Birdshot chorioretinopathy: current knowledge and new concepts in pathophysiology, diagnosis, monitoring and treatment.

Birdshot chorioretinopathy (BCR) is a rare form of chronic, bilateral, posterior uveitis with a distinctive clinical phenotype, and a strong association with HLA-A29. It predominantly affects people in middle age. Given its rarity, patients often encounter delays in diagnosis leading to delays in adequate treatment, and thus risking significant visual loss. Recent advances have helped increase our understanding of the underlying autoimmune mechanisms involved in disease pathogenesis, and new diagnostic approaches such as multimodality imaging have improved our ability to both diagnose and monitor disease activity. Whilst traditional immunosuppressants may be effective in BCR, increased understanding of immune pathways is enabling development of newer treatment modalities, offering the potential for targeted modulation of immune mediators. In this review, we will discuss current understanding of BCR and explore recent developments in diagnosis, monitoring and treatment of this disease. Synonyms for BCR: Birdshot chorioretinopathy, Birdshot retinochoroiditis, Birdshot retino-choroidopathy, Vitiliginous choroiditis. Orphanet number: ORPHA179 OMIM: 605808.

Visual Acuity in Birdshot Retinochoroidopathy Evaluation.

PURPOSE: To determine the statistical correlation between visual acuity (VA) and various quantitative parameters relevant to birdshot retinochoroidopathy (BRC) evaluation. DESIGN: Hospital-based retrospective observational study. METHODS: setting: Institutional. STUDY POPULATION: Consecutive HLA29+ BRC patients were included between May and August 2013 at a single tertiary center (Pitié-Salpétrière Hospital, Paris). OBSERVATION PROCEDURES: Demographic data and quantitative parameters relevant to BRC at baseline were collected: VA, degree of anterior and posterior inflammatory reaction, foveal thickness measured by optical coherence tomography (OCT), Arden ratio, and electrooculography (EOG) light peak. MAIN OUTCOME MEASURES: Correlation between VA and the other parameters of the ipsilateral and fellow eye was performed using Spearman rank correlation coefficients. RESULTS: Fifty-five patients were included. Mean VA was 6/9.5 in the right eye (OD) and 6/12 in the left eye (OS). Mean foveal thickness was 240 µm OD (range: 112-606) and 251 µm OS (range: 85-662). Mean Arden ratio was 159% OD and 160% OS. EOG light peak was 714 mV OD (range: 316-1379) and 746 mV OS (range: 272-1652). VA of a given eye was moderately correlated with VA of the contralateral eye (r = 0.4). On the contrary, all other parameters showed a strong correlation between both eyes (all r > 0.7, P < .01). Overall, none of the studied parameters was correlated with its VA (all r < 0.5). CONCLUSION: In BRC, visual acuity alone does not seem to fully reflect the disease severity in terms of clinical or ancillary quantitative findings at baseline.

A genome-wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy.

Birdshot chorioretinopathy (BSCR) is a rare form of autoimmune uveitis that can lead to severe visual impairment. Intriguingly, >95% of cases carry the HLA-A29 allele, which defines the strongest documented HLA association for a human disease. We have conducted a genome-wide association study in 96 Dutch and 27 Spanish cases, and 398 unrelated Dutch and 380 Spanish controls. Fine-mapping the primary MHC association through high-resolution imputation at classical HLA loci, identified HLA-A*29:02 as the principal MHC association (odds ratio (OR) = 157.5, 95% CI 91.6-272.6, P = 6.6 × 10(-74)). We also identified two novel susceptibility loci at 5q15 near ERAP2 (rs7705093; OR = 2.3, 95% CI 1.7-3.1, for the T allele, P = 8.6 × 10(-8)) and at 14q32.31 in the TECPR2 gene (rs150571175; OR = 6.1, 95% CI 3.2-11.7, for the A allele, P = 3.2 × 10(-8)). The association near ERAP2 was confirmed in an independent British case-control samples (combined meta-analysis P = 1.7 × 10(-9)). Functional analyses revealed that the risk allele of the polymorphism near ERAP2 is strongly associated with high mRNA and protein expression of ERAP2 in B cells. This study further defined an extremely strong MHC risk component in BSCR, and detected evidence for a novel disease mechanism that affects peptide processing in the endoplasmic reticulum.

Interleukin-6 gene polymorphism (-174 G/C) is associated with toxoplasmic retinochoroiditis.

PURPOSE: Experimental data have demonstrated a relevant role for IL-6 in the modulation of acute ocular toxoplasmosis. Therefore, we aim to investigate the possible association between the IL-6 gene polymorphism at position -174 and toxoplasmic retinochoroiditis (TR) in humans. METHODS: Ninety-seven patients with diagnosed TR were recruited from the Uveitis Section, Federal University of Minas Gerais. For comparison, 83 healthy blood donors with positive serology for toxoplasmosis and without retinal signs of previous TR were included in the study. Genomic DNA was obtained from oral swabs of individuals and amplified using polymerase chain reaction (PCR) with specific primers flanking the locus -174 of IL-6 (-174G/C). PCR products were submitted to restriction endonuclease digestion and analysed by polyacrylamide gel electrophoresis to distinguish allele G and C of the IL-6 gene, allowing the detection of the polymorphism and determination of genotypes. RESULTS: There was a significant difference in the genotype (χ(2) = 12.9, p = 0.001) and allele (χ(2) = 6.62, p = 0.01) distribution between TR patients and control subjects. In a subgroup analysis, there was no significant difference in genotypes and allele frequencies regarding TR recurrence. CONCLUSIONS: This study suggests that the genotypes related with a lower production of IL-6 may be associated with the occurrence of TR.

Intraocular interleukin-17 and proinflammatory cytokines in HLA-A29-associated birdshot chorioretinopathy.

PURPOSE: To determine the levels of 23 immune mediators in paired aqueous humor (AqH) and serum samples from patients with birdshot chorioretinopathy (BSCR). DESIGN: Single-centre case-control study. METHODS: A multiplex immunoassay was used to determine the levels of 23 immune mediators (T-cell, proinflammatory, and vascular-active mediators) in paired AqH and serum of 16 BSCR patients. The AqH of 11 age-related cataract controls served as controls. RESULTS: AqH levels of the T-cell mediators interleukin (IL)-2 (P=.044) and IL-17 (P=.039) and proinflammatory mediators IL-1ß (P=.032), IL-6 (P=.034), and tumor necrosis factor α (P=.041) were elevated compared with that of age-related cataract controls. The elevated intraocular levels of IL-1ß, IL-17, and tumor necrosis factor α in BSCR samples were higher than their concurrent serum levels. A significant positive correlation of intraocular mediators was noted between IL-17 and both IL-2 (r=0.744; P<.0001) and IL-23 (r=0.921; P<.0001) and between IL-2 and IL-23 (r=0.776; P<.0001). AqH levels of vascular-active mediators were not distinct between the groups. CONCLUSIONS: BSCR patients have elevated intraocular levels of proinflammatory and T cell-associated cytokines. Our results suggest the novel pathogenic concept that BSCR is an autoimmune inflammatory disease restricted to the eye and associated with elevated IL-17.

Efficacy of low-dose methotrexate treatment in birdshot chorioretinopathy.

PURPOSE: To ascertain the effect of treatment with methotrexate (MTX) on the visual prognosis of birdshot chorioretinopathy (BSCR). METHODS: Retrospective case series of 76 consecutive patients with HLA-A29-positive BSCR, of whom 46 were followed for at least 5 years and 18 for longer than 10 years. A review of the medical records of 76 patients with BSCR. Treatment regimens were subdivided into the following groups: 1) No systemic immunomodulatory treatment; 2) Treatment with systemic corticosteroids; and 3) Treatments which comprised MTX. First, we calculated eye-years for the different therapeutic regimens and second, we subdivided the patients according to their initial treatment regimen and assessed visual outcomes. RESULTS: Mean visual acuity increased over time in the MTX-treated patients; remained unchanged in patients on systemic corticosteroids and decreased in the patients without systemic treatment (yearly change in LogMar -0.020, -0.034 and 0.028 with P = 0.034, P = 0.71 and P = 0.006 respectively). In the group treated initially with MTX, VA gradually increased in contrast to the remaining groups of patients (P = 0.003). CONCLUSION: In this series, treatment comprising MTX showed better visual outcomes than the untreated patients and corticosteroid-based treatment regimens.

Clinical application of autofluorescence densitometry with a scanning laser ophthalmoscope.

PURPOSE: Fundus autofluorescence (FAF) affects the overlying absorptive retinal pigments within the eye and can potentially be used to assess their density. This study reports a clinical application of FAF in measuring photopigments by scanning laser ophthalmoscopy (SLO). METHODS: The study group comprised 20 healthy subjects, 4 patients with branch retinal artery occlusion (BRAO), 3 with macular hole, 3 with branch retinal vein occlusion (BRVO), and 4 with resolved central serous chorioretinopathy (CSC). Serial FAF images were taken during exposure to light. The intensity of the FAF was measured at the site of the macular hole or the photocoagulation laser burn in the eyes with BRVO. The autofluorescence optical density difference (fODD) was measured from the FAF images and mapped to elucidate the topographic pattern. RESULTS: The autofluorescence intensity showed little change at the sites of the macular holes or photocoagulation burns during exposure to light. The fODD was smallest at the center of the fovea and gradually increased with the eccentricity within 270 x 270 pixels around the fovea in healthy subjects. The amplitude of the fODD did not change in the area affected with BRAO in comparison to the unaffected area. By contrast, the fODD decreased in the area of resolved serous retinal detachment in the eyes with CSC. CONCLUSIONS: In eyes with retinal disease, measuring the autofluorescence intensity using SLO is a feasible method of assessing the changes in the photopigments. Further studies comparing this approach with conventional methods for examining photopigments are needed.

HLA-B27-associated uveitis with a chorioretinitis manifestation.

A 29-year-old man who had been treated for acute anterior uveitis in a local medical office and observed for 1 month presented complaining of distorted vision in his left eye for 1 week. On ophthalmic examination, the anterior segment was relatively quiet with few cells. A posterior segment examination revealed cystoid macular edema and multiple splinter retinal hemorrhages. Results of all laboratory and imaging studies were negative, except for a positive HLA-B27 haplotype. Fluorescein angiography revealed massive leakage in the mid and late phase, consistent with chorioretinitis. Periocular corticosteroid injections and oral prednisolone were administered. The patient responded to the treatment well with subsequent resolution of chorioretinitis 2 months later. Although rare, chorioretinitis can occur in the setting of uveitis associated with HLA-B27 and seems to respond well to corticosteroid treatment.

Ornithine aminotransferase, a potential target for the treatment of hyperammonemias.

Ornithine-delta-aminotransferase (OAT) (EC 2.6.1.13) is a pyridoxal-5' phosphate dependent mitochondrial matrix enzyme. It controls the L-ornithine (Orn) level in tissues by catalysing the transfer of the delta-amino group of Orn to 2-oxoglutarate. The products of this reaction are L-glutamate-gamma-semialdehyde and L-glutamate. Among the compounds known to inhibit (or inactivate) OAT, only L-canaline and (SS)-5-(fluoromethyl)ornithine [(SS)-5FMOrn] are selective for OAT. Treatment of laboratory animals with 5FMOrn causes a dramatic accumulation of Orn in most tissues and organs, and the enhanced formation of urea due to saturation of ornithine:carbamoyltransferase with its substrate. The enhancement of urea formation by increased endogenous levels of Orn is comparable with that produced by large doses of Orn and arginine, a treatment known to enhance the detoxification of ammonia. However, protection to lethal doses of ammonium salts by exogenous Orn is rapidly fading. In contrast, inactivation of OAT by a small dose of 5FMOrn renders a long-lasting protective effect against various forms of hyperammonemic states. Among these the reduction of ammonia concentrations in blood and tissues, and the reduction of the pathologic excretion of orotic acid to normal levels in mice with hereditary defects of the urea cycle, were most impressive. In human hereditary OAT deficiency the elevated intraocular concentrations of Orn are considered to be a cause of gyrate atrophy. This is presumably the reason, why OAT has not been considered as a therapeutically useful target. Chronic inactivation of OAT by repeated administration of 5FMOrn, caused elevated intraocular Orn concentrations, but this treatment had no effect on the function and histology of the visual system, or the behaviour of adult mice. The confirmation of this and related observations in higher species will show, whether OAT inactivation has potentials in the treatment of hyperammonemic states.

[Determination of cortisol in plasma and 24-hour urine of patients with central serous chorioretinopathy].

OBJECTIVE: To study the cortisol levels in patients with central serous chorioretinopathy (CSCR). METHODS: Endogenous cortisol levels in plasma and urine were determined in 44 patients with CSCR by radioimmunoassay and chromatography, and their results were compared with that of 41 controls. RESULTS: In acute CSCR, the mean values of the plasma cortisol (296.53 +/- 77.03) ng/ml and 24-hour urine 17-hydroxysteroids (the major metabolite of cortisol metabolism) (12.08 +/- 4.82) mg/24 h revealed significantly higher values in the patient group (P < 0.05). CONCLUSIONS: Increased levels of endogenous cortisol play a role in the development of CSCR.

Analysis of immunoregulatory cytokines in ocular fluid samples from patients with uveitis.

PURPOSE: To investigate the T-helper cell cytokine profiles in two well-defined clinical uveitis entities caused by an infectious mechanism. METHODS: Cytokines (interleukin [IL]-2, IL-4, IL-6, IL-10, and interferon [IFN]-gamma) were measured in ocular fluid samples obtained from patients with herpes simplex- or varicella-zoster virus-induced acute retinal necrosis (ARN; n = 17) and toxoplasma chorioretinitis (n = 27) using enzyme-linked immunosorbent assay techniques. The data were compared with data for 51 control samples taken during cataract surgery (n = 10), vitrectomy in diabetic retinopathy (n = 10), eye bank eyes (n = 10) and with samples from patients with "autoimmune" uveitis (n = 21). RESULTS: Interleukin-6 was detected in 44 of 51 control samples and 43 of 44 eyes of patients with uveitis. The highest levels in the control samples were detected in 9 of 10 vitreous samples from patients with diabetic retinopathy (mean, 648 pg/ml). In 8 of 10 samples taken from patients during cataract surgery and in 7 of 10 eye bank eyes the amount of IL-6 was significantly lower (mean, 10 pg/ml and 136 pg/ml, respectively). Interleukin-6 levels in patients with ARN (mean, 1436 pg/ml) were significantly higher than in those with toxoplasma chorioretinitis (mean, 272 pg/ml). Interleukin-2 was detected in one of the samples from patients with toxoplasma chorioretinitis (1105 pg/ml) and in three samples from the control subjects suffering from Fuchs' heterochromic anterior uveitis (mean, 752 pg/ml). No IL-4 (<2 pg/ml) was detected either in patient or control samples. Interferon-gamma could be detected in 7 of 17 ARN patients (range, 277-3483 pg/ml), in 13 of 27 samples from patients with toxoplasma chorioretinitis (range, 12-250 pg/ml), and in 1 of 21 of the samples from control subjects with uveitis (31 pg/ml) but was absent in nonuveitic control samples. Interleukin-10 was detected in 10 of 17 ARN patients (range, 29-3927 pg/ml), in 13 of 27 samples from patients with toxoplasma chorioretinitis (range, 4-67 pg/ml), and in only 3 of 51 control samples (6 pg/ml, 16 pg/ml, and 20 pg/ml). CONCLUSIONS: Various immunoregulatory cytokines (IL-6, IL-10, and IFN-gamma) were detected in ocular fluid samples from patients with uveitis. A separate role for either a T-helper type 1 or T-helper type 2 response in the pathogenesis of clinical uveitis could not be proven.

Tissue repair in the iris in experimental autoimmune uveoretinitis.

Our previous work on rats with S-antigen-induced experimental autoimmune uveoretinitis showed iris tissue changes involving infiltration of inflammatory cells, destruction of the iris architecture, and breakdown of the blood-retinal barrier. The present study reports the remarkable ability of the iris to regenerate during the postinflammatory period. The iris regenerates 50% of its architecture by Day 20 postimmunization. The number of lymphocytes and polymorphonuclear leukocyte (PMNs) was relatively high at this stage. Many capillaries showed abnormal endothelial cells. Unmyelinated nerve axons were often seen near blood vessels. The iris stroma was edematous. By Day 30, approximately 95% of the iris had regenerated, the number of lymphocytes and PMNs decreased, and the number of macrophages increased. Most capillaries looked normal and numerous axons in different stages of myelination were apparent. The stroma, the dilator muscle, and the posterior epithelium were almost completely restored. By Day 45, the iris appeared to be virtually normal. Most striking was the abundance of myelinated nerve axons located near blood vessels. Type I collagen immunoreactivity in vascular endothelial cells increased from Day 20 to Day 60 postimmunization, suggesting that blood vessel endothelial cells may play a role in collagenization of the iris stroma.

Ultrasonic chorioretinopathy: a chloroquine vs control study.

High frequency ultrasound was used to produce chorioretinal lesions in two groups of pigmented rabbits. The control group received no medications. The other group was treated with subretinotoxic doses of chloroquine. Our experiment showed that the untreated group developed focal chorioretinal lesions and ricochet lesions at lower energies than did the chloroquinated group. We postulated that chloroquine, a melanin binding drug, altered melanin's ability to process ultrasonic energy by sonic-thermal conversion. This work suggests that chloroquine, even in subretinotoxic doses, may still exert an effect on the retina by chemically binding melanin and preventing its function as an energy transport system.