Carel B. Hoyng’s research while affiliated with Radboud University Medical Centre (Radboudumc) and other places

Introduction: Half-dose photodynamic therapy (HD-PDT) with verteporfin is the mainstay treatment in central serous chorioretinopathy (CSC). Since 2021, there is a worldwide shortage of verteporfin. This called for adjustments of daily practice. Here, we provide a comprehensive evaluation of the adapted treatment methods and outcomes in patients with non-resolving and chronic CSC. Methods: In this retrospective cohort study, we compared patients referred in the year before the verteporfin shortage (group 1), with patients referred in the first year of verteporfin shortage (group 2). Treatment strategies, subretinal fluid (SRF) resolution, and visual acuity (VA) were evaluated during a follow-up period of at least 4 months. Results: Eighty-five eyes of 79 patients were analyzed, 36 eyes in group 1 and 49 in group 2. The treatment strategy at the first visit shifted from HD-PDT as the most performed treatment in group 1 to a more patient-tailored approach in group 2, with a wait-and-see policy in most cases. During follow-up, HD-PDT was performed significantly less in group 2 (89% vs. 45%; p < 0.001). At a mean follow-up time of 6.2 months, SRF resolved in 61% of the eyes in group 1 and in 55% in group 2 (p = 0.821). No difference in VA was observed between the groups at follow-up (p = 0.637). Conclusion: During the shortage of verteporfin, a different treatment strategy was applied, with HD-PDT being performed less frequently. By implementing a more patient-tailored approach, the VA and the resolution rate of SRF remained similar to the year before the shortage.

High anisotropy in volumetric medical images can lead to the inconsistent quantification of anatomical and pathological structures. Particularly in optical coherence tomography (OCT), slice spacing can substantially vary across and within datasets, studies, and clinical practices. We propose to standardize OCT volumes to less anisotropic volumes by conditioning 3D diffusion models with en face scanning laser ophthalmoscopy (SLO) imaging data, a 2D modality already commonly available in clinical practice. We trained and evaluated on data from the multicenter and multimodal MACUSTAR study. While upsampling the number of slices by a factor of 8, our method outperforms tricubic interpolation and diffusion models without en face conditioning in terms of perceptual similarity metrics. Qualitative results demonstrate improved coherence and structural similarity. Our approach allows for better informed generative decisions, potentially reducing hallucinations. We hope this work will provide the next step towards standardized high-quality volumetric imaging, enabling more consistent quantifications.

Purpose: To evaluate functional and structural assessments as endpoints for clinical trials for USH2A-related retinal degeneration. Methods: People with biallelic disease-causing variants in USH2A, visual acuity ≥ 20/80, and visual field ≥ 10° diameter were enrolled in a 4-year, natural history study. Participants underwent static perimetry, microperimetry, visual acuity, fullfield stimulus testing (FST), and optical coherence tomography annually. Rates of change estimated from mixed-effects linear models and percentages of eyes with changes exceeding the coefficient of repeatability (CoR) or thresholds conforming with U.S. Food and Drug Administration (FDA) guidelines were evaluated. Results: Rates of change were generally more sensitive to change than proportions of eyes exceeding a threshold such as the CoR. Baseline ellipsoid zone area ≥ 3 mm2 was necessary to detect change. Mean sensitivity and volumetric hill of vision measures on static perimetry had similar properties and were the most sensitive to changes of the continuous measures. The highest 4-year proportions of eyes exceeding the CoR were from FST testing (47%) and microperimetry (32%). Specification of loci as functional transition points (FTPs) resulted in 45% (static perimetry) and 46% (microperimetry) at 4 years, meeting FDA guidelines for progression. Conclusions: Rate of change of mean sensitivity on static perimetry was a sensitive perimetric continuous measure. Percentages of within-eye change were largest with FST testing and microperimetry. FTPs appear to be particularly sensitive to change. These results affect clinical trial design for USH2A-related retinal degeneration. Translational relevance: Analyses of natural history data from the Rate of Progression in USH2A-Related Retinal Degeneration (RUSH2A) study can inform eligibility criteria and endpoints for clinical trials.

Age-related macular degeneration (AMD) is a multifactorial retinal disease with a large genetic risk contribution. Reticular pseudodrusen (RPD) is a sub-phenotype of AMD with a high risk of progression to late vision threatening AMD. In a genome-wide association study of 2,165 AMD+/RPD+ and 4,181 AMD+/RPD- compared to 7,660 control participants, both chromosomes 1 (CFH) and 10 (ARMS2/HTRA1) major AMD risk loci were reidentified. However association was only detected for the chromosome 10 locus when comparing AMD+/RPD+ to AMD+/RPD- cases. The chromosome 1 locus was notably absent. The chromosome 10 RPD risk region contains a long non-coding RNA (ENSG00000285955/BX842242.1) which colocalizes with genetic markers of retinal thickness. BX842242.1 has a strong retinal eQTL signal, pinpointing the parafoveal photoreceptor outer segment layer. Whole genome sequencing of phenotypically extreme RPD cases identified even stronger enrichment for the chromosome 10 risk genotype.

Purpose The purpose of this study was to develop a deep learning algorithm for detecting and quantifying incomplete retinal pigment epithelium and outer retinal atrophy (iRORA) and complete retinal pigment epithelium and outer retinal atrophy (cRORA) in optical coherence tomography (OCT) that generalizes well to data from different devices and to validate in an intermediate age-related macular degeneration (iAMD) cohort. Methods The algorithm comprised a domain adaptation (DA) model, promoting generalization across devices, and a segmentation model for detecting granular biomarkers defining iRORA/cRORA, which are combined into iRORA/cRORA segmentations. Manual annotations of iRORA/cRORA in OCTs from different devices in the MACUSTAR study (168 patients with iAMD) were compared to the algorithm's output. Eye level classification metrics included sensitivity, specificity, and quadratic weighted Cohen's κ score (κw). Segmentation performance was assessed quantitatively using Bland-Altman plots and qualitatively. Results For ZEISS OCTs, sensitivity and specificity for iRORA/cRORA classification were 38.5% and 93.1%, respectively, and 60.0% and 96.4% for cRORA. For Spectralis OCTs, these were 84.0% and 93.7% for iRORA/cRORA, and 62.5% and 97.4% for cRORA. The κw scores for 3-way classification (none, iRORA, and cRORA) were 0.37 and 0.73 for ZEISS and Spectralis, respectively. Removing DA reduced κw from 0.73 to 0.63 for Spectralis. Conclusions The DA-enabled iRORA/cRORA segmentation algorithm showed superior consistency compared to human annotations, and good generalization across OCT devices. Translational Relevance The application of this algorithm may help toward precise and automated tracking of iAMD-related lesion changes, which is crucial in clinical settings and multicenter longitudinal studies on iAMD.

Objective Hydroxychloroquine (HCQ) effectively treats autoimmune diseases but prolonged use may lead to retinopathy and subsequent vision loss. Guidelines suggest annual follow-up after 5 years for low-risk and 1 year for high-risk patients. This study evaluates the cost-effectiveness of current screening guidelines and a reduced regimen in the Netherlands from a societal perspective. Methods A Markov model assessed costs and quality-adjusted life-years (QALYs) for current and reduced screening regimens. The model included 359 HCQ-treated patients from Radboud University Medical Center. Cost-effectiveness was examined in the general population and patients using < 5.0 mg/kg, 5.0–6.0 mg/kg, or > 6.0 mg/kg HCQ per day for several reduced regimens. Results Compared to no screening, the current screening guideline saves costs (i.e., €210 per patient), while gaining QALYs (i.e., 0.79 QALY per patient) over a lifetime in the Netherlands. However, in patients receiving < 5.0 mg/kg HCQ per day, a biennial screening regimen after 10 years using SD-OCT was more cost-effective. For those with 5.0–6.0 mg/kg and > 6.0 mg/kg per day, initiating annual screening with an SD-OCT after 5 years was more cost-effective than the current guideline. Conclusions Screening for HCQ retinopathy is cost-effective, but delayed initiation and a reduced frequency, using solely an SD-OCT, are more cost-effective. We recommend screening with an SD-OCT and a biennial regimen after 10 years for low-risk patients, an annual regimen after 5 years for intermediate- and high-risk patients.

Objective To improve the understanding of the natural disease progression of retinitis pigmentosa GTPaseregulator (RPGR)-associated X-linked retinitis pigmentosa (XLRP). Design A multicenter, prospective, observational natural history study over 24 months. Participants Male participants aged ≥7 years with a pathogenic variant in the RPGR gene, a best-corrected visual acuity (BCVA) score of ≥34 ETDRS letters, and a mean 68-loci retinal sensitivity (assessed by microperimetry) of 0.1 to 20 decibels (dB). Methods Participants were divided into subgroups based on their BCVA score at baseline: 34 to 73 (lower BCVA) or ≥74 (higher BCVA) ETDRS letters. There were 7 visits over 24 months. Main Outcome Measures Change from baseline in BCVA, retinal sensitivity, low luminance visual acuity (LLVA), fixation stability, contrast sensitivity, visual field, anatomical measures, 25-item Visual Function Questionnaire (VFQ-25), intraocular pressure, and adverse events (AEs). Results Overall, 201 participants were included. The mean (standard deviation [SD]) age was 30.3 (11.9) years in the lower BCVA subgroup (n = 170) and 27.7 (10.1) years in the higher BCVA subgroup (n = 31). The study eye baseline mean (SD) BCVA scores were 59.4 (10.30) and 77.3 (3.95) in the lower and higher BCVA subgroups, respectively; the lower BCVA subgroup had lower retinal sensitivity in the study eye at baseline than the higher BCVA subgroup. Over 24 months, there were small observed changes in BCVA, retinal sensitivity, LLVA, fixation, contrast sensitivity, and fundus photography findings. There were observed mean (SD) changes at 24 months in the lower and higher BCVA subgroups of −1.01 (4.67) and 0.03 (5.83) dB-steradians in the volume of full-field hill of vision, −330.6 (869.51) and −122.7 (22.01) μm in distance from foveal center to the nearest border of preserved fundus autofluorescence, −104.3 (277.80) and −207.1 (171.01) μm in central ellipsoid width, and −2.8 (9.7) and −0.6 (7.6) in VFQ-25 composite score, respectively. There was 1 death from completed suicide. There were no ocular serious adverse events, and most AEs were mild/moderate. Conclusions This study provides evidence of the slow natural progression of XLRP over 24 months in both subgroups and provides important functional, anatomical, and safety data. Financial Disclosure(s) Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Purpose: Gene-based therapies for inherited retinal dystrophies (IRDs) are upcoming. Treatment before substantial vision loss will optimize outcomes. It is crucial to identify common phenotypes and causative genes in children. This study investigated the frequency of these in pediatric IRD with the aim of highlighting relevant groups for future therapy. Methods: Diagnostic, genetic, and demographic data, collected from medical charts of patients with IRD aged up to 20 years (n = 624, 63% male), registered in the Dutch RD5000 database, were analyzed to determine frequencies of phenotypes and genetic causes. Phenotypes were categorized as nonsyndromic (progressive and stationary IRD) and syndromic IRD. Genetic causes, mostly determined by whole-exome sequencing (WES), were examined. Additionally, we investigated the utility of periodic reanalysis of WES data in genetically unresolved cases. Results: Median age at registration was 13 years (interquartile range, 9-16). Retinitis pigmentosa (RP; n = 123, 20%), Leber congenital amaurosis (LCA; n = 97, 16%), X-linked retinoschisis (n = 64, 10%), and achromatopsia (n = 63, 10%) were the most frequent phenotypes. The genetic cause was identified in 76% of the genetically examined patients (n = 473). The most frequently disease-causing genes were RS1 (n = 32, 9%), CEP290 (n = 28, 8%), CNGB3 (n = 21, 6%), and CRB1 (n = 17, 5%). Diagnostic yield after reanalysis of genetic data increased by 7%. Conclusions: As in most countries, RP and LCA are the most prominent pediatric IRDs in the Netherlands, and variants in RS1 and CEP290 were the most prominent IRD genotypes. Our findings can guide therapy development to target the diseases and genes with the greatest needs in young patients.

Purpose: To assess the association of age-related macular degeneration (AMD) progression and statins, connected with AMD genetic risk, and if there is an interplay between statins and genetics. Methods: In this analysis, 682 subjects made two visits (6.5-year follow-up) of the Coimbra Eye Study. Subjects who started taking statins at any time point between the two visits were considered. Progressors were defined as not having AMD at baseline and having any AMD at follow-up. Genetic risk scores (GRSs) were calculated individually with 52 independent variants associated with AMD. Time to progression was estimated using unadjusted Kaplan-Meier curves. An extended Cox model was used for the association between statins and GRS with the risk for AMD progression. Multiplicative and additive interactions were assessed. Results: Median survival time was 7.50 years for subjects not taking statins and 7.62 for subjects taking statins (P < 0.001). Statin intake reduced the risk for progression to AMD in 48%, adjusting for age, sex, body mass index, smoking, and diabetes (model 1) and GRS (model 2). The combined effects of not taking statins and having high GRS increased the progression risk fourfold compared to taking statins and having low GRS (hazard ratio [HR] = 4.25; 95% confidence interval [CI], 1.62-11.16; P = 0.003). For subjects not taking statins, an increased risk of progression was found for those subjects with high GRS compared to subjects with low GRS (HR = 1.80; 95% CI, 1.13-2.85; P = 0.013). No statistically significant multiplicative or additive interactions were found. Conclusions: Statins seem to be protective against AMD progression, and genetics may play a role in treatment response.

Rare variants (RVs) in the gene encoding the regulatory enzyme complement factor I (CFI; FI) that reduce protein function or levels increase age-related macular degeneration risk. A total of 3357 subjects underwent screening in the SCOPE natural history study for geographic atrophy secondary to age-related macular degeneration, including CFI sequencing and serum FI measurement. Eleven CFI RV genotypes that were challenging to categorize as type I (low serum level) or type II (normal serum level, reduced enzymatic function) were characterized in the context of pure FI protein in C3b and C4b fluid phase cleavage assays and a novel bead-based functional assay (BBFA) of C3b cleavage. Four variants predicted or previously characterized as benign were analyzed by BBFA for comparison. In all, three variants (W51S, C67R, and I370T) resulted in low expression. Furthermore, four variants (P64L, R339Q, G527V, and P528T) were identified as being highly deleterious with IC50s for C3b breakdown >1 log increased versus the WT protein, while two variants (K476E and R474Q) were ∼1 log reduced in function. Meanwhile, six variants (P50A, T203I, K441R, E548Q, P553S, and S570T) had IC50s similar to WT. Odds ratios and BBFA IC50s were positively correlated (r = 0.76, p < 0.01), while odds ratios versus combined annotation dependent depletion (CADD) scores were not (r = 0.43, p = 0.16). Overall, 15 CFI RVs were functionally characterized which may aid future patient stratification for complement-targeted therapies. Pure protein in vitro analysis remains the gold standard for determining the functional consequence of CFI RVs.