Role of IgG avidity in eyes with active Toxoplasma retinochoroiditis.

PURPOSE: To study the role of Toxoplasma IgG avidity in evaluating the stage of systemic infection during manifestation as toxoplasma retinochoroiditis and its clinical implications in eastern India. METHODS: Retrospective chart review of Toxoplasma retinochoroiditis cases with Toxoplasma serology for IgG, IgM, and IgG avidity. RESULTS: Included in this study were 17 eyes of 17 patients who had active retinitis located in the macula (14), mid-periphery (2), or periphery (1). They were either primary lesions (12) or reactivations (5). All the cases had Toxoplasma IgG positive; one case had IgM positivity, while all the cases had high IgG avidity values. IgG avidity had a positive correlation with the duration of symptoms. CONCLUSION: We observed high IgG avidity values in active retinochoroiditis in both primary ocular Toxoplasmosis and reactivation subgroups. These results indicate a late ocular manifestation after initial systemic infection with a possible incubation period ranging from 5 weeks to 5 months.

Posterior segment findings by spectral-domain optical coherence tomography and clinical associations in active toxoplasmic retinochoroiditis.

Toxoplasmic retinochoroiditis is a common, potentially blinding parasitic infection. We sought to define the spectrum and frequency of signs of active toxoplasmic retinochoroiditis by spectral domain optical coherence tomography (SD-OCT), and to identify clinical associations. Ninety eyes of 90 individuals presenting consecutively to a tertiary referral uveitis service with active toxoplasmic retinochoroiditis and gradable SD-OCT scans were evaluated prospectively. SD-OCT features were collated, and associations with lesion location, primary versus recurrent episode, serological status, human immunodeficiency virus infection and best-corrected Snellen visual acuity were explored. Active toxoplasmic retinochoroiditis presented with thickened (65%) and hyperreflective (61%) retina, choroidal thickening (55%) and hyporeflectivity (61%), hyperreflective vitreous dots (80%) and deposits (36%), and posterior hyaloid thickening (35%) on SD-OCT. Most signs occurred with similar frequency across clinical groups. Retinal hyporeflectivity (17%) was significantly associated with a visual acuity of 20/200 or worse at resolution. Our observations demonstrate that active toxoplasmic retinochoroiditis has diverse SD-OCT signs and that none are universally present. Retinal hyporeflectivity-suggesting liquefactive necrosis-predicts poor visual outcome.

CONGENITAL TOXOPLASMOSIS ASSOCIATED WITH TRACTIONAL RETINAL DETACHMENT.

PURPOSE: We report a case of congenital toxoplasmosis associated with retinal detachment. METHODS: A 9-month-old white boy presented a unilateral tractional retina detachment associated with congenital toxoplasmosis retinochoroiditis. RESULTS: The diagnosis is supported by positive IgG (>400) for toxoplasmosis and intracranial calcification on magnetic resonance imaging, along with positive family history of Toxoplasma infection in the mother. CONCLUSION: Tractional retinal detachment is an infrequent and unconventional presentation of congenital Toxoplasma infection. Inflammatory interference with normal sequence of vitreous development may explain pathogenesis of tractional retinal detachments in the setting of congenital ocular toxoplasmosis.

Immune Mediators against Toxoplasma Gondii during Reactivation of Toxoplasmic Retinochoroiditis.

Purpose: The purpose of this article is to analyze possible associations between systemic and ocular cytokine levels and specific clinical ophthalmologic signs from patients with a reactivation of toxoplasmic retinochoroiditis (RTR). Methods: A total of 18 patients with an active RTR episode, 8 patients with inactive scars, and 14 control patients were included in the study. Serum samples and aqueous humor (AH) samples were analyzed for IFN (interferon)-γ, interleukin (IL)-10, and IL-6 levels by ELISA. Inflammation grade, location, and size of the retinochoroidal active lesion, sampling time, and time to resolution were recorded. Results: A significantly negative correlation between AH and serum levels of IFN-γ was detected (p < 0.05). Patients with an AH IFN-γ/IL-10 ratio lower than 1 were associated with the longest time to resolution and/or severe complications. Conclusion: Serum IFN-γ levels may be used as a prognostic marker for both time to resolution and the development of possible severe complications during a given RTR episode.

Clinical and Biological Factors Associated With Recurrences of Severe Toxoplasmic Retinochoroiditis Confirmed by Aqueous Humor Analysis.

PURPOSE: To investigate clinical and biological factors influencing recurrences of severe toxoplasmic retinochoroiditis (TRC) confirmed by aqueous humor analysis. DESIGN: Retrospective case series. METHODS: Retrospective analysis of 87 subjects with severe TRC, proven by positive Goldmann-Witmer coefficient (GWC), Toxoplasma gondii (T. gondii) immunoblot, or T. gondii-specific polymerase chain reaction (PCR) in aqueous humor. Cases with immunosuppression or retinal scars without previous recorded episode were excluded. Time-dependent, clinical, treatment-related, and biological factors were explored by univariate and multivariate shared frailty survival analyses. RESULTS: Among 44 included subjects (age, 40.4 ± 17.6 years; follow-up, 8.3 ± 2.7 years), 22 presented recurrences. There was 0.11 recurrence/patient/year and mean disease-free interval was 5.0 ± 2.9 years. The risk of recurrence was higher immediately after an episode (P < .0001). Among recurrent cases, the risk of multiple recurrences was higher when the first recurrence occurred after longer disease-free intervals (P = .046). In univariate analysis, the recurrence risk declined with higher number of intense bands on aqueous T. gondii immunoblot (P = .006), and increased when venous vasculitis was present initially (P = .019). Multivariate analysis confirmed that eyes with more intense bands on immunoblot had fewer recurrences (P = .041). There was a near-significant risk elevation after pyrimethamine/azithromycin treatment (P = .078 and P = .054, univariate and multivariate). Intravenous corticosteroid administration, oral corticosteroid administration, aqueous GWC, and T. gondii PCR did not influence recurrences (P = .12, P = .10, P = .39, and P = .96, respectively). CONCLUSIONS: Recurrences of severe TRC are not random and may be influenced by clinical and biological factors possibly related to blood-retinal barrier alterations. These results may contribute to identifying biomarkers for TRC reactivation.

How ERAP1 and ERAP2 Shape the Peptidomes of Disease-Associated MHC-I Proteins.

Four inflammatory diseases are strongly associated with Major Histocompatibility Complex class I (MHC-I) molecules: birdshot chorioretinopathy (HLA-A*29:02), ankylosing spondylitis (HLA-B*27), Behçet's disease (HLA-B*51), and psoriasis (HLA-C*06:02). The endoplasmic reticulum aminopeptidases (ERAP) 1 and 2 are also risk factors for these diseases. Since both enzymes are involved in the final processing steps of MHC-I ligands it is reasonable to assume that MHC-I-bound peptides play a significant pathogenetic role. This review will mainly focus on recent studies concerning the effects of ERAP1 and ERAP2 polymorphism and expression on shaping the peptidome of disease-associated MHC-I molecules in live cells. These studies will be discussed in the context of the distinct mechanisms and substrate preferences of both enzymes, their different patterns of genetic association with various diseases, the role of polymorphisms determining changes in enzymatic activity or expression levels, and the distinct peptidomes of disease-associated MHC-I allotypes. ERAP1 and ERAP2 polymorphism and expression induce significant changes in multiple MHC-I-bound peptidomes. These changes are MHC allotype-specific and, without excluding a degree of functional inter-dependence between both enzymes, reflect largely separate roles in their processing of MHC-I ligands. The studies reviewed here provide a molecular basis for the distinct patterns of genetic association of ERAP1 and ERAP2 with disease and for the pathogenetic role of peptides. The allotype-dependent alterations induced on distinct peptidomes may explain that the joint association of both enzymes and unrelated MHC-I alleles influence different pathological outcomes.

Infectious chorioretinitis in an immunocompetent patient: A diagnostic dilemma.

A 44-year-old male presented with a history of defective vision in the right eye for the past 5 months with the previous history of tubercular cervical lymphadenitis. On examination, right eye revealed panuveitis with dense vitritis and chorioretinitis in the superotemporal quadrant. His Mantoux test was positive (25 mm × 25 mm induration), QuantiFERON-TB Gold was test positive, aqueous aspirate was positive for Mycobacterium tuberculosis genome, negative for viruses and toxoplasma, and hence he was initiated on four-drug antitubercular therapy (ATT) with oral steroids. On follow-up, he had worsening of vitritis and intravenous methylprednisolone was given suspecting paradoxical reaction to ATT; however, a repeat AC tap was positive for toxoplasma B1 genome, IgG antitoxoplasma antibody was also positive in serum and aqueous; hence, we switched to systemic antitoxoplasma therapy. He underwent a therapeutic vitrectomy along with intravitreal clindamycin and dexamethasone for persistent vitreous membranes and vitritis. The patient responded well to the treatment with a reduction in vitritis and scarring of the lesion.

Visualization of Photoreceptors in Birdshot Chorioretinopathy Using Adaptive Optics Scanning Laser Ophthalmoscopy: A Pilot Study.

PURPOSE: Adaptive optics scanning laser ophthalmoscopy (AOSLO) allows en face visualization of specific layers of the retina. This pilot study evaluated the ability of AOSLO to visualize photoreceptor integrity in patients with birdshot chorioretinopathy (BCR). METHOD: A total of 16 consecutive patients with HLA-A29+ BCR were imaged using the prototype Apaeros retinal imaging system. Images of high quality were aligned with infrared reflectance photos and correlated with spectral domain optical coherence tomography (SD-OCT). RESULTS: Images of four eyes of three patients were of sufficient quality to allow posterior pole montage and point-to-point correlation with SD-OCT. Areas of photoreceptor disruption on SD-OCT were seen as patchy areas of loss on AOSLO, whereas areas of intact interdigitation zone and inner segment/outer segment junction correlated with normal appearing photoreceptors on AOSLO. CONCLUSIONS: Using AOSLO, we found one instance of subclinical photoreceptor disruption not seen on SD-OCT. Ultimately, there are unique challenges associated with imaging BCR patients using AOSLO.

Molecular and pathogenic effects of endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 in MHC-I-associated inflammatory disorders: Towards a unifying view.

The inflammatory diseases that are most strongly associated with major histocompatibility Complex class I (MHC-I) alleles are also influenced by endoplasmic reticulum aminopeptidase (ERAP) 1 and/or 2, often in epistasis with the susceptibility MHC-I allele. This review will focus on the four major MHC-I-associated inflammatory disorders: ankylosing spondylitis, birdshot chorioretinopathy, Behçet's disease and psoriasis. The genetics of ERAP1/ERAP2 association and the alterations induced by polymorphism of these enzymes on the risk MHC-I allotypes will be examined. A pattern emerges of analogous effects on peptide length, sequence and affinity of disparate peptidomes, suggesting that similar peptide-mediated mechanisms underlie the pathogenesis and the joint contribution of ERAP1/ERAP2 and MHC-I to distinct inflammatory diseases. Processing of specific antigens, peptide-dependent changes in global properties of the MHC-I molecules, such as folding and stability, or both may be pathogenic.

Birdshot Retinochoroidopathy: Prognostic Factors of Long-term Visual Outcome.

PURPOSE: To determine the prognostic factors of long-term visual outcome in birdshot retinochoroidopathy (BRC). METHODS: Design: Retrospective case series. Study Population: Successive HLA-A29+ BRC patients whose latest visit was between May and August 2013 at a single tertiary center (Pitié-Salpétrière Hospital, Paris). OBSERVATION PROCEDURE: Endpoint visual status (remission or deterioration) was determined for each patient based on clinical and ancillary data from the latest visit including optical coherence tomography (OCT), automated visual field (AVF), and angiograms. Main Outcome Measure: Epidemiologic, clinical, OCT, AVF, angiographic, and electrophysiological data at baseline were correlated to final visual status. RESULTS: Fifty-five patients were included. Mean observation period was 8 years (range: 0.6-23 years). Mean disease duration was 9.8 years (range: 1.2-32.7 years). Female-to-male sex ratio was 1.6:1. Factors of good visual prognosis (remission vs deterioration) included at baseline: late age of disease onset (49.5 vs 45 years, P = .05), presence of vitreous inflammatory reactions >2+ (35.9% vs 6.2%, P = .04), vascular leakage on fluorescein angiograms (FA) (44.4% vs 12.5%, P = .03), absence of macular pigment epithelium atrophy on FA (88.9% vs 62.5%, P = .05), and presence of macular edema on OCT (33.3% vs 6.2%, P = .04). Preserved electrooculography light peak and Arden ratio (P = .06) and presence of choroidal spots on infracyanine green angiograms (80.0% vs 53.3%, P = .08) seemed associated with the best prognoses. CONCLUSION: This study suggests a series of prognostic factors of long-term visual outcome in BRC. Keeping in mind the insidious evolution of the disease, knowledge of such prognostic factors should help tailor the treatment and monitoring of birdshot patients.

In-vivo immunofluorescent imaging in cases of posterior uveitis.

In-vitro immunofluorescent assays/imaging are routinely used methods of detecting antigens. The ability to perform ocular angiography to study the choroidal and retinal vasculature in real time provides us with a unique opportunity to perform real time in-vivo immunofluorescent imaging. This unique combination of in-vivo immunofluorescent imaging and live imaging of choroidal and retinal circulation can help detect antigens of infective organisms in-vivo to diagnose causative infective aetiology in cases of choroiditis/retinitis. The following paper describes the basic designing of such an imaging platform.

Cytokine Signatures Associated With Early Onset, Active Lesions and Late Cicatricial Events of Retinochoroidal Commitment in Infants With Congenital Toxoplasmosis.

BACKGROUND: Ocular toxoplasmosis is a prominent and severe condition of high incidence in Brazil. The current study provides new insights into the immunological events that can be associated with retinochoroiditis in the setting of congenital toxoplasmosis in human infants. METHODS: Flow cytometry of intracytoplasmic cytokines in leukocyte subsets following in vitro short-term antigenic recall in infants with congenital T. gondii infection. RESULTS: Our data demonstrates that whereas neutrophils and monocytes from T. gondii-infected infants display a combination of proinflammatory and regulatory cytokine profiles, natural killer cells showed a predominantly proinflammatory profile upon in vitro T. gondii stimulation. The proinflammatory response of CD4(+) and CD8(+) T cells, characterized by the production of interferon γ (IFN-γ) and interleukin 17 in patients with an active retinochoroidal lesion, revealed the presence of IFN-γ and tumor necrosis factor α during early and late immunological events. This specific proinflammatory pattern is associated with early events and active retinochoroidal lesion, whereas a robust monocyte-derived interleukin 10-mediated profile is observed in children with cicatricial ocular lesions. CONCLUSIONS: These findings support the existence of a progressive immunological environment concomitant with the initial, apical, and cicatricial phases in the process of retinochoroidal lesion formation in infants with congenital toxoplasmosis that may be relevant in the establishment of stage-specific clinical management.

HLA-A29-positive Birdshot Chorioretinopathy in a Hispanic Patient.

PURPOSE: To report the first documented case of HLA-A29(+) birdshot chorioretinopathy in a Hispanic patient. CASE DESCRIPTION: A 62-year-old female from Mexico presented with a 15-year history of progressive nyctalopia, floaters, and decreasing vision. She carried multiple previous diagnoses, including posterior vitreous detachment and macular edema. Both fundi showed characteristic creamy ill-defined lesions of birdshot chorioretinopathy, mostly atrophic, with evidence of old periphlebitis and arteriolar attenuation. Bilateral macular atrophy resulted in compromised visual acuity. Workup revealed positive HLA-A29 and was negative for TB and syphilis. CONCLUSION: Despite having been reported almost exclusively in non-Hispanic Caucasians, HLA-A29-positive birdshot chorioretinopathy may occur in Hispanic patients. This patient's ethnicity may have resulted in a significant delay in diagnosis.

Diagnostic Sensitivity of Indocyanine Green Angiography for Birdshot Chorioretinopathy.

IMPORTANCE: To describe a cohort of patients with birdshot chorioretinopathy who did not manifest birdshot lesions on clinical examination but had retinal vasculitis, low-grade to moderate vitritis, and hypocyanescent lesions on indocyanine green angiography (ICGA). OBSERVATIONS: Case series of 3 patients with mild to moderate vitritis and retinal vasculitis without definite birdshot lesions on clinical examination evaluated from January 2007 to December 2014 at 4 academic ophthalmology centers. All patients' results were positive for human leukocyte antigen-A29. All cases had hypocyanescent lesions visible on ICGA but not detectable on fluorescein angiography. CONCLUSIONS AND RELEVANCE: Patients with retinal vasculitis and low-grade vitritis with or without macular edema may have birdshot chorioretinopathy evident on ICGA before lesions are visible on clinical examination or fluorescein angiography. Expanding birdshot chorioretinopathy diagnostic criteria to include the presence of hypocyanescent lesions on ICGA could improve the sensitivity of diagnosis.

Birdshot retinochoroidopathy review.

Birdshot retinochoroidopathy (BSRC) is a distinct type of posterior uveitis originally described in the 1940s. Its characteristics include minimal anterior segment inflammation and diffuse posterior choroidopathy with vitritis and retinal vasculitis. The precise etiology of this disease is yet to be elucidated. However, various treatment modalities have been employed with the ultimate goal of durable remission of this vision threatening intraocular disease. The purpose of this review is not only to emphasize the importance of recognizing BSRC, but also to discuss the new discoveries, immune mediators, current and new therapies, and techniques applied to monitor and accomplish disease remission.