Rotterdam Eye Hospital

Patient-reported pain during intravitreal injection (IVI) may vary by injection quadrant and influence adherence to repeated treatments. Hence, this study aimed to quantify whether patient-reported pain differs by IVI quadrant and identify the least-painful approach. We searched 13 literature databases on 15 October 2025 for clinical studies reporting patient-reported IVI pain stratified by injection quadrant (superotemporal [ST], superonasal [SN], inferotemporal [IT], inferonasal [IN]). Random-effects meta-analyses synthesized mean differences (MD) in 0-10 visual analogue scale (VAS) pain across all six pairwise quadrant contrasts. All eligible studies were included for a qualitative review and a meta-analysis. The review was prospectively registered (PROSPERO CRD420251164189). Seven studies comprising 2048 IVI were included (ST 611, SN 469, IT 556, IN 412). Most injections involved anti-VEGF agents. All injections were performed under topical anesthesia (100%; drops or gel), with no subconjunctival anesthesia reported (0%), and pain was recorded immediately post-procedure using VAS-derived scales. Across all six pairwise contrasts, pooled mean differences between quadrants were small (typically < 1 VAS unit on a 0-10 scale), and all 95% confidence intervals crossed zero. Across quadrant comparisons, pooled pain differences were small and inconsistent; none of the pairwise pooled estimates demonstrated a statistically consistent difference, and between-study heterogeneity was substantial to considerable (I2 generally > 80%). Current evidence does not demonstrate a clearly less painful quadrant for intravitreal injections. Estimates varied across studies and heterogeneity was substantial, limiting confidence in any single average quadrant effect. Efforts to minimize IVI-related pain should prioritize optimized anesthesia protocols, communication, and injection technique, while future studies should standardize pain measurement and quadrant allocation to clarify whether subtle quadrant effects exist. PROSPERO registration:CRD420251164189.

Recording reliable pattern-reversal VEPs (prVEPs) in children is challenging due to limited attention. Superimposing dynamic cartoons may enhance engagement, but their effects on the prVEP are unclear. Fifteen healthy adults underwent prVEP testing under three conditions: (F) fixation on a central target (standard condition); (C) free viewing of a single-line cartoon superimposed onto the checkerboard pattern; and (M) a mixed condition, in which participants maintained fixation on the central target while the overlaid cartoon played. Eye movements were tracked to verify stable gaze in conditions F and M and to record gaze positions and velocities during condition C. P100 amplitude and peak time were analyzed for check sizes of 60' and 15'. Under condition (C) (free viewing), P100 was significantly reduced to 74% of that observed during F (standard fixation) at 60' (***p = 0.001) and to 82% at 15' (**p = 0.004), along with a reduction in peak time (60': - 2.4ms, ***p < 0.001; 15': - 3.1ms, **p = 0.009). The M condition (mixed condition, fixation with the cartoon) produced minor, mostly non-significant changes in amplitude (60': 88%, p = 0.076; 15': 96%, p = 0.383) and peak time (60': - 1.7ms, *p = 0.045; 15': 1.1ms, p = 0.056). Eye tracking confirmed that 90% (C) to 96% (F and M) of reversals occurred during stable gaze. In condition (C), gaze was on average directed approximately 2° below the central position used for fixation in the other conditions. The effect of cartoon overlays on the P100 component of adult prVEPs is small, albeit statistically significant. The effects likely reflect subtle influences of attention and adaptation rather than eye movements. These findings support the use of a single-line cartoon in pediatric testing to enhance engagement and response reliability without compromising clinical interpretation.

Conventional optical coherence tomography (OCT) has a floor effect in patients with severe visual field loss, such as seen in advanced primary open-angle glaucoma (POAG). OCT angiography (OCTA) does not suffer from such a floor effect. However, which OCTA parameters are most useful for monitoring longitudinal progression is unclear. We conducted a systematic review and meta-analysis to investigate the clinical use of OCTA in monitoring the progression of intermediate and advanced POAG by searching four databases (Medline, Embase, Web of Science and Cochrane Database of Systematic Reviews) for longitudinal studies on POAG and OCTA. For each meta-analysed OCTA parameter, we calculated a pooled effect estimate with a 95% confidence interval (95% CI). Parameters that could not be meta-analysed were compared narratively. A total of 18 studies were included in the systematic review and seven in the meta-analyses. In the meta-analyses, a lower baseline peripapillary vessel density (VD) significantly increased the risk of visual field (VF) progression (HR [95% CI]: 1.05 [1.02, 1.07] for each percentage decrease in peripapillary VD per year). Baseline parafoveal VD and risk of VF progression showed no significant association. The inferior hemifield foveal avascular zone parameters and the presence of peripapillary choroidal microvascular dropout were significantly associated with the risk of VF progression in the systematic review. Peripapillary VD may be a useful predictor of VF progression in intermediate and advanced glaucoma patients. Although FAZ and MvD also seem to be potential predictors, longitudinal studies on advanced POAG are limited and heterogeneous, highlighting the need for more consistent and comprehensive research.

Comparing multimodal imaging characteristics in patients with central serous chorioretinopathy (CSC) with spontaneous subretinal fluid (SRF) resolution to SRF resolution after half-dose photodynamic therapy (HD-PDT). Forty-six patients with CSC who had spontaneous SRF resolution were compared with 46 age- and gender-matched CSC patients with SRF resolution after HD-PDT. Patients in the HD-PDT group were selected from the randomized multicentre PLACE and SPECTRA trials. In the 2 groups, differences were evaluated on fluorescein angiography (FA), indocyanine green angiography (ICGA), and fundus autofluorescence (FAF). Subfoveal choroidal thickness (SFCT), central foveal thickness (CFT), external limiting membrane (ELM) and ellipsoid zone (EZ) continuity, and pigment epithelial detachments (PEDs) were analysed on optical coherence tomography (OCT). The median time between the last observed SRF on OCT and the resolution visit was 10.0 weeks in both groups. At the visit after SRF resolution, the area of hyperfluorescence on ICGA was larger (p = 0.001), the SFCT was thicker (p = 0.006), and EZ continuity was observed less frequently (p = 0.008) in the spontaneous SRF resolution group when compared with the HD-PDT group. No differences were observed in CFT, ELM continuity, number of PEDs, and the area of hyperfluorescence on FA. CSC patients with spontaneous SRF resolution presumably show less favourable choroidal anatomical characteristics in the short term, compared to CSC patients with resolution after HD-PDT, as the area of ICGA hyperfluorescence was larger and the SFCT was thicker after spontaneous resolution. This observation might explain why recurrences in CSC are seen less frequently after HD-PDT.

Screening op diabetische retinopathie (DR) middels fundusfotografie en beoordeling door humane graders is een grote personele belasting voor het zorgsysteem. Een oplossing voor dit probleem zouden op artificial intelligence (AI) gebaseerde systemen voor geautomatiseerde DR-screening kunnen zijn. In de laatste jaren is een aantal systemen met klasse IIa-keurmerk op de markt gekomen, die in prospectieve validatiestudies even goed scoren als humane graders ten aanzien van sensitiviteit en specificiteit in het herkennen van (verwijsbare) DR. Er zijn echter nog een aantal kanttekeningen en hordes die genomen moeten worden voor introductie van deze systemen in de klinische praktijk: real-life validatiestudies of vergelijkende studies zijn nu nog maar voor weinig systemen beschikbaar. Bovendien bereiken deze systemen in deze real-life studies over het algemeen nog wel een hoge sensitiviteit, maar een lagere specificiteit dan humane graders. Ook zijn er ethische overwegingen, medisch-wettelijke vraagstukken en organisatorische uitdagingen waarmee rekening gehouden moet worden.

Background/objectives: Obtaining a genetic diagnosis for patients with inherited retinal diseases has become even more important since gene-specific therapies have become available. When genetic screening reveals variants of uncertain significance (VUS), additional evidence is required to determine genetic eligibility for therapy. Confirming the effect on splicing that is predicted by SpliceAI could change their classification to either likely pathogenic or pathogenic and would therefore be of great importance when interpreting these variants when geneticists worldwide are trying to reach a diagnosis. Methods: Using minigene assays, we established a pipeline to assess the effect on splicing for all variants. We selected 73 RPE65 variants that were classified as either VUS or likely benign in the RPE65 Leiden Open Variant Database (LOVD) or ClinVar and were predicted to affect splicing by SpliceAI with a delta score of >0.1 and by using an analysis window of 5000 bp up- and downstream of the variant. Results: Using four wild-type vectors, we generated 59 constructs containing the variants of interest. Through these minigene assays, we assessed the effect on splicing of these VUS to enable reclassification. Upon quantification, we identified seven variants with a full, aberrant splicing effect without residual wild-type transcript. Eleven variants had between 5% and 20% remaining wild-type transcript. Forty-one variants had ≥20% residual wild-type transcript, among which fifteen variants showed no effect on splicing. Conclusions: Following the 2023 established ClinGen specific ACMG guidelines for RPE65 (Criteria Specification Registry), evidence from splice assays enabled reclassification of seven RPE65 variants from VUS to pathogenic through an assigned PVS1-very-strong criterium, as less than 5% of wild-type transcript was present. These findings contribute to the interpretation of variants observed in patients, which will in turn dictate their eligibility for gene therapy.

Senior-Løken syndrome is a rare ciliopathy characterized by retinal dystrophy and nephronophthisis. This autosomal recessive inherited disease is caused by pathogenic variants in several genes, including IQCB1. We present a Senior-Løken case that remained genetically unexplained after routine genetic testing, including exome and genome sequencing. To identify the genetic cause for this individual, a combination of innovative long-read technologies was employed. Using optical genome mapping, an intronic 6.2-kb insertion in IQCB1 was revealed. Validation by long-read genome sequencing determined that this insertion consisted of a LINE-1/ERV1-mobile element. The variant was found in trans with a pathogenic IQCB1 2-bp deletion previously identified by exome sequencing. To investigate the consequences of the insertion, targeted long-read RNA-sequencing was performed, revealing a complex splice defect causing the introduction of a premature stop codon. This finding suggests that mobile element insertions represent a yet underestimated variant type that is difficult to detect using short-read sequencing.

PurposeThis study evaluates the effectiveness and safety of multiple PDT sessions for cases of persistent and recurrent subretinal fluid (SRF) in chronic central serous chorioretinopathy (CSC).MethodsThis multicentre, retrospective cohort study included patients aged ≥18 years with chronic CSC who received at least two sessions of PDT at Amsterdam University Medical Center or Leiden University Medical Center between August 2009 and February 2025. Outcomes included the resolution of SRF, changes in visual acuity (VA), subfoveal choroidal thickness (SFCT) and continuity of the external limiting membrane (ELM) and ellipsoid zone (EZ).ResultsThe study included 88 patients with chronic CSC, of whom 88.6% were male. Of the 105 eyes treated, 62.5% had persistent SRF after the first PDT, while 37.5% achieved complete SRF resolution. After the second PDT, SRF resolved completely in 62.8% of eyes overall, with 53.1% in the persistent SRF group and 64.1% in the recurrent SRF group. Following the third PDT, 67.7% of patients showed complete SRF resolution. VA improved by 3 ± 2 letters (p = 0.033) above baseline after the second PDT, with the recurrent SRF group showing greater improvements. SFCT was lower than baseline after PDT treatments in both groups. ELM and EZ continuity also generally showed improvements on optical coherence tomography, particularly in the recurrent SRF group, suggesting retinal integrity restoration rather than atrophic changes.ConclusionRepeated PDT is an effective and safe treatment for both persistent and recurrent chronic CSC, with improvements in SRF, VA, SFCT and retinal layer continuity.

BackgroundThe vitrectomy, subretinal Tissue plasminogen activator and Intravitreal Gas for submacular haemorrhage secondary to Exudative Age-Related macular degeneration (TIGER) trial is a pan-European, two-group, non-commercial, active-control, observer-masked, superiority, randomised controlled surgical clinical trial of an investigational medicinal product.MethodsThe original protocol for this trial was published on 31 January 2022 (https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-021-05966-3). This update reports on key changes in the study protocol in version 2.0 which was approved for trial sites from 18 January 2022, and the current version 3.0 which was approved for trial sites from 25 April 2023, and includes current versions of the statistical analysis plan and health economics analysis plan. In summary, there have been changes to three eligibility criteria: removing the word “Actilyse” from exclusion criterion 2, updating exclusion criterion 5 to state abstinence from heterosexual intercourse or the use of highly effective methods of birth control is mandatory for up to 12 weeks after last aflibercept exposure on trial, and clarifying exclusion criterion 6 relating to international normalised ratio (INR) is only applicable to participants receiving warfarin. Changes to secondary outcomes include Radner Reading speed being limited to the study eye only, and moving EQ-5D-5L from a secondary reported efficacy outcome to a component of health economic analysis reporting only. Actilyse Cathflo was added as an additional permitted investigational medicinal product as this is already used in practice in the UK and is molecularly identical to Actilyse 10 mg. Instructions were added to account for participants who had already been exposed to aflibercept or a similar anti-vascular endothelial growth factor (anti-VEGF) within 21 days (the minimum window between anti-VEGF treatments permitted on trial) prior to study enrolment, storage of tissue plasminogen activator in theatre and operating room environments, and the recording of additional, as-needed aflibercept treatments in-between study visits at the discretion of the study investigator. Finally, sections and subsections have been added to detail the imaging analysis plan, patient public involvement plan, INR testing, and recruitment and informed consent components of the trial. The primary analysis of the trial as stated in the statistical analysis plan is the difference between groups in the proportion of participants gaining ≥ 10 ETDRS letters in their study eye at the month 12 visit, whilst the primary health economic analysis of the trial is the difference in quality-adjusted life years between groups at 12 months.Trial registrationClinicalTrials.gov identifier: NCT04663750; EudraCT: 2020–004917-10.