Uveitis causes according to immune status of patients

Purpose: The advances in medicine have led to an increased number of people living with some form of immunodeficiency. Most ocular infections in immunocompromised patients may lead to irreversible blindness. We identify the causes of uveitis in immunocompetent and immunocompromised patients. Methods: A retrospective cohort study of 1354 consecutive patients. All patients underwent a standard work-up for uveitis. Results: An immunocompromised state was identified in 171/1354 patients (13%), of whom 40 had Human immunodeficiency virus (HIV) infection, 52 received immunosuppressive medications, 28 had concurrent malignant disorder and 20 had other causes for their immunosuppression. In addition, 93/1354 patients (7%) had diabetes mellitus (DM). The prevalence of intraocular infections was much higher in immunocompromised patients than in immunocompetent patients and DM (p < 0.001). Causes of uveitis differed between the diverse immunocompromised groups. The non-HIV immunocompromised patients showed primarily intraocular herpes simplex and varicella zoster virus infections, whilst HIV-positive patients exhibited frequently cytomegalovirus (CMV) retinitis and syphilis. Patients with generalized malignancies were characterized by a lower prevalence of infections and higher prevalence of sarcoidosis. Patients with DM typically showed sarcoidosis and bacterial intraocular infections. The percentage of undetermined uveitis diagnoses was markedly lower in immunosuppressed patients (p < 0.001). Conclusion: In immunocompromised patients with uveitis, infections were diagnosed in 46% of cases in contrast to 12% in the immunocompetent patients. The causes of uveitis differed among the various types of immunosuppression. Immunocompromised patients with uveitis require a rapid assessment for the

Differences in clinical presentation of primary open-angle glaucoma between African and European populations

PURPOSE: Primary open‐angle glaucoma (POAG) has been reported to occur more frequently in Africans, and to follow a more severe course compared to Europeans. We aimed to describe characteristics of POAG presentation and treatment across three ethnic groups from Africa and one from Europe. METHODS: We ascertained 151 POAG patients from South African Coloured (SAC) and 94 South African Black (SAB) ethnicity from a university hospital in South Africa. In Tanzania, 310 patients were recruited from a university hospital and a referral hospital. In the Netherlands, 241 patients of European ancestry were included. All patients were over 35 years old and had undergone an extensive ophthalmic examination. Patients were diagnosed according to the ISGEO criteria. A biogeographic ancestry analysis was performed to estimate the proportion of genetic African ancestry (GAA). RESULTS: The biogeographic ancestry analysis showed that the median proportion of GAA was 97.6% in Tanzanian, 100% in SAB, 34.2% in SAC and 1.5% in Dutch participants. Clinical characteristics at presentation for Tanzanians, SAB, SAC and Dutch participants, respectively: mean age: 63, 57, 66, 70 years (p < 0.001); visual acuity in the worse eye: 1.78, 1.78, 0.3, 0.3 LogMAR (p < 0.001); maximum intraocular pressure of both eyes: 36, 34, 29, 29 mmHg (p (anova)  < 0.001); maximum vertical cup to disc ratio (VCDR) of both eyes: 0.90, 0.90, 0.84, 0.83 (p < 0.001); mean central corneal thickness: 506, 487, 511, 528 μm (p < 0.001). Fourteen percent of Tanzanian patients presented with blindness (<3/60 Snellen) in the better eye in contrast to only 1% in the Dutch. CONCLUSION: In this multi‐ethnic comparative study, Sub‐Saharan Africans present at a younger age with lower visual acuity, higher IOP, larger VCDR, than SAC and Dutch participants. This indicates the more progressive and destructive course in Sub‐Saharan Africans

Cone-rod dystrophy can be a manifestation of Danon disease

Background Danon disease is a neuromuscular disorder with variable expression in the eye. We describe a family with Danon disease and cone-rod dystrophy (CRD). Methods Affected males of one family with Danon were invited for an extensive ophthalmologic examination, including color vision testing, fundus photography, Goldmann perimetry, full-field electroretinogram (ERG), and SD-OCT. Previous ophthalmologic data were retrieved from medical charts. The LAMP2 and RPGR gene were analyzed by direct sequencing. Results Two siblings had no ocular phenotype. The third sibling and a cousin developed CRD leading to legal blindness. Visual acuity deteriorated progressively over time, color vision was severely disturbed, and ERG showed reduced photopic and scotopic responses. SD-OCT revealed thinning of the photoreceptor and RPE layer. Visual fieldsdemonstrated central scotoma. The causal mutation was p. Gly384Arg in LAMP2; no mutations were found in RPGR. Conclusions This is the first description of CRD in Danon disease. The retinal phenotype was a late onset but severe dystrophy characterized by loss of photoreceptors and RPE cells. With this report, we highlight the importance of a comprehensive ophthalmologic examination in the clinical work-up of Danon disease

Quality of life in patients with CRB1-associated retinal dystrophies:A longitudinal study

Purpose: To assess the longitudinal vision-related quality of life among patients with CRB1-associated inherited retinal dystrophies. Methods: A longitudinal questionnaire study included 22 patients with pathogenic CRB1 variants. The National Eye Institute Visual Function Questionnaire (39 items, NEI VFQ-39) was applied at baseline, two-year follow-up, and 4-year follow-up. Classical test theory was performed to obtain subdomain scores and in particular ‘near activities’ and ‘total composite’ scores. The Rasch analysis based on previous calibrations of the NEI VFQ-25 was applied to create visual functioning and socio-emotional subscales. Results:In total, 22 patients with pathogenic CRB1 variants were included, with a median age of 25.0 years (IQR: 13–31 years) at baseline and mean follow-up of 4.0 ± 0.3 years. A significant decline at 4 years was observed for ‘near activities’ (51.0 ± 23.8 vs 35.4 ± 14.7, p = 0.004) and ‘total composite’ (63.0 ± 13.1 vs 52.0 ± 12.1, p = 0.001) subdomain scores. For the Rasch-scaled scores, the ‘visual functioning’ scale significantly decreased after 4 years (−0.89 logits; p = 0.012), but not at 4-year follow-up (+0.01 logits; p = 0.975). The ‘socio-emotional’ scale also showed a significant decline after 2 years (−0.78 logits, p = 0.033) and 4 years (−0.83 logits, p = 0.021). Conclusion: In the absence of an intervention, a decline in vision-related quality of life is present in patients with pathogenic CRB1 variants at 4-year follow-up. Patient-reported outcome measures should be included in future clinical trials, as they can be a potential indicator of disease progression and treatment efficacy.</p

Stargardt disease:monitoring incidence and diagnostic trends in the Netherlands using a nationwide disease registry

PURPOSE: To assess the incidence of Stargardt disease (STGD1) and to evaluate demographics of incident cases. METHODS: For this retrospective cohort study, demographic, clinical and genetic data of patients with a clinical diagnosis of STGD1 were registered between September 2010 and January 2020 in a nationwide disease registry. Annual incidence (2014-2018) and point prevalence (2018) were assessed on the basis of this registry. RESULTS: A total of 800 patients were registered, 56% were female and 83% were of European ancestry. The incidence was 1.67-1.95:1,000,000 per year and the point prevalence in 2018 was approximately 1:22,000-1:19,000 (with and without 10% of potentially unregistered cases). Age at onset was associated with sex (p = 0.027, Fisher's exact); 1.9x more women than men were observed (140 versus 74) amongst patients with an age at onset between 10 and 19 years, while the sex ratio in other age-at-onset categories approximated one. Late-onset STGD1 (≥45 years) constituted 33% of the diagnoses in 2014-2018 compared to 19% in 2004-2008. Diagnostic delay (≥2 years between the first documentation of macular abnormalities and diagnosis) was associated with older age of onset (p = 0.001, Mann-Whitney). Misdiagnosis for age-related macular degeneration (22%) and incidental STGD1 findings (14%) was common in patients with late-onset STGD1. CONCLUSION: The observed prevalence of STGD1 in real-world data was lower than expected on the basis of population ABCA4 allele frequencies. Late-onset STGD1 was more frequently diagnosed in recent years, likely due to higher awareness of its phenotype. In this pretherapeutic era, mis- and underdiagnosis of especially late-onset STGD1 and the role of sex in STGD1 should receive special attention

Genome-wide association study of primary open-angle glaucoma in continental and admixed African populations.

Primary open angle glaucoma (POAG) is a complex disease with a major genetic contribution. Its prevalence varies greatly among ethnic groups, and is up to five times more frequent in black African populations compared to Europeans. So far, worldwide efforts to elucidate the genetic complexity of POAG in African populations has been limited. We conducted a genome-wide association study in 1113 POAG cases and 1826 controls from Tanzanian, South African and African American study samples. Apart from confirming evidence of association at TXNRD2 (rs16984299; OR[T] 1.20; P = 0.003), we found that a genetic risk score combining the effects of the 15 previously reported POAG loci was significantly associated with POAG in our samples (OR 1.56; 95% CI 1.26-1.93; P = 4.79 × 10-5). By genome-wide association testing we identified a novel candidate locus, rs141186647, harboring EXOC4 (OR[A] 0.48; P = 3.75 × 10-8), a gene transcribing a component of the exocyst complex involved in vesicle transport. The low frequency and high degree of genetic heterogeneity at this region hampered validation of this finding in predominantly West-African replication sets. Our results suggest that established genetic risk factors play a role in African POAG, however, they do not explain the higher disease load. The high heterogeneity within Africans remains a challenge to identify the genetic commonalities for POAG in this ethnicity, and demands studies of extremely large size

Association of Risk Variants in the <i>CFH </i>Gene With Elevated Levels of Coagulation and Complement Factors in Idiopathic Multifocal Choroiditis

Importance: Idiopathic multifocal choroiditis (MFC) is poorly understood, thereby hindering optimal treatment and monitoring of patients. Objective: To identify the genes and pathways associated with idiopathic MFC. Design, Setting, and Participants: This was a case-control genome-wide association study (GWAS) and protein study of blood plasma samples conducted from March 2006 to February 2022. This was a multicenter study involving 6 Dutch universities. Participants were grouped into 2 cohorts: cohort 1 consisted of Dutch patients with idiopathic MFC and controls, and cohort 2 consisted of patients with MFC and controls. Plasma samples from patients with idiopathic MFC who had not received treatment were subjected to targeted proteomics. Idiopathic MFC was diagnosed according to the Standardization of Uveitis Nomenclature (SUN) Working Group guidelines for punctate inner choroidopathy and multifocal choroiditis with panuveitis. Data were analyzed from July 2021 to October 2022. Main outcomes and measures: Genetic variants associated with idiopathic MFC and risk variants associated with plasma protein concentrations in patients. Results: This study included a total of 4437 participants in cohort 1 (170 [3.8%] Dutch patients with idiopathic MFC and 4267 [96.2%] controls; mean [SD] age, 55 [18] years; 2443 female [55%]) and 1344 participants in cohort 2 (52 [3.9%] patients with MFC and 1292 [96.1%] controls; 737 male [55%]). The primary GWAS association mapped to the CFH gene with genome-wide significance (lead variant the A allele of rs7535263; odds ratio [OR], 0.52; 95% CI, 0.41-0.64; P = 9.3 × 10-9). There was no genome-wide significant association with classical human leukocyte antigen (HLA) alleles (lead classical allele, HLA-A*31:01; P = .002). The association with rs7535263 showed consistent direction of effect in an independent cohort of 52 cases and 1292 control samples (combined meta-analysis OR, 0.58; 95% CI, 0.38-0.77; P = 3.0 × 10-8). In proteomic analysis of 87 patients, the risk allele G of rs7535263 in the CFH gene was strongly associated with increased plasma concentrations of factor H-related (FHR) proteins (eg, FHR-2, likelihood ratio test, adjusted P = 1.1 × 10-3) and proteins involved in platelet activation and the complement cascade. Conclusions and relevance: Results suggest that CFH gene variants increase systemic concentrations of key factors of the complement and coagulation cascades, thereby conferring susceptibility to idiopathic MFC. These findings suggest that the complement and coagulation pathways may be key targets for the treatment of idiopathic MFC.</p

Clinical characteristics and natural history of rho-associated retinitis pigmentosa : a long-term follow-up study

Purpose: To investigate the natural history of RHO-associated retinitis pigmentosa (RP). Methods: A multicenter, medical chart review of 100 patients with autosomal dominant RHO-associated RP. Results: Based on visual fields, time-to-event analysis revealed median ages of 52 and 79 years to reach low vision (central visual field <20 degrees) and blindness (central visual field <10 degrees), respectively. For the best-corrected visual acuity (BCVA), the median age to reach mild impairment (20/67 <= BCVA < 20/40) was 72 years, whereas this could not be computed for lower acuities. Disease progression was significantly faster in patients with a generalized RP phenotype (n = 75; 75%) than that in patients with a sector RP phenotype (n = 25; 25%), in terms of decline rates of the BCVA (P < 0.001) and V4e retinal seeing areas (P < 0.005). The foveal thickness of the photoreceptor-retinal pigment epithelium (PR + RPE) complex correlated significantly with BCVA (Spearman's rho = 0.733; P < 0.001). Conclusion: Based on central visual fields, the optimal window of intervention for RHO-associated RP is before the 5th decade of life. Significant differences in disease progression are present between generalized and sector RP phenotypes. Our findings suggest that the PR + RPE complex is a potential surrogate endpoint for the BCVA in future studies

The common ABCA4 variant p.Asn1868ile shows nonpenetrance and variable expression of stargardt disease when present in trans with severe variants

PURPOSE. To assess the occurrence and the disease expression of the common p.Asn1868Ile variant in patients with Stargardt disease (STGD1) harboring known, monoallelic causal ABCA4 variants. METHODS. The coding and noncoding regions of ABCA4 were sequenced in 67 and 63 STGD1 probands respectively, harboring monoallelic ABCA4 variants. In case p.Asn1868Ile was detected, segregation analysis was performed whenever possible. Probands and affected siblings harboring p.Asn1868Ile without additional variants in cis were clinically evaluated retrospe