Combination of KIR and HLA gene variants augments the risk of developing birdshot chorioretinopathy in HLA-A*29-positive individuals.

Birdshot chorioretinopathy (BCR), a chronic ocular inflammatory disease with characteristic choroidal lymphocytic infiltrates, has been strongly associated with human leukocyte antigen (HLA)-A29. Although HLA-A29 occurs frequently in all populations, BCR affects only a small percentage of HLA-A29-positive Caucasians, indicating additional susceptibility factors for BCR. Discovery of HLA class I-specific killer cell immunoglobulin-like receptors (KIR) led to a series of epidemiological studies implicating KIR-HLA gene combinations in disease. Here, we characterized KIR-HLA pairs in BCR patients and controls carrying HLA-A*29 as well as controls lacking HLA-A*29. KIR-HLA pairs implicated for weak inhibition (KIR2DL2/3+HLA-C1 and KIR3DL1+HLA-Bw4(T80)) in combination with activating KIR genes associated with autoimmunity (KIR2DS2, 2DS3 and 2DS4) augment the risk of developing BCR in HLA-A*29-positive individuals. The reciprocal association of strong inhibitory pairs (KIR3DL1+HLA-Bw4(I80) and KIR2DL1+HLA-C2) in combination with those implicated in protection from infection (KIR3DS1+HLA-Bw4(I80) and KIR2DS1+HLA-C2) was observed in HLA-A*29-negative controls. These results suggest that a profound effect of KIR2DS2/S3/S4 in the absence of strong inhibition may enhance the activation of natural killer cells and T-cell subsets against intraocular self-antigens, thereby contributing to pathogenesis of BCR.

Cluster of Mycobacterium chelonae keratitis cases following laser in-situ keratomileusis.

PURPOSE: To describe a cluster of Mycobacterium chelonae keratitis cases involving patients who underwent laser in-situ keratomileusis (LASIK) at a single refractive surgery center. DESIGN: Descriptive case series of four patients and cohort study to identify disease associations. METHODS: Examination schedules, diagnostic tests, and therapy were based on best medical judgment. Isolates from three patients were compared by pulsed-field gel electrophoresis. Epidemiologic studies were performed to identify the source of infection. RESULTS: Seven of eight eyes developed M. chelonae keratitis following bilateral simultaneous LASIK. Each patient was thought to have diffuse lamellar keratitis initially, but all seven eyes were noted to have opacities suggestive of infectious keratitis by 13 to 21 days after surgery. All eyes had undergone hyperopic LASIK over four days in April 2001 by one surgeon in a community-based refractive surgery center. A cohort study of all patients undergoing LASIK at the same center in April 2001 revealed that M. chelonae keratitis occurred only in persons undergoing correction of hyperopia (seven of 14 eyes vs. none of 217 eyes undergoing myopic LASIK, P <.001). The only difference identified between procedures was use of masks created from a soft contact lens in hyperopic LASIK. Three isolates (three patients) were indistinguishable by pulsed-field gel electrophoresis. Eyes were treated with a combination of antimicrobial agents, including topical azithromycin in three patients, with resolution of infection in all eyes over 6 to 14 weeks. The source of infection was not identified on environmental cultures. CONCLUSION: Postoperative nontuberculous mycobacterial keratitis can occur in an epidemic fashion following LASIK. Topical amikacin, azithromycin, clarithromycin, ciprofloxacin, or a combination of these agents, appears to be effective treatment for these infections.

Relationships between laser flare photometry values and complications of uveitis.

OBJECTIVE: To determine whether relationships exist between elevated laser flare photometry values and common abnormalities and complications associated with uveitis. METHODS: We retrospectively studied all patients with uveitis on whom laser flare photometry measurements ("flare") were obtained (N = 111) at 2 academic medical centers. The first laser flare photometry values obtained for each patient were compared with the presence or absence of the following abnormalities or complications associated with uveitis: keratic precipitates, posterior synechiae, cataract, macular edema, optic disc edema, and glaucoma. In bilateral cases, the eye with the higher flare was used in primary analyses. RESULTS: Flare was significantly higher in patients with posterior synechiae (P<.001) and in those with macular edema (P =.02) than in patients with uveitis who did not have these complications. Flare was significantly higher in patients with prior cataract surgery or cataract at the study visit than in those without cataracts (P =.001). There was no significant difference in flare between patients with and without keratic precipitates, optic disc edema, or glaucoma. No relationships were found between abnormalities or complications and the level of inflammatory cells or flare as determined by clinical assessment. We also identified an inverse relationship between flare and visual acuity that was not completely explained by the presence of complications in a stepwise regression model. CONCLUSIONS: Although causal relationships were not established, associations between flare and some complications of uveitis suggest that aqueous humor protein may be an important factor in the development of these problems. Consequently, laser flare photometry could play a role in predicting outcomes or monitoring therapy for patients with uveitis.

The tubulointerstitial nephritis and uveitis syndrome.

The world's medical literature on tubulointerstitial nephritis and uveitis (TINU) syndrome was reviewed, and data on 133 patients with TINU syndrome were identified. The median age of onset was 15 years (range 9-74 years) with a 3:1 female-to-male predominance. Common laboratory abnormalities included elevated Westergren erythrocyte sedimentation rates and elevated urinary beta-2-microglobulin levels. Ocular symptoms preceded systemic symptoms in 21% of cases, and followed systemic symptoms by up to 14 months in 65% of cases. Uveitis involved only the anterior segment in 80% of cases. Uveitis was bilateral at presentation in 77% of cases. Patients were treated with systemic corticosteroids in 80% of cases and with immunosuppressive drugs in 9% of cases. Uveitis recurred or followed a chronic course in 56% of patients and persisted for several years in some cases. Ocular complications (including posterior synechiae, cataracts, and elevated intraocular pressure) were reported in 21% of cases. The visual prognosis appears to be good. Persistent renal dysfunction was reported in 11% of cases, including five patients who required renal dialysis. TINU syndrome is a distinct clinical entity that may be under-recognized and may account for some cases of unexplained chronic or recurrent uveitis. It is important for ophthalmologists, nephrologists, and primary care providers to be familiar with this disorder to ensure early diagnosis and appropriate treatment.

Decreased macular leukocyte velocity in human immunodeficiency virus-infected individuals.

PURPOSE: To determine whether human immunodeficiency virus (HIV)-infected individuals have decreased macular capillary blood flow in vivo. DESIGN: Case control study. METHODS: Macular leukocyte velocity and perceived leukocyte density were determined in 41 HIV-infected individuals without cytomegalovirus retinitis and 31 HIV-negative control subjects using the blue field simulation technique (BFS-2000, Oculix, Inc., Jenkintown, PA). Velocity and density measurements for HIV-infected individuals were compared to current and lowest previous CD4+ T-lymphocyte counts, HIV RNA blood levels, and blood leukocyte counts. RESULTS: Mean macular leukocyte velocity was lower in HIV-infected individuals than in controls (P = 0.0006). No correlations were identified between velocity measurements and the following factors in HIV-infected individuals: current or lowest previous CD4+ T-lymphocyte count; or HIV RNA blood level. Mean perceived leukocyte density in HIV-infected individuals was lower than in controls (P = 0.003), but was not correlated with blood leukocyte count in HIV-infected individuals. No relationships were identified between macular leukocyte velocity and duration of medication use or duration of elevated CD4+ T-lymphocyte count in patients receiving potent antiretroviral therapy. CONCLUSIONS: Reduced macular leukocyte velocity may have important implications for understanding the retinal microvasculopathy of HIV disease, the pathogenesis of opportunistic retinal infections, and visual dysfunction in HIV-infected individuals who do not have opportunistic retinal infections. We found no evidence that macular leukocyte velocity increased with immune reconstitution.

Ischemic maculopathy in patients with acquired immunodeficiency syndrome.

PURPOSE: To describe the characteristics of ischemic maculopathy in patients with human immunodeficiency virus (HIV) infection, as a means of understanding this uncommon disorder more fully. METHODS: This is a multicenter, retrospective review of clinical data available for five HIV-infected patients who were given the diagnosis of ischemic maculopathy. RESULTS: All cases had been diagnosed on the basis of fluorescein angiograms obtained after patients complained of vision loss. Four of the five patients had bilateral macular disease. Visual acuity at presentation in the nine affected eyes ranged from 20/20 to count fingers. Vision loss was gradual in both eyes of one patient and was abrupt in onset in seven eyes. Each of the seven eyes with abrupt vision loss had opacification of the superficial retina and/or intraretinal hemorrhages near the fovea. Fluorescein angiography revealed enlargement of the foveal avascular zone and mild staining of the juxtafoveal vessels in affected eyes. Six eyes had active or clinically inactive cytomegalovirus retinitis at presentation, and a seventh eye developed cytomegalovirus retinitis 2 weeks later. All patients were receiving anticytomegalovirus drugs when they developed visual symptoms. Visual acuity remained stable in five eyes, became worse in two eyes, and improved in two eyes; final visual acuity ranged from 20/25 to count fingers. CONCLUSIONS: Ischemic maculopathy may cause profound and permanent vision loss in HIV-infected individuals. Fluorescein angiography should be considered in all HIV-infected patients with unexplained loss of vision. The pathogenesis of ischemic maculopathy remains unknown.

Relationship between aqueous humor protein level and outflow facility in patients with uveitis.

PURPOSE: To determine whether there is a relationship between the aqueous humor protein level and outflow facility in patients with uveitis. METHODS: Aqueous humor protein levels were determined by laser flare photometry, and outflow facility was determined by Schiotz tonography. RESULTS: Thirty patients with uveitis and 10 control subjects were studied. Outflow facility was lower in patients with uveitis (0.21 +/- 0.12 microl/min x mm Hg) than in control subjects (0.33 +/- 0.05 microl/min x mm Hg, P < 0.001). Patients with uveitis and laser flare photometry results (flare) more than 20 photon units/msec (n = 21) had a lower outflow facility (0.17 +/- 0.07 microl/min x mm Hg) than patients with uveitis and flare less than 20 photon units/msec (n = 9, 0.32 +/- 0.14 microl/min x mm Hg, P = 0.004). Furthermore, no difference was identified between outflow facility in patients with active uveitis (those who had anterior chamber cells) and flare less than 20 photon units/msec and outflow in control subjects. In patients with uveitis, there was a linear correlation between flare and outflow facility (r = -0.50, P = 0.005). There was no relationship between flare measurements and either intraocular pressure or aqueous humor cell levels when scored with a clinical, semiquantitative system. CONCLUSIONS: Outflow facility is significantly reduced in patients with uveitis who have high aqueous humor protein levels. Outflow facility appears to be normal in patients with active uveitis whose flare levels are low, and therefore the association between flare and outflow facility does not appear to be an indirect reflection of elevated anterior chamber cells. It is possible that elevated aqueous humor protein levels contribute to the development of uveitic glaucoma in some individuals by decreasing aqueous humor outflow facility, although a causal relationship cannot be established on the basis of this study.

Differential efficacy of tumor necrosis factor inhibition in the management of inflammatory eye disease and associated rheumatic disease.

OBJECTIVE: To evaluate the clinical usefulness of tumor necrosis factor (TNF) inhibitors in patients with inflammatory eye disease that is resistant to conventional immunosuppressive therapies. METHODS: Sixteen patients (4 males and 12 females aged 7 to 78 years) who received etanercept (n = 14) or infliximab (n = 2) for either inflammatory eye disease or associated joint disease were studied retrospectively to determine the effect of these medications on their ocular inflammation. RESULTS: Nine cases of uveitis and 7 cases of scleritis were treated. Systemic diagnoses included rheumatoid arthritis (n = 8), juvenile rheumatoid arthritis (n = 3), ankylosing spondylitis (n = 1), and psoriatic spondylarthropathy (n = 1). Three patients had uveitis without associated systemic disease. Although 12 of 12 patients with active articular inflammation (100%) experienced improvement in joint disease, only 6 of 16 with ocular inflammation (38%) experienced improvement in eye disease. Five patients developed inflammatory eye disease for the first time while taking a TNF inhibitor. No patient discontinued treatment because of adverse drug effects. CONCLUSION: TNF inhibitors are well tolerated immunosuppressive medications that may benefit certain subgroups of patients with inflammatory eye disease, but they appear to be more effective in controlling associated inflammatory arthritis.

An association between Vogt-Koyanagi-Harada disease and Guillain-Barré syndrome.

PURPOSE: To describe an association between Vogt-Koyanagi-Harada disease and Guillain-Barré syndrome. METHODS: Case series, describing three patients. RESULTS: In two patients, the disorders had their onsets within 2 weeks of each other; in the third patient, Vogt-Koyanagi-Harada disease occurred after 3 months, as Guillain-Barré syndrome resolved. All three patients had bilateral panuveitis typical of Vogt-Koyanagi-Harada disease. Each also developed well-accepted manifestations of Guillain-Barré syndrome, including paresis of the lower extremities (all patients), paresis of the upper extremities (two patients), paresis of cranial nerves (two patients), areflexia (all patients), and abnormal electromyography findings (two patients). CONCLUSIONS: Vogt-Koyanagi-Harada disease may follow or occur simultaneously with Guillain-Barré syndrome. The fact that these two autoimmune disorders occur together in some patients suggest that they may share common disease mechanisms.

Revised diagnostic criteria for Vogt-Koyanagi-Harada disease: report of an international committee on nomenclature.

PURPOSE: To present revised criteria for the diagnosis of Vogt-Koyanagi-Harada disease, a chronic, bilateral, granulomatous ocular and multisystem inflammatory condition of unknown cause. METHODS: Diagnostic criteria and nomenclature were subjects of discussion at the First International Workshop on Vogt-Koyanagi-Harada Disease on October 19-21, 1999, at the University of California, Los Angeles, Conference Center, Lake Arrowhead, California. A committee appointed by the workshop participants was charged with drafting revised criteria for Vogt-Koyanagi-Harada disease, based on discussions held during the conference. This article is the consensus committee report. RESULTS: New criteria, taking into account the multisystem nature of Vogt-Koyanagi-Harada disease, with allowance for the different ocular findings present in the early and late stages of the disease, were formulated and agreed upon by the committee. These criteria are based on additional knowledge and experience of experts in the field and are believed to reflect disease features more fully than previously published criteria. CONCLUSIONS: The revised definition of Vogt-Koyanagi-Harada disease, with expanded diagnostic criteria, will facilitate performance of studies involving homogeneous populations of patients, at various stages of disease, that address unanswered questions regarding treatment and disease mechanisms.

Herpes simplex virus type 2 as a cause of acute retinal necrosis syndrome in young patients.

PURPOSE: To determine the causative virus in acute retinal necrosis (ARN) syndrome in a series of patients by calculation of modified Witmer coefficients. DESIGN: Noncomparative case series. PARTICIPANTS: Ten patients with ARN syndrome from four medical centers. METHODS: Aqueous samples, vitreous samples, or both were collected prospectively during surgery from patients with a clinical diagnosis of ARN syndrome. Serologic measures of intraocular and serum antibodies to potentially causative viruses were measured by enzyme-linked immunosorbent assay. MAIN OUTCOME MEASURES: Modified Witmer coefficients (immunoglobulin G and immunoglobulin A) for herpes simplex virus types 1 (HSV-1) and 2 (HSV-2), varicella zoster virus (VZV), and cytomegalovirus (CMV), as well as adenovirus type 2, were calculated from aqueous or vitreous samples, or both. RESULTS: Intraocular antibody measurements were strongly suggestive of a single diagnosis in 9 of 10 patients tested. Modified Witmer coefficients demonstrated intraocular antibody production to HSV in five patients and antibodies to VZV in four patients, and the measurement was inconclusive in one patient. No patients were positive for adenovirus or CMV. Strain-specific antibody titers demonstrated that all HSV-positive patients were reactive only to HSV-2. Herpes simplex virus type 2 was found predominantly in younger patients with ARN syndrome (mean age, 21.2 +/- 10 years; range, 17-39 years), whereas VZV was more commonly seen in older patients (mean age, 40.8 +/- 12.2 years; range, 29-58 years; P = 0.033). Immunoglobulin A testing confirmed immunoglobulin G testing in all patients examined. CONCLUSIONS: Although VZV is thought to be the most common cause of ARN syndrome, HSV-2 is an important cause of ARN syndrome, particularly in younger patients. Because infection with HSV-2 has important medical ramifications, these results suggest that determination of a causal agent should be considered in some cases of ARN syndrome.

Cytomegalovirus (CMV)-specific CD4+ T lymphocyte immune function in long-term survivors of AIDS-related CMV end-organ disease who are receiving potent antiretroviral therapy.

To better understand the relation of cytomegalovirus (CMV)-specific CD4+ T lymphocyte immunity and clinical outcome in AIDS-related CMV end-organ disease, 2 patient groups were prospectively studied: patients recently diagnosed with active CMV end-organ disease and survivors of CMV retinitis who had responded to highly active antiretroviral therapy and had quiescent retinitis when anti-CMV therapy was discontinued. Most patients with active CMV disease had negative CMV-specific CD4+ T lymphocyte responses at diagnosis, as measured by lymphoproliferation (7/7) or cytokine flow cytometry (3/5) assays. In contrast, all 10 subjects with quiescent retinitis and >150 absolute CD4+ T lymphocytes/microL whose anti-CMV therapy was discontinued during 6 months of follow-up had positive CMV-specific immune responses at least once by each assay. However, 6 of these 10 subjects also had negative CMV-specific immune responses > or =1 time. Such patients may be at risk for future CMV disease progression and should be closely monitored.

A follow-up study of Toxoplasma gondii infection in southern Brazil.

PURPOSE: To understand better the natural history of ocular toxoplasmosis by reexamining a well-characterized population in Southern Brazil. METHODS: Ophthalmological examination and serologic tests for Toxoplasma gondii infection were performed in 1997 on 383 individuals who had undergone the same evaluation in 1990. RESULTS: Of 109 seronegative subjects in 1990, 21 (19.3%) became seropositive by 1997, and 2 (1.5% of previously seronegative patients; 9.5% of those known to have seroconverted) developed ocular toxoplasmosis. Seroconversion occurred more frequently in individuals under 17 years of age (16 of 46 patients, 34.8%) than in those greater than 17 years of age (5 of 63 patients, 7.9%; p = 0.002). Of 131 seropositive individuals who did not have ocular lesions in 1990, 11 (8.3%) had typical toxoplasmic lesions in 1997. Of the 13 individuals with non-specific hyperpigmented small retinal lesions in 1990, 3 (23%) presented with typical lesions in 1997. CONCLUSIONS: Acquired T. gondii infection can result in late development of ocular lesions. Small, non-specific hyperpigmented retinal lesions may represent sites of T. gondii infection in seropositive individuals.

Ocular involvement in patients with posttransplant lymphoproliferative disorder.

OBJECTIVES: To describe ocular disease in 3 patients with posttransplant lymphoproliferative disorder (PTLD) and to identify the frequency of such ocular involvement. METHODS: Medical record reviews. Using Kaplan-Meier analysis, we calculated the frequency of ocular involvement among pediatric patients with systemic PTLD after liver transplantation. RESULTS: Each patient had bilateral anterior chamber cells. Biopsy of an iris nodule from a patient who had undergone cardiac transplantation confirmed the diagnosis of PTLD, but no signs of systemic PTLD were found. The other 2 patients had systemic PTLD after liver transplantation; 1 presented with iris nodules in both eyes and a subretinal mass in the left eye, while the other had bilateral anterior chamber cells only. Ocular signs improved slowly after reduction of immunosuppressive drug therapy. Ophthalmological examinations were performed on 22 of 25 pediatric patients with PTLD after liver transplantation; 2 had ocular disease. Kaplan-Meier analysis indicated a 20% risk of ocular involvement at 3 years after development of PTLD (95% confidence intervals, 0%-50%). CONCLUSIONS: Posttransplant lymphoproliferative disorder should be considered in the differential diagnosis of uveitis after organ transplantation. Anterior chamber cells and iris nodules are the most common ocular signs, but the posterior segment can be involved. Ocular involvement can occur without evidence of systemic disease and can be asymptomatic. Reduction of immunosuppressive drug therapy is an appropriate treatment.

Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel.

PURPOSE: To provide recommendations for the use of immunosuppressive drugs in the treatment of patients with ocular inflammatory disorders. PARTICIPANTS: A 12-person panel of physicians with expertise in ophthalmologic, pediatric, and rheumatologic disease, in research, and in the use of immunosuppressive drugs in patient care. EVIDENCE: Published clinical study results. Recommendations were rated according to the quality and strength of available evidence. PROCESS: The panel was convened in September of 1999 and met regularly through May 2000. Subgroups of the panel summarized and presented available information on specific topics to the full panel; recommendations and ratings were determined by group consensus. CONCLUSIONS: Although corticosteroids represent one of the mainstays in the management of patients with ocular inflammation, in many patients, the severity of the disease, the presence of corticosteroid side effects, or the requirement for doses of systemic corticosteroids highly likely to result in corticosteroid complications supports the rationale for immunosuppressive drugs (for example, antimetabolites, T-cell inhibitors, and alkylating agents) being used in the management of these patients. Because of the potential for side effects, treatment must be individualized and regular monitoring performed. With careful use of immunosuppressive drugs for treatment of ocular inflammatory disorders, many patients will benefit from them either with better control of the ocular inflammation or with a decrease in corticosteroid side effects.

Risk factors for advancement of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome. Studies of Ocular Complications of AIDS Research Group.

OBJECTIVE: To identify ocular and systemic factors that predict advancement of cytomegalovirus (CMV) retinitis during treatment. METHODS: Patients with acquired immunodeficiency syndrome were enrolled in a multicenter clinical trial designed to evaluate foscarnet sodium and ganciclovir sodium as therapy for newly diagnosed CMV retinitis. Ocular characteristics at baseline and measurements of retinitis were assessed from fundus photographs by graders at a fundus photograph reading center. The following measures of advancement were assessed: (1) lesion border movement of at least 750 microm or development of a new lesion in involved eyes; (2) rate of increase in retinal area with CMV in involved eyes; and (3) development of retinitis in uninvolved eyes of patients with unilateral disease at baseline. RESULTS: In eyes with retinitis, risk factors at baseline for advancement while receiving treatment included smaller area involved, active margins of retinitis, and posterior location. Risk factors for development of retinitis in uninvolved fellow eyes included blood and urine cultures positive for CMV and lower CD8(+) T-lymphocyte count. CONCLUSIONS: Lesion characteristics can be used to predict advancement of preexisting disease, whereas only systemic factors are associated with development of bilateral disease. These analyses describe retinitis activity before the introduction of potent antiretroviral therapies but provide an important reference point for patients in whom CMV retinitis develops after failure or intolerance of antiretroviral agents. Arch Ophthalmol. 2000;118:1196-1204

Increased polymorphonuclear leucocyte rigidity in HIV infected individuals.

AIM: Individuals with human immunodeficiency virus (HIV) infection were evaluated for evidence of abnormal polymorphonuclear leucocyte (PMN) rigidity, which can alter capillary blood flow. METHODS: The transit time of individual PMN through 8 microm pores in a cell transit analyser was used as a measure of cell rigidity. PMN transit time was compared between HIV infected individuals (n=45) with and without CMV retinitis and HIV negative controls (n=17). RESULTS: Transit times were longer for PMN from HIV infected individuals than for PMN from controls (p<0.001). PMN from HIV infected individuals with CMV retinitis (n=13) had longer transit times than PMN from those without CMV retinitis (n=32, p<0.001). Transit times were longer in HIV infected individuals with lower CD4+ T lymphocyte counts (p<0.001). Regression analysis indicated that the relation between transit times and the presence of CMV retinitis could not be explained solely on the basis of low CD4+ T lymphocytes. In HIV infected individuals, mean transit time was not correlated with age, blood pressure, or serum creatinine, cholesterol, or triglycerides. CONCLUSIONS: HIV infected individuals appear to have increased PMN rigidity, a cellular change that might be involved in the pathogenesis of HIV related retinal microvasculopathy. PMN rigidity appears to be related to severity of immune dysfunction. PMN rigidity may remain high in patients with CMV retinitis after elevations of CD4+ T lymphocyte counts that result from potent antiretroviral therapy.