciclovir for 9.5 ± 9.5 months vs 3.5 ± 4.6 months in cases ( P = .003). The mean (± SE) time to progression of retinitis after implantation of the device was 26.7 ± 2.4 months (95% confidence interval, 22.1 to 31.3) in the cases receiving highly active antiretroviral therapy vs 6.2 ± 0.9 months (95% confidence interval, 4.5 to 7.9) in the controls ( P = .001). Multivariate analysis, adjusted for preoperative variables, confirmed a significantly prolonged time to progression in patients receiving highly active antiretroviral therapy ( P = .0003). The odds ratio for progression in the cases vs controls was 0.034 (95% confidence interval, 0.003 to 0.350). Cases had higher CD4 + T-lymphocyte counts ( P = .004) and longer survival ( P CONCLUSION: Highly active antiretroviral therapy is associated with improved outcomes in patients with AIDS and recurrent CMV retinitis treated with the ganciclovir implant.

To evaluate preoperative characteristics and outcome of the treatment of recurrent cytomegalovirus (CMV) retinitis with the ganciclovir implant.Records of 54 patients with acquired immunodeficiency syndrome and active, previously treated CMV retinitis who received a ganciclovir implant in one (n = 31) or both (n = 23) eyes were reviewed. Entry criteria included prior insertion and removal of an indwelling catheter or failure to respond to tolerated doses of ganciclovir and foscarnet. Preoperative factors that might correlate with outcome were analyzed, including demographic factors, duration of human immunodeficiency virus disease and CMV retinitis, indications for surgery, prior anti-CMV treatment, and extent of retinitis.Forty-six patients completed 1 month of follow-up and were analyzed for outcome. Thirty-one (67.4%) had inactive retinitis at 1 month vs 15 (32.6%) with active retinitis, and they received a mean of 23.5 +/- 22.9 weeks of preoperative ganciclovir vs 58.0 +/- 52.0 weeks in patients with active retinitis (P = .003). Involvement of more than 25% of retinal area by CMV retinitis was also correlated with activity at 1 month (P.001). Patients who received implants because of lack of venous access had a median time to progression of 8.0 +/- 3.0 months vs 2.0 +/- 1.2 months for patients who had inadequate response or intolerance to intravenous medication (P = .073). Patients with 6 months or less vs more than 6 months of preoperative ganciclovir treatment had progression at a median time of 8.0 +/- 1.7 months vs 2.0 +/- 0.3 months, respectively (P = .016).Longer duration of preoperative ganciclovir or larger area of CMV retinitis correlates with lower success of ganciclovir implant therapy for recurrent retinitis.

○ PURPOSE: To describe the risks, benefits, and recommended use of the ganciclovir implant for the treatment of human immunodeficiency virus-related cytomegalovirus (CMV) retinitis in the era of potent antiretroviral therapy. ○ METHODS: A panel of physicians with expertise in the use of the ganciclovir implant and in the management of CMV retinitis was convened by the International AIDS Society-USA. The panel reviewed and discussed available data, and developed recommendations for the use of the ganciclovir implant, the surgical technique, and related management issues. Recommendations were rated according to the strength and quality of the supporting evidence. ○ RESULTS: The effect of potent antiretroviral therapy on the immunologic status of patients with human immunodeficiency virus disease has changed the manifestation and course of CMV retinitis in many patients. The clinical management of CMV retinitis and the role of the ganciclovir implant are thus changing. Factors in the decision to choose the ganciclovir implant include the patient's potential for immunologic improvement, location and severity of CMV retinitis, and the risks and costs associated with implantation and concomitant oral ganciclovir therapy. ○ CONCLUSIONS: The ganciclovir implant is safe and effective for the treatment of CMV retinitis. The indications for its use should be modified to account for increased patient survival and the potential for CMV retinitis to be controlled by effective antiretroviral therapy. Optimal use of the ganciclovir implant and discontinuation of therapy in selected patients with improvement in immunity may result in better long-term visual outcomes.

PURPOSE: To describe our experience with discontinuation of anticytomegalovirus maintenance therapy in patients who have had immune reconstitution after initiation of highly active antiretroviral therapy. METHODS: Fifteen patients with treated cytomegalovirus retinitis, who had immune reconstitution after initiation of highly active retroviral therapy, had anticytomegalovirus maintenance therapy discontinued. Patients were followed closely for relapse of retinitis. RESULTS: Median nadir CD4 + T-cell count, before institution of highly active antiretroviral therapy, was 20 cells/μl. At the time of discontinuation of anticytomegalovirus therapy, median CD4 + T-cell count was 297 cells/μl. Patients were followed for a median of 8 months off anticytomegalovirus therapy (range, 3 to 16 months). The median CD4 + T-cell count at last follow-up was 267 cells/μl. No patient off anticytomegalovirus therapy relapsed. CONCLUSION: In selected patients with immune reconstitution after initiation of highly active antiretroviral therapy, anticytomegalovirus therapy may be safely discontinued, at least temporarily. Longer follow-up of these patients is needed to determine how long such therapy may be interrupted, and when anticytomegalovirus therapy should be reinstituted.

PURPOSE: To evaluate the relationship between blood and urine cultures for cytomegalovirus and clinical outcomes in patients with cytomegalovirus retinitis. METHODS: Prospective epidemiologic study of 108 patients with newly diagnosed cytomegalovirus retinitis. Blood and urine were cultured for cytomegalovirus at diagnosis of retinitis, at 1 month and 3 months after diagnosis, and every 3 months thereafter. RESULTS: Of the patients, 80.6% were found to have either a positive blood culture or urine culture for cytomegalovirus at the time of diagnosis of retinitis, and a positive blood culture at diagnosis was associated with an increased mortality (odds ratio=1.91, P = .012). Follow-up cultures were positive in approximately 20% of patients, and the rate was constant over time. The development of a positive blood or urine culture during follow-up correlated with the occurrence of cytomegalovirus retinitis in the contralateral eye in those patients with unilateral disease at diagnosis (odds ratio=5.74, P = .001). CONCLUSIONS: Patients with cytomegalovirus retinitis and positive blood cultures for cytomegalovirus have a poorer prognosis.

Purpose To describe the clinical and fluorescein angiographic appearance of cystoid macular edema associated with cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome (AIDS). Methods We retrospectively examined the clinical and photographic records of four patients with AIDS and cytomegalovirus retinitis who developed cystoid macular edema. Results Seven eyes of four patients with AIDS and cytomegalovirus retinitis experienced decreased vision associated with cystoid macular edema. Vitreous inflammation was mild in each patient. In all eyes, the retinitis involved zone 1, and in all but one eye, the cytomegalovirus retinitis was inactive. In one eye, the cystoid macular edema was worsened by formation of a dense juxtafoveal epiretinal membrane. Conclusions Although infrequently recognized, cystoid macular edema can cause visual loss in patients with AIDS and cytomegalovirus retinitis. Fluorescein angiography should be considered in any patient with cytomegalovirus retinitis and unexplained visual loss.

Purpose To report two patients with progressive outer retinal necrosis, which is presumed to be caused by the varicella-zoster virus in patients with acquired immunodeficiency syndrome (AIDS). Method Case report. Results The patients were treated with intravenous foscarnet, 60 mg per kg of body weight three times per week, without response. Remission of retinal necrosis occurred with the commencement of intravitreal ganciclovir treatment, 400 mg two times per week. Laser photocoagulation was performed in both cases. Neither patient developed retinal detachment. Conclusions Intravitreal ganciclovir treatment combined with systemic antiviral agent therapy in patients with progressive outer retinal necrosis may delay progress of the disease. Early photocoagulation may prevent the development of retinal detachment if retinal necrosis is controlled.

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-μg 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 Conclusions Intraocular pressure decreases after the initial 20-μg 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.

Purpose To investigate visual dysfunctions in ophthalmoscopically normal human immunodeficiency virus (HIV)-positive patients and to correlate the results to the stage of HIV disease and neuropsychological status. Methods Fifty-one randomly selected eyes (26 right, 25 left) of 51 HIV-positive patients with visual acuity measurements of 20/20 or better and no ophthalmoscopically detectable disorders were prospectively examined using achromatic and short-wavelength automated perimetry, color vision testing, and contrast sensitivity testing. CD4 + T-lymphocyte count, presence of systemic infection, hemoglobin, hematocrit, serum β 2 -microglobulin levels, and results of neuropsychological testing were also analyzed. Results On achromatic automated perimetry, 21.6% (11/51) of patients performed abnormally according to the mean defect and 27.5% (14/51) according to the Glaucoma Hemifield Test; 29.4% (15/51) performed abnormally on short-wavelength automated perimetry according to the mean defect and 23.5% (12/51) according to the Glaucoma Hemifield Test. On contrast sensitivity, 5.9% (3/51) of patients performed abnormally in the 1.5-cycles per degree (cpd) line, 2.0% (2/51) in the 3-cpd line, 23.5% (12/51) in the 6-cpd line, 25.5% (13/51) in the 12-cpd line, and 33.3% (17/51) in the 18-cpd line. On the Farnsworth-Munsell 100-hue test, 29.4% (15/51) of patients performed abnormally. After correction for multiple correlations, two statistically significant correlations were found: sum of log contrast sensitivity with achromatic automated perimetry and sum of log contrast sensitivity with the Farnsworth-Munsell 100-hue test. Conclusions A significant percentage of HIV-positive patients with visual acuity of 20/20 or better and no ophthalmologic evidence of retinitis performed abnormally on visual psychophysical tests. The severity of visual dysfunction was not correlated with the stage of HIV infection or the degree of neuropsychological dysfunction.

Purpose To develop a rapid, sensitive, and specific laboratory assay based on the polymerase chain reaction for the diagnosis of varicella-zoster virus retinitis in patients with acquired immunodeficiency syndrome (AIDS). Methods We developed and tested a polymerase chain reaction-based assay for the detection of varicella-zoster virus DNA in vitreous samples. We attempted to detect varicella-zoster virus DNA in 14 vitreous samples from patients with AIDS and a clinical diagnosis of progressive outer retinal necrosis syndrome. For controls, we also attempted to detect varicella-zoster virus DNA in vitreous samples from 75 immunocompetent patients with vitreoretinal disease and 88 patients with AIDS and vitreoretinal inflammatory disease not related to progressive outer retinal necrosis syndrome. Results Varicella-zoster virus DNA was detected in 11 of 14 vitreous samples from AIDS patients with progressive outer retinal necrosis syndrome. All three samples that scored negative for varicella-zoster virus DNA came from eyes that had been treated aggressively with antiviral drugs and had clinically inactive disease at the time of vitreous biopsy. Varicella-zoster virus DNA was detected in only two of 75 control vitreous samples from immunocompetent patients with vitreoretinal disease and two of 88 control vitreous samples from patients with AIDS and vitreoretinal inflammatory disease not related to progressive outer retinal necrosis syndrome. Conclusion We have developed a rapid, sensitive, and specific polymerase chain reaction-based diagnostic assay for varicella-zoster virus DNA that will assist in the diagnosis of varicella-zoster virus retinitis in patients with AIDS.

Purpose To report a novel mutation in the RLBP1 gene and optical coherence tomographic findings in a Japanese patient with retinitis punctata albescens. Design Observational case report. Methods The RLBP1 gene was analyzed by direct genomic sequencing. A complete ophthalmologic examination was performed. Results Compound heterozygous mutations in the RLBP1 gene were identified in the patient. The mutations were a novel missense Arg103Trp mutation and a missense Arg234Trp mutation, the causative mutation of Bothnia dystrophy. The patient's fundi showed numerous white dots with diffuse retinal mottling and bilateral macular degeneration. Her visual function deteriorated progressively during 12-year follow-up. Optical coherence tomography demonstrated decreased retinal thickness, especially the photoreceptor layer. Conclusion A novel mutation in RLBP1 gene was found in a Japanese patient with retinitis punctata albescens. Degenerative changes of the outer retina were detected by optical coherence tomography.

To determine the frequency of cytomegalovirus (CMV) viremia in patients with acquired immunodeficiency syndrome (AIDS) and untreated CMV retinitis using conventional cell culture isolation and the sensitive CMV antigenemia assay.We examined 24 AIDS patients with ophthalmologic diagnosis of untreated CMV retinitis and 24 AIDS patients without present or past retinitis (control patients) from three medical centers between September 1992 and March 1994. Cytomegalovirus antigenemia was detected by an indirect peroxidase staining in 300,000 cytocentrifuged neutrophils, using a mixture of murine monoclonal antibodies directed against the pp65 lower matrix protein of CMV.Positive antigenemia was demonstrated in eight (33.3%) of the 24 retinitis patients and in none of the 24 control patients (P.001). Only two of the eight antigenemia-positive patients had a concurrent positive CMV isolation from blood leukocytes by conventional cell culture assay.These results emphasize the risk of extraocular disease in AIDS patients with CMV retinitis because the virus is often present in peripheral blood leukocytes. The CMV antigenemia assay may be a simple and rapid means of identifying those patients with unilateral retinitis at highest risk of developing CMV retinitis of the fellow eye or of visceral CMV disease if intravitreal injections or implants are used as sole treatment for CMV retinitis.

To determine the intraocular pressure in patients with human immunodeficiency virus (HIV) with and without cytomegalovirus retinitis, and to correlate intraocular pressure with CD4+ T-lymphocyte count and the presence, extent, and activity of cytomegalovirus retinitis.Intraocular pressure was measured with calibrated Goldmann applanation tonometers in two groups of patients. Group A included 84 patients with HIV (120 eyes) with cytomegalovirus retinitis, and Group B included 110 patients with HIV (183 eyes) without cytomegalovirus retinitis. Thirty-three patients without HIV (66 eyes) were included as a control group. Step-wise regression analysis of intraocular pressure included correlation with cytomegalovirus retinitis (presence, extent, and activity), CD4+ T-lymphocyte count, age, and gender.The mean intraocular pressure was 9.8 mm Hg in Group A, 12.6 mm Hg in Group B, and 16.1 mm Hg in the control group. All three groups were statistically different from each other when intraocular pressure was compared (P.0001). Step-wise regression showed that low CD4+ T-lymphocyte count (r2 = .20; P.0001) and extent of cytomegalovirus retinitis (r2 = .08; P = .007) both correlated to low intraocular pressure.Intraocular pressure is lower than normal in patients with HIV. Decreased CD4+ T-lymphocyte count is the major association with low intraocular pressure (20% of the effect); extent of cytomegalovirus retinitis accounts for 8% of the effect. Knowledge of the normal range of intraocular pressure in patients with HIV will be important to the understanding and treatment of glaucoma and other disorders or treatments affecting intraocular pressure.

Purpose To describe a patient with retinitis punctata albescens (RPA) associated with compound heterozygosity for two novel mutations in the RLBP1 encoding cellular retinaldehyde-binding protein (CRALBP). Design Observational case report. Methods The proband underwent a complete ophthalmic examination and leukocyte genomic DNA samples were obtained from him and his parents. The RLBP1 exons were analyzed by direct sequencing of PCR-amplified fragments. Results The patient had a clinical phenotype suggestive of slowly progressive RPA, characterized by numerous yellow-white dots in the fundus. The RLBP1 sequence analysis revealed a novel compound heterozygotic mutation of Gly145Asp and Ile200Thr transmitted from the mother and father, respectively. Analysis of 100 control chromosomes showed no individuals with these sequence alterations. Conclusions Only eight RLBP1 mutations have been reported to date, and here we describe two novel mutations. These additional mutations will aid ongoing functional studies and add to our understanding of the molecular pathology pertaining to RLBP1 -associated retinopathies.

stimulus and background lights. The rod and maximum ERGs were elicited with white stimuli of 0.48 and 3.3 log cd/m 2 , respectively, with 3 ms duration. Subsequently, cone ERGs and 30 Hz flicker ERGs were recorded by stimuli of 3.0 log cd/m 2 with 3 ms duration and 2.0 log cd/m 2 with 33.3 ms, respectively, under a white background of 40 cd/m 2 . The PhNR amplitude was measured from the baseline to the negative trough between the cone b-waves and the i-waves (Figure 1). After a full explanation on the nature of the study, informed consent was obtained from all subjects. The procedure used in this study conformed to the tenets of the Declaration of Helsinki. The rod and maximum b-wave were attenuated in the affected eye with little change in the maximum a-wave. In the photopic ERGs, the PhNR amplitude was greatly depressed in the affected eye whereas the cone b-wave was reduced only to two thirds of that in the unaffected eye. Additionally, the 30 Hz flicker ERG showed approximately 50% reduction in amplitude (Figure 1). Each ERG amplitude measured in the affected eyes was expressed as a percentage of the amplitude of corresponding waves in the unaffected eyes in Figure 2. The PhNR amplitude was reduced to 12.3 11.7% (mean standard deviation [SD]) of that observed in unaffected eyes while the cone b-wave was attenuated to only 73.4 30.4%. This reduction of the PhNR amplitude was significantly greater compared with that of other waves including rod b-waves, maximum a-waves and b-waves, cone a-waves and b-waves, and 30 Hz flicker ERG (indicated by *, P .00005 for the maximum a-waves and cone a-waves; P .001 for the 30 Hz flicker ERG; P .004 for the rod b-waves, maximum b-waves and cone b-waves, Student t test). It has been demonstrated that the PhNR amplitude is selectively attenuated and is significantly correlated with degree of visual field loss in glaucoma, 4 indicating that the PhNR amplitude quantitatively reflects activity of ganglion cells and their axons. Therefore, severe depression of the PhNR observed in CRAO suggests massive loss of ganglion cells and their axons, which would account for severe visual loss despite relative preservation of the cone b-wave in CRAO. The present electrophysiological finding is compatible with clinicopathological observation showing profound loss of ganglion cells and severe edema of the nerve fiber layer with relative preservation of the deeper retinal layers in CRAO. 5 The current result suggests that the PhNR could be used to evaluate the inner retinal function in retinal circulatory disturbance.

Purpose We reviewed the clinical and histopathologic features of 33 intraocular tissue biopsy specimens from 32 patients and assessed the value of retinal and chorioretinal biopsies performed in patients with intraocular inflammation. Methods Twenty-four endoretinal biopsies and nine chorioretinal or choroidal biopsies were performed. On the basis of clinical indications, the specimens were processed for light microscopy, electron microscopy, immunohistochemical staining, in situ DNA hybridization, and polymerase chain reaction. Results Of the 24 endoretinal biopsy specimens, 19 were from patients with clinical signs suggestive of viral retinitis. Overall, the diagnosis of viral retinitis was suggested by electron microscopy, immunohistochemical staining, in situ DNA hybridization, or polymerase chain reaction in 53% (ten of 19) biopsies. The preoperative diagnosis was confirmed in seven of ten biopsies in cases of suspected cytomegalovirus retinitis, in one of seven biopsies in cases of suspected acute retinal necrosis, and in two of two biopsies in cases of progressive outer retinal necrosis. The remaining five endoretinal biopsies disclosed Candida in one specimen, subretinal fibrosis in one, and chronic inflammation in three. Histologic examination of the nine chorioretinal or choroidal biopsies disclosed lymphoma in two specimens, a subretinal neovascular membrane in one, uveal melanocytic proliferation in one, toxoplasmic retinochoroiditis in one, viral retinitis in one, and long-standing inflammation in three. Conclusion In select cases of intraocular inflammation, intraocular tissue biopsies may provide clinically useful information.

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 μg of cidofovir, the median time to retinitis progression was between 49 and 92 days (mean, 78 days). In Group 2 eyes treated with 20 μg cidofovir, the median time to retinitis progression was 64 days (mean, 63 days). Hypotony occurred in the two eyes treated with a 100-μg dose of cidofovir and in one of three eyes receiving a 40-μg 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.

Purpose A 23-year-old man developed a rapid-onset, large, dense scotoma that was associated with a peculiar gray intraretinal ring corresponding to the edge of the scotoma and normal fluorescein angiographic findings. This disorder may represent a variant of acute zonal occult outer retinopathy. Methods We studied one patient by ophthalmoscopic examination and fluorescein angiography. Results The patient experienced a short period of concentric enlargement of the scotoma and narrowing of the retinal vessels within the ring, followed by stabilization of the scotoma and slow progressive depigmentation and intraretinal migration of the retinal pigment epithelium within the zone of visual loss. The cause of this disorder, which affects primarily the outer retina, was not determined. Conclusions We speculate that this disorder is part of the spectrum of acute zonal occult outer retinopathy and that the gray border, which separates the normal from the abnormal retina, represents an immune ring phenomenon.

Purpose To report two cases of progressive outer retinal necrosis occurring in immunocompetent individuals after treatment with corticosteroids for presumed optic neuropathy. Design Observational case report. Setting University–based tertiary eye hospital. Methods Retrospective review of existing clinical records. Results Two patients were treated empirically with systemic corticosteroids for suspected inflammatory papillopathy. Subsequently, both were diagnosed with necrotizing herpetic retinitis with features of progressive outer retinal necrosis. Anterior chamber paracentesis confirmed varicella-zoster infection. Both patients were human immunodeficiency virus negative; one patient with rheumatoid arthritis was taking etanercept. Both became completely blind in one eye despite intensive treatment with antiviral medication intravenously and intravitreally. Conclusions Progressive outer retinal necrosis is not confined to patients with underlying severe immunodeficiency, such as acquired immune deficiency syndrome. Initial treatment of acute, unexplained vision loss with systemic corticosteroids may lead to catastrophic visual loss in patients with evolving necrotizing herpetic retinopathy.

Purpose We studied the clinical effects of the immunosuppressive agent FK506 in patients with noninfectious uveitis. Methods This study was designed as a multicenter open clinical trial in Japan. Sixteen patients with noninfectious uveitis who had visited the Uveitis Survey Clinic of the Yokohama City University Hospital were given FK506. Eight had Behcet's disease; five, Vogt-Koyanagi-Harada syndrome; one, sympathetic ophthalmia; one, retinal vasculitis; and one, sarcoidosis. In patients with Behcet's disease, ocular attack score before and after therapy was compared to judge clinical status. For the other diseases, the ocular inflammatory symptoms were observed after the initiation of FK506 treatment. All patients underwent blood and urine examinations, electrocardiography, and chest x-rays before and after FK506 treatment. Results Of the patients with Behcet's disease, five improved, one remained unchanged, one deteriorated, and the status of one could not be determined. Of the patients with Vogt- Koyanagi-Harada syndrome, four improved, and one remained unchanged. The patient with sympathetic ophthalmia improved, the patient with retinal vasculitis remained unchanged, and the status of the patient with sarcoidosis could not be determined. Major adverse effects were sensations of warmth, hypomagnesemia, renal dysfunction, glucose intolerance, nausea, vomiting, and disorders of the central nervous system. All adverse effects disappeared or improved when FK506 was stopped or when the dosage was decreased. Renal dysfunction and glucose intolerance appeared when the blood level of FK506 was high. Conclusions FK506 was effective in patients with uveitis, but it is important to monitor the occurrence of adverse effects.

We examined an immunocompetent patient with uniocular acute progressive outer retinitis. The retinitis was curvilinear in shape, showed progressive enlargement, and appeared to be altered by treatment with intravenous acyclovir. When regressed, the affected area of retina appeared atrophic and, at one-year follow-up, demonstrated intraretinal pigment migration with retinal pigment epithelial atrophy and atrophy of the choriocapillaris. Although visual acuity was unaffected, a dense scotoma was recorded on field testing. The response to acyclovir implicates the herpesvirus family, and acyclovir or another antiherpetic agent should be considered for such cases.

Varicella zoster virus retinitis in patients with the acquired immunodeficiency syndrome is known to be a devastating disease. We studied a series of six consecutive patients that sheds new light on the clinical manifestations and treatment options of this disorder. All patients had episodes of cutaneous zoster, long-term exposure to oral acyclovir, and CD4+ T lymphocyte counts less than 50 cells/mm 3 . Two of the six patients had simultaneous radiographically demonstrable and histologically proven varicella zoster virus encephalitis; this is an important association. Histologic examination of autopsy specimens disclosed that the retinal infection by varicella zoster virus involves the retinal pigment epithelium more heavily than the inner retina, which is consistent with the characteristic clinical impression of an outer retinal necrosis.

Central visual loss in cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome (AIDS) occurs in two forms: direct macular tissue destruction and secondary involvement as part of rhegmatogenous retinal detachment. We treated 32 patients (35 eyes) with macular exudation that caused reversible visual loss and initially manifested as neurosensory retinal detachment and lipid exudates. Of 35 eyes, 25 showed papillary or peripapillary active retinitis and ten showed retinitis 1,500 to 3,000 microns from the fovea. Of 23 eyes with reduced vision that were followed up until healing of the retinitis and resolution of subretinal fluid and lipid exudates, 22 (96%) showed visual improvement with anti-cytomegalovirus treatment. Our findings suggest that macular exudation is a reversible cause of visual loss in patients with cytomegalovirus retinitis.

Acute retinal necrosis is a severe form of necrotizing retinitis. Acute retinal necrosis has been demonstrated to be caused by varicella-zoster virus and herpes simplex virus type 1. We treated three patients with acute retinal necrosis apparently caused by recrudescence of latent herpes simplex virus type 2. Primary viral infection was probably congenital, with documented perinatal herpes simplex virus type 2 infection in two patients. Bilateral chorioretinal scars were present in two patients, neither of whom had a history of ocular herpetic infection, suggesting that earlier subclinical chorioretinitis had occurred. In each case, periocular trauma preceded the development of retinitis by two to three weeks. These cases are evidently caused by trauma-induced reactivation of latent virus rather than the onset of a primary infection.

We encountered two cases of human intraocular infection with mesocercariae of Alaria (Trematoda), involving unrelated Asian men who had unilateral decreased vision. Both patients had pigmentary tracks in the retina, areas of active or healed retinitis, or both, and other signs of diffuse unilateral subacute neuroretinitis. Similar, nonnematode worms were seen in the patients' retinas and vitreous, respectively, several years after apparent infection. The worm in Case 1 was analyzed from projected fundus photographs and diagnosed as an Alaria mesocercaria on the basis of its shape, size (500 × 150 μm), and movement; it was successfully killed with laser. The worm in Case 2 was removed surgically from the vitreous and identified as A. mesocercaria , 555 × 190 μm, most likely A. americana. The probable source of infection in the patients was ingestion, in local restaurants, of undercooked frogs' legs containing A. mesocercaria. In addition to causing prolonged intraocular infection, A. mesocercaria was found to be a cause of diffuse unilateral subacute neuroretinitis, a condition previously attributed only to intraocular nematode larvae.