Search

Purpose To utilize next generation sequencing (NGS) and identity‐by‐descent mapping to identify mutations in known and new genes in patients with autosomal recessive (ar) or isolated (i) retinitis pigmentosa (RP). Methods We employed Roche 454‐NGS to screen the exons of 111 inherited retinal disease (IRD) genes in 12 IRD patients with known compound heterozygous variants and 100 unsolved ar/i RP patients. We used identity‐by‐descent mapping and SOLiD‐NGS to identify novel genes for arRP. We carried out segration analysis in the relevant families using Sanger sequencing. Results The NGS approach enabled us to robustly identify 21/24 known IRD‐associated variants. Taking into consideration that a proportion of the RP patients was previously screened for mutations in selected genes, we could solve 55 ar/i RP cases. Mutations were identified in arRP genes (n=45), X‐linked RP genes (n=4), and autosomal dominant RP genes (n=6). In at least 4 families de novo mutations were found. Targeted NGS of exons in selected chromosomal regions based on homozygosity mapping enabled us to identify at least one novel arRP gene. The interpretation of sequence variants derived from whole genome exon (exome) sequencing heavily depends on positional information (linkage analysis, homozygosity mapping). Conclusion NGS can be used for comprehensive mutation scanning of known IRD genes and for the identification of novel IRD genes. The known RP genes contain 55% of the causative mutations. In a significant proportion of isolated patients, we identified X‐linked and de novo autosomal dominant mutations, which has important repercussions for genetic counselling. [ABSTRACT FROM AUTHOR]

Although the benefit of extra-oral implants in the reconstruction of maxillofacial oncological defects is undisputable, some relevant issues need to be clarified. The purpose of this retrospective study was to evaluate the relationship between implants placed during ablation (DA-implants) and after ablation (AA-implants) of the tumor with respect to implant survival. In total, 103 implants were assessed: 44 nasal implants (17 patients) and 59 orbital implants (18 patients). All patients received their implant-retained maxillofacial epithesis between 1997 and 2010, with a mean follow-up of 35months (range 8-156months). The survival rate of DA-implants was 90.0% for the orbital region and 93.5% for the nasal region. The survival rate of the AA-implants for the orbital and the nasal region was 82.8% and 61.5%, respectively. This study shows a significant higher survival rate of extra-oral implants placed during ablative surgery compared to implants in a later stage (p=0.044), thereby stressing the importance of installing extra-oral implants during the ablative surgical session. [ABSTRACT FROM AUTHOR]

Peripherin/rds is an integral membrane glycoprotein, mainly located in the rod and cone outer segments. The relevance of this protein to photoreceptor outer segment morphology was first demonstrated in retinal degeneration slow (rds) mice. Thus far, over 90 human peripherin/RDS gene mutations have been identified. These mutations have been associated with a variety of retinal dystrophies, in which there is a remarkable inter- and intrafamilial variation of the retinal phenotype. In this paper, we discuss the characteristics of the peripherin/RDS gene and its protein product. An overview is presented of the broad spectrum of clinical phenotypes caused by human peripherin/RDS gene mutations, ranging from various macular dystrophies to widespread forms of retinal dystrophy such as retinitis pigmentosa. Finally, we review the proposed genotype-phenotype correlation and the pathophysiologic mechanisms underlying this group of retinal dystrophies. [ABSTRACT FROM AUTHOR]

Purpose: High Magnification Module (HMM™, Heidelberg Engineering, Heidelberg, Germany) imaging is a novel technique, designed to visualize the retina at a cellular level. To assess the potential of HMM™-based metrics as endpoints for future trials, we evaluated correlations between structural HMM™ cone metrics, spectral-domain OCT (SD-OCT, Heidelberg Engineering, Heidelberg, Germany) and retinal sensitivity on microperimetry (MP, MAIA, CenterVue, Padova, Italy) in healthy subjects and p.(Arg142Trp) PRPH2-associated Central Areolar Choroidal Dystrophy (CACD) patients., Methods: We projected a default 10° MP grid on composite HMM™ images and performed automated cone density (CD), intercell distance (ICD) and nearest neighbour distance (NND) analysis at stimuli located at 3° and 5° retinal eccentricity. We manually measured intrasubject outer retinal thickness on SD-OCT in absolute and relative scotomas, located outside of focal atrophy., Results: We included 15 CACD patients and five healthy subjects. We found moderate-to-strong correlations of HMM™ metrics and MP sensitivity at 3° eccentricity from the fovea. We found the outer retina at the locations of absolute scotomas to be statistically significant thinner (p = 0.000003, one-sample t-test), as the outer retinal thickness at locations of relative scotomas. Interestingly, HMM™ metrics of these areas did not differ significantly., Conclusions: We found significant correlations between structural photoreceptors metrics on HMM™ imaging and retinal sensitivity on MP in healthy subjects and CACD patients. A multimodal approach, combining SD-OCT, MP and HMM™ imaging, allows for detailed mapping of retinal photoreceptor integrity and restitution potential, important data that could serve as biomarkers in future clinical trials., (© 2023 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Purpose: To describe clinical characteristics and management in a large cohort of patients with retinal detachment due to a giant retinal tear (GRT)., Methods: We performed a retrospective cohort study with 222 eyes of 206 patients with a primary and non-traumatic GRTs between 2005 and 2022. We analysed the relevant clinical and surgical data from these patients., Results: Eighty-six per cent (n = 177) of patients were male. We observed no relation between refractive error and GRT size (Spearman's rho: r = -0.018, p = 0.83). We achieved a primary and final treatment success in 77%, respectively 92%, of eyes. The final visual outcome was 20/40 or better in 65% and 36% of eyes in fovea-on and fovea-off GRTs respectively. Thirty-five per cent (n = 73) of patients developed a retinal detachment in the fellow eye. The median time until a retinal detachment in the fellow eye occurred after GRT was 20 months, and 10% developed within 1 month. A prediction model for the development of retinal detachment in the fellow eye resulted in a receiver operating characteristics curve with an area under the curve of 0.68 (95% CI: 0.57-0.78, p = 0.001)., Conclusion: We observed a highly significant gender imbalance in patients with a non-traumatic GRT. One third of patients developed a retinal detachment bilaterally. Ten per cent of fellow eye's retinal detachment that develop after GRT, occur within 1 month. Clinical parameters showed limited predictive value for a retinal detachment in the fellow eye. These findings suggest an underlying genetic factor., (© 2023 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Purpose: To explore whether a patient's prior knowledge of the symptoms associated with rhegmatogenous retinal detachment (RRD) relates to the visual outcome after treatment., Methods: We performed a prospective survey study on 126 patients receiving treatment for primary RRD between March and July 2021., Results: Thirty-seven per cent (n = 47) of patients responded that they were aware of the RRD symptoms prior to the detachment. A history of RRD in the fellow eye or knowledge of family members treated for RRD was frequently reported as a reason for the patient's awareness of RRD symptoms. Patients aware of RRD symptoms presented significantly more often with an attached macula (χ 2 , p = 0.002) and a better visual outcome following surgery (Mann-Whitney U, p = 0.028) compared to patients who were not aware of RRD-related symptoms. Among 76 patients with a myopic refractive error, only 15% (n = 11) indicated that they had been warned about the increased RRD risk related to myopia, suggesting that three-quarters of patients were not actively informed by their eye care professionals., Conclusion: RRD symptom awareness is significantly related to a higher rate of macula-on RRDs and better visual outcomes after treatment. There is limited awareness of increased RRD risk in myopic RRD patients. These findings suggest that counselling individuals at high risk of RRD about related symptoms is inadequate and better counselling may improve visual outcomes following RRD treatment., (© 2023 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Rhegmatogenous retinal detachment (RRD) is a sight threatening condition that warrants immediate surgical intervention. To date, 29 genes have been associated with monogenic disorders involving RRD. In addition, RRD can occur as a multifactorial disease through a combined effect of multiple genetic variants and non-genetic risk factors. In this review, we provide a comprehensive overview of the spectrum of hereditary disorders involving RRD. We discuss genotype-phenotype correlations of these monogenic disorders, and describe genetic variants associated with RRD through multifactorial inheritance. Furthermore, we evaluate our current understanding of the molecular disease mechanisms of RRD-associated genetic variants on collagen proteins, proteoglycan versican, and the TGF-β pathway. Finally, we review the role of genetics in patient management and prevention of RRD. We provide recommendations for genetic testing and prophylaxis of at-risk patients, and hypothesize on novel therapeutic approaches beyond surgical intervention., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims: To describe the prevalence of the Charles Bonnet syndrome (CBS) and search for potential CBS risk factors in a Dutch Stargardt disease (STGD1) cohort., Methods: Eighty-three patients with STGD1 were screened for CBS. They underwent a full eye examination. All patients completed the social functioning domain of the 36-Item Short Form Health Survey questionnaire. Participants suspected of CBS were interviewed to further evaluate their visual hallucinations., Results: CBS prevalence was 8.4%. Six out of seven patients with CBS were women. CBS was not associated with age (p=0.279, Mann-Whitney). Patients with CBS had a significant lower social functioning score (p<0.05, Mann-Whitney). All seven patients with CBS were in the category of vision impairment (visual acuity <6/12, but ≥3/60). Moreover, first hallucinations manifested after a drop in visual acuity. The retinal atrophic area of the worst eye tended to be lower in the CBS group (range 0.11-9.86 mm 2 ) as compared with controls (range 0-180 mm 2 ). There was no relation between the position of the scotoma and the location of the visual hallucinations., Conclusion: The relative high CBS prevalence in STGD1 suggests that CBS may be more prevalent in younger ophthalmic patients than currently presumed. In this specific group of patients, we established social isolation and acquired vision impairment as risk factors for CBS. There was a female preponderance among patients with CBS. Age and retinal pigment epithelium atrophy were not identified as significant risk factors. We should actively diagnose CBS in patients of any age who fulfil the criteria for the category vision impairment, especially in cases where social isolation is suspected., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To compare the treatment success of air with fluorinated gas (20% SF 6 or 14% C 3 F 8 ) tamponade in pars plana vitrectomy for primary rhegmatogenous retinal detachment., Methods: A retrospective cohort study comprised of 1023 consecutive primary retinal detachment cases between 2014 and 2020. We employed a univariate multivariable binary logistic regression model., Results: We used intraocular gas tamponades in 872 cases with PVR grade B or lower: air tamponade was used in 414 eyes and 458 eyes were treated with a type of fluorinated gas tamponade. There was no significant difference in the type of tamponade with regard to the re-detachment rate (95% CI -1.0% and 4.1%). Additionally, also in the subgroup of rhegmatogenous retinal detachments with inferior located retinal defects we found no significant difference between the two types of tamponade (p = 0.54 Fisher's exact). The multivariable model, which included tamponade, PVR grade, a retinal detachment involving the 6 o'clock position and age as covariates, also showed no significant effect of tamponade choice on treatment success (OR 0.5, 95% 0.2-1.0, p = 0.10)., Conclusion: We found no difference in treatment success with air tamponade versus fluorinated gas tamponades in the repair of primary retinal detachments, this also includes inferiorly located retinal tears and detachments., (© 2022 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Diabetic retinopathy (DR) is a sight-threatening complication of diabetes mellitus (DM) and it contributes substantially to the burden of disease globally. During the last decades, the development of multiple imaging modalities to evaluate DR, combined with emerging treatment possibilities, has led to the implementation of large-scale screening programmes resulting in improved prevention of vision loss. However, not all patients are able to participate in such programmes and not all are at equal risk of DR development and progression. In this review, we discuss the relevance of the currently available imaging modalities for the evaluation of DR: colour fundus photography (CFP), ultrawide-field photography (UWFP), fundus fluorescein angiography (FFA), optical coherence tomography (OCT), OCT angiography (OCTA) and functional testing. Furthermore, we suggest where a particular imaging technique of DR may aid the evaluation of the disease in different clinical settings. Combining information from various imaging modalities may enable the design of more personalized care including the initiation of treatment and understanding the progression of disease more adequately., (© 2022 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

The Roma population is the largest transnational ethnic minority group in Europe, often facing socioeconomic inequalities and various health problems. In the present study, we investigated visual acuity and its influencing factors along with spectacle use of the Roma population in comparison with the general population in Hungary. A cross-sectional survey was carried out including 832 participants aged 20-64 years. We recorded the uncorrected visual acuity along with anthropometric, demographic, socioeconomic and health-related data of each individual. Although the average uncorrected visual acuity was somewhat higher, the use of a visual aid was significantly less frequent in the Roma population, especially in the group with a visual acuity below 0.5 in both eyes (14.3% vs. 77.1%, p < 0.001). Age, abdominal obesity and disturbances of carbohydrate metabolism had a negative impact on visual acuity in both populations; however, the latter was a much stronger risk factor in the Roma population (OR 5.789, 95% CI 2.239-14.964, p < 0.001) than in the general population (OR 2.075, 95% CI 1.097-3.926, p = 0.025). Our results show serious unmet health needs within the Roma population, which calls for public health programs to improve poor primary care indicators on regular eye examination and much more rigorous diabetes control., (© 2022. The Author(s).)

Purpose: To evaluate reliability and repeatability of computer-assisted measurements of cone photoreceptor metrics on Heidelberg Engineering Spectralis™ High Magnification Module (HMM™) Automatic Real-time Tracking (ART™) images., Methods: We analyzed HMM™ images in three separate study arms. Computer-assisted cone identification software was validated using an open-access adaptive optics (AO) dataset. We compared results of the first arm to data from AO and histology. We evaluated intersession repeatability of our computer-assisted cone analysis in the second arm. We assessed the capability of HMM™ to visualize cones in the presence of pathology in the third arm., Results: We included 10 healthy subjects in the first arm of our study, 5 additional healthy participants in the second arm and 5 patients in the third arm. In total, we analyzed 225 regions of interest on HMM™ images. We were able to automatically identify cone photoreceptors and assess corresponding metrics at all eccentricities between 2 and 9° from the fovea. Cone density significantly declined with increasing eccentricity (p = 4.890E-26, Friedman test). With increasing eccentricity, we found a significant increase in intercell distance (p = 2.196E-25, Friedman test) and nearest neighbor distance (p = 1.997E-25, Friedman test). Cone hexagonality ranged between 71 and 85%. We found excellent automated intersession repeatability of cone density counts and spacing measurements. In pathology, we were also able to repeatedly visualize photoreceptors., Conclusion: Computer-assisted cone photoreceptor analysis on Spectralis™ HMM™ images is feasible, and most cone metrics show excellent repeatability. HMM™ imaging may be useful for photoreceptor analysis as progression marker in outer retinal disease., (© 2021. The Author(s).)

Background/aim: To validate a previously developed model for prediction of diabetic retinopathy (DR) for personalised retinopathy screening in persons with type 1 diabetes., Methods: Retrospective medical data of persons with type 1 diabetes treated in an academic hospital setting were used for analysis. Sight-threatening retinopathy (STR) was defined as the presence of severe non-proliferative DR, proliferative DR or macular oedema. The presence and grade of retinopathy, onset of diabetes, systolic blood pressure, and levels of haemoglobin A 1c were used to calculate an individual risk estimate and personalised screening interval. In persons with STR, the occurrence was compared with the calculated date of screening. The model's predictive performance was measured using calibration and discrimination techniques., Results: Of the 268 persons included in our study, 24 (9.0%) developed STR during a mean follow-up of 4.6 years. All incidences of STR occurred after the calculated screening date. By applying the model, the mean calculated screening interval was 30.5 months, which is a reduction in screening frequency of 61% compared with annual screening and 21% compared with biennial screening. The discriminatory ability was good (Harrell's C-statistic=0.82, 95% CI 0.74 to 0.90), and calibration showed an overestimation of risk in persons who were assigned to a higher risk for STR., Conclusion: This validation study suggests that a screening programme based on the previously developed prediction model is safe and efficient. The use of a personalised screening frequency could improve cost-effectiveness of diabetic eye care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To evaluate the clinical characteristics and investigate the role of surgical antibiotic prophylaxis (SAP) in acute endophthalmitis cases after cataract surgery., Design: Retrospective, consecutive case series., Participants: A total of 126 patients referred to a tertiary center from 2007 to 2015 for acute endophthalmitis after unilateral cataract surgery., Methods: All patients who underwent a vitreous biopsy were included. Clinical and microbiology data were reviewed, and associations with visual outcome were analyzed using multivariate logistic regression. Data regarding SAP via intracameral injection were also retrieved., Main Outcome Measures: Bacterial culture results and visual acuity outcome., Results: Bacterial growth was observed in 92 of 126 cases (73%). Among these positive cultures, 49 (53.3%), 29 (31.5%), and 13 (14.1%) were coagulase-negative staphylococci, other gram-positive, and gram-negative bacteria, respectively. Among the 77 gram-positive strains tested, 76 (98.7%) were vancomycin-sensitive; among the 12 gram-negative strains tested, all 12 (100%) were ceftazidime-sensitive. Best achieved visual acuity outcome was ≥20/40 Snellen in 77 of 114 cases (67.5%). On multivariate analysis, we found an association between visual outcome of worse than 20/40 Snellen and a positive culture of more virulent bacteria (gram-negative and other gram-positive groups) and presentation with light perception or worse, with an odds ratio of 3.3 and 3.0, respectively. A subgroup of 25 cases (19.8%) developed endophthalmitis despite receiving a SAP by cefuroxime at the end of cataract surgery., Conclusions: Two-thirds of the patients in this endophthalmitis cohort experienced a visual outcome of ≥20/40 Snellen. Efficacy of primary treatment with vancomycin combined with ceftazidime is supported by this study. A subgroup treated prophylactically with cefuroxime demonstrated that SAP alone does not prevent endophthalmitis. This highlights the importance of surgical factors in the prevention of postoperative endophthalmitis., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to evaluate the functional relevance of longitudinal changes in hyperautofluorescent areas and flecks in Stargardt disease (STGD1) using short-wavelength autofluorescence (SW-AF) imaging., Methods: In this prospective, longitudinal study, 31 patients with STGD1 (56 eyes) underwent microperimetry (MP) and SW-AF imaging twice in 3 to 5 years. A total of 760 MP test points were included in the statistical analysis based on stable fixation and accurate alignment of SW-AF and MP. Autofluorescence intensity was qualitatively assessed in all MP test points. Small circumscriptive hyperautofluorescent lesions were defined as flecks. Longitudinal imaging characteristics observed on SW-AF were classified into the following categories: appearing, disappearing, and stable flecks, stable hyperautofluorescent, and stable background autofluorescence. The relationship between SW-AF intensity changes and MP changes was analyzed using a linear mixed model corrected for baseline sensitivity., Results: Retinal sensitivity declined most in locations without change in SW-AF intensity. Functional decline per year was significantly larger in flecks that disappeared (-0.72 ± 1.30 dB) compared to flecks that appeared (-0.34 ± 0.65 dB), if baseline sensitivity was high (≥10 dB; P < 0.01). The correlation between the change observed on SW-AF and the sensitivity change significantly depended on the sensitivity at baseline (P = 0.000)., Conclusions: Qualitative longitudinal assessment of SW-AF poorly reflected the retinal sensitivity loss observed over the course of 3 to 5 years., Translational Relevance: When aiming to assess treatment effect on lesion level, a multimodal end point including MP focused on hyperautofluorescent lesions appears essential but needs further studies on optimizing MP grids, eye-tracking systems, and alignment software.

Purpose: To investigate the long-term outcomes of patients who underwent vitrectomy for proliferative diabetic retinopathy., Methods: Cumulative incidences were calculated for low vision (<0.3), re-vitrectomy in the study eye and fellow eye vitrectomy. To identify potential prognostic factors that associate with these outcomes, we used multivariable Cox regression models., Results: In a total of 217 patients, we found 1-, 5- and 10-year cumulative incidences of low vision in the study eye of 24%, 31% and 39%, respectively. For both eyes, these rates were, respectively, 10%, 14% and 14%. Low vision in both eyes was associated with higher age and worse contralateral visual acuity. The 1-, 5- and 10-year cumulative incidences for re-vitrectomy in the study eye were 16%, 27% and 27%, respectively, and for a vitrectomy in the fellow eye 24%, 40% and 54%, respectively. Re-vitrectomy of the study eye was associated with worse contralateral visual acuity, while vitrectomy of the fellow eye was associated with shorter diabetes duration, worse contralateral visual acuity, higher HbA1c level and worse diabetic retinopathy severity stage of the fellow eye., Conclusion: Functional visual acuity in at least one eye was achieved or preserved in most patients. After 10 years, about a quarter of all patients underwent a re-vitrectomy, while more than half of the patients needed a vitrectomy of the fellow eye. Knowledge of these long-term outcomes is essential when counselling patients for a vitrectomy., (© 2020 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Purpose: To investigate hyperreflective foci (HF) on spectral-domain optical coherence tomography in patients with Type 1 diabetes mellitus across different stages of diabetic retinopathy (DR) and diabetic macular edema (DME) and to study clinical and morphological characteristics associated with HF., Methods: Spectral-domain optical coherence tomography scans and color fundus photographs were obtained of 260 patients. Spectral-domain optical coherence tomography scans were graded for the number of HF and other morphological characteristics. The distribution of HF across different stages of DR and DME severity were studied. Linear mixed-model analysis was used to study associations between the number of HF and clinical and morphological parameters., Results: Higher numbers of HF were found in patients with either stage of DME versus patients without DME (P < 0.001). A trend was observed between increasing numbers of HF and DR severity, although significance was only reached for moderate nonproliferative DR (P = 0.001) and proliferative DR (P = 0.019). Higher numbers of HF were associated with longer diabetes duration (P = 0.029), lower high-density lipoprotein cholesterol (P = 0.005), and the presence of microalbuminuria (P = 0.005). In addition, HF were associated with morphological characteristics on spectral-domain optical coherence tomography, including central retinal thickness (P = 0.004), cysts (P < 0.001), subretinal fluid (P = 0.001), and disruption of the external limiting membrane (P = 0.018)., Conclusion: The number of HF was associated with different stages of DR and DME severity. The associations between HF and clinical and morphological characteristics can be of use in further studies evaluating the role of HF as a biomarker for disease progression and treatment response.

Purpose: To study the levels of complement activation in different disease stages of AMD and the influence of genetic polymorphisms in complement genes., Methods: We included 797 patients with AMD and 945 controls from the European Genetic Database. Patients were grouped into five AMD stages: early AMD, intermediate AMD, central geographic atrophy, active choroidal neovascularization or inactive choroidal neovascularization. Differences in complement activation, as defined by the systemic C3d/C3 ratio, between AMD stages were evaluated using general linear modeling. In addition, we evaluated the influence of 18 genetic AMD polymorphisms in complement genes and their effect on complement activation. Differences in complement activation between stages were evaluated stratifying by complement associated haplotypes., Results: Complement activation levels differed significantly between AMD disease stages. As compared with controls, the C3d/C3 ratio was higher in patients with intermediate AMD (P < 0.001) and central geographic atrophy (P = 0.001). Two polymorphisms in CFH (rs10922109 and rs570618) and one in CFB (rs116503776) were significantly associated with complement activation. The association between AMD disease stage and complement activation was more pronounced in patients with haplotypes associated with the highest complement activation., Conclusions: In general, consecutive AMD disease stages showed increasing levels of complement activation, especially in individuals with a genetic burden in complement genes. These findings contribute to the discussion on the pathogenesis of AMD in relation to complement activation and might suggest refinement in patient selection and the optimum window of treatment with complement inhibitors. Prospective studies are needed to confirm these results.

Purpose: To describe foveal sparing (FS) in central retinal dystrophies (RD)., Methods: Participants for this retrospective study were identified from the retinal dystrophy database of the Department of Ophthalmology at Radboud University Medical Center. FS was defined as an intact foveal structure surrounded by at least 180° of chorioretinal atrophy, and a best-corrected visual acuity (BCVA) of <1.0 logMAR (>20/200 Snellen). Eligible eyes were identified using fundus autofluorescence (FAF) images, and FS was confirmed using near-infrared reflectance (NIR) imaging and spectral-domain optical coherence tomography when available. Clinical and demographic data were extracted from medical records. We performed quantification of FS and chorioretinal atrophic areas using semiautomated software on fundus autofluorescence and NIR images. We calculated the chronologic change using eye-wise linear regression., Results: We identified 36 patients (56 eyes) with FS. RDs included: Stargardt disease (STGD1;20 patients), central areolar choroidal dystrophy (CACD; 7 patients), mitochondrial retinal dystrophy (MRD; 6 patients), pseudo-Stargardt pattern dystrophy (PSPD; 3 patients). Median age at first presentation was 60 (interquartile range [IQR] 54-63) years. Median BCVA at first presentation ranged from 20/25 Snellen in STGD1, to 20/38 Snellen in MRD. Progression of the chorioretinal atrophic area ranged from 0.26 (0.25-0.28) mm/year in PSPD, to 0.14 (0.11-0.22) in CACD. Change in FS area over time was similar between the different dystrophies., Conclusions: The presence of FS in different RDs suggests a disease-independent mechanism that prolongs the survival of the fovea. The associated preservation of BCVA is important for the individual prognosis and has implications for the design of therapeutic trials for RDs.

Background: Early-onset photoreceptor dystrophies are a major cause of irreversible visual impairment in children and young adults. This clinically heterogeneous group of disorders can be caused by mutations in many genes. Nevertheless, to date, 30%-40% of cases remain genetically unexplained. In view of expanding therapeutic options, it is essential to obtain a molecular diagnosis in these patients as well. In this study, we aimed to identify the genetic cause in two siblings with genetically unexplained retinal disease., Methods: Whole exome sequencing was performed to identify the causative variants in two siblings in whom a single pathogenic variant in TULP1 was found previously. Patients were clinically evaluated, including assessment of the medical history, slit-lamp biomicroscopy, and ophthalmoscopy. In addition, a functional analysis of the putative splice variant in TULP1 was performed using a midigene assay., Results: Clinical assessment showed a typical early-onset photoreceptor dystrophy in both the patients. Whole exome sequencing identified two pathogenic variants in TULP1, a c.1445G>A (p.(Arg482Gln)) missense mutation and an intronic c.718+23G>A variant. Segregation analysis confirmed that both siblings were compound heterozygous for the TULP1 c.718+23G>A and c.1445G>A variants, while the unaffected parents were heterozygous. The midigene assay for the c.718+23G>A variant confirmed an elongation of exon 7 leading to a frameshift., Conclusion: Here, we report the first near-exon RNA splice variant that is not present in a consensus splice site sequence in TULP1, which was found in a compound heterozygous manner with a previously described pathogenic TULP1 variant in two patients with an early-onset photoreceptor dystrophy. We provide proof of pathogenicity for this splice variant by performing an in vitro midigene splice assay, and highlight the importance of analysis of noncoding regions beyond the noncanonical splice sites in patients with inherited retinal diseases., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Purpose: To raise awareness of Stargardt disease (STGD1) patients without fundus abnormalities., Methods: Medical records were evaluated for age at onset, initial symptoms and diagnosis, reason for delay of diagnosis, age at STGD1 diagnosis, best-corrected visual acuity (BCVA), ophthalmoscopy, fundus photography, fundus autofluorescence (FAF), fluorescein angiography (FA), spectral-domain optical coherence tomography (SD-OCT), full-field electroretinography (ffERG), color vision test, and the presence of ABCA4 variants., Results: In 11.1% of our STGD1 cohort of 280 patients, no fundus abnormalities were observed at first ophthalmic consultation. The median age at onset was 8 years (range, 1-18). There was a median delay in diagnosis of 3 years (range, 0-19) in 27 out of 31 patients, which resulted in a median age at diagnosis of 12 years (range, 7-26). Patients were misdiagnosed with amblyopia, myopia, optic disk pathology, mental health problems, tension headache, neuritis bulbaris, and uveitis. Subtle abnormalities, such as lipofuscin accumulation, were seen on FAF at an earlier disease stage than in ophthalmoscopy. On SD-OCT, this included a thickened external limiting membrane. Color vision tests showed red-green insufficiency in 79% of patients. Reduced ERG amplitudes were only present in 26% (N = 8) and a dark choroid sign in 65% of the patients. Visual acuity considerably fluctuated in the first 5 years after onset. The majority of the patients (65%) carried a least one variant with a severe effect on ABCA4 function., Conclusions: Childhood-onset STGD1 patients were diagnosed with a delay of median 3 years. The presence of accurate competence, equipment, and the possibility for genetic screening is required; therefore, we recommend to refer children with visual complaints without initial fundus abnormalities to a specialized ophthalmologic center. In particular, to diagnose patients at an early stage of disease is of increased importance with the advent of new therapeutic possibilities.

Purpose: To describe the clinical and genetic spectrum of RP1-associated retinal dystrophies., Methods: In this multicenter case series, we included 22 patients with RP1-associated retinal dystrophies from 19 families from The Netherlands and Japan. Data on clinical characteristics, visual acuity, visual field, ERG, and retinal imaging were extracted from medical records over a mean follow-up of 8.1 years., Results: Eleven patients were diagnosed with autosomal recessive macular dystrophy (arMD) or autosomal recessive cone-rod dystrophy (arCRD), five with autosomal recessive retinitis pigmentosa (arRP), and six with autosomal dominant RP (adRP). The mean age of onset was 40.3 years (range 14-56) in the patients with arMD/arCRD, 26.2 years (range 18-40) in adRP, and 8.8 years (range 5-12) in arRP patients. All patients with arMD/arCRD carried either the hypomorphic p.Arg1933* variant positioned close to the C-terminus (8 of 11 patients) or a missense variant in exon 2 (3 of 11 patients), compound heterozygous with a likely deleterious frameshift or nonsense mutation, or the p.Gln1916* variant. In contrast, all mutations identified in adRP and arRP patients were frameshift and/or nonsense variants located far from the C-terminus., Conclusions: Mutations in the RP1 gene are associated with a broad spectrum of progressive retinal dystrophies. In addition to adRP and arRP, our study provides further evidence that arCRD and arMD are RP1-associated phenotypes as well. The macular involvement in patients with the hypomorphic RP1 variant suggests that macular function may remain compromised if expression levels of RP1 do not reach adequate levels after gene augmentation therapy.

Purpose: To investigate the relationship between baseline number of hyperreflective foci (HF) on spectral domain optical coherence tomography (SD-OCT) in patients with diabetic macular edema (DME), as well as the dynamics of HF during treatment with anti-vascular endothelial growth factor (VEGF), and treatment response., Methods: We evaluated patients diagnosed with DME scheduled for treatment with intravitreal bevacizumab. Eyes were classified as adequate or insufficient treatment responders based on logMAR visual acuity improvement and central retinal thickness (CRT) decrease after three consecutive injections. Associations between number of HF at baseline and treatment response, the change in HF over the course of treatment, and the distribution of HF within the retinal layers were evaluated., Results: In 54 eyes of 41 patients, mean number of HF and CRT decreased after intravitreal treatment with bevacizumab (p = 0.002 and p<0.001 respectively). Decrease in CRT after 3 months was independently associated with a higher number of HF at baseline (estimated effect -2.61, 95% CI [-4.42--0.31], p = 0.006). Eyes with adequate treatment response presented with more HF at baseline (OR 1.106, 95% CI [1.012-1.210], p = 0.030) than eyes with insufficient treatment response. Most HF were located within the inner retinal layers, and decrease of HF was mostly due to a decrease of inner retinal HF., Conclusions: In patients with DME treated with anti-VEGF, higher baseline numbers of HF have predictive value for treatment response in terms of visual acuity improvement and CRT decrease after 3 months. In addition, HF were responsive to anti-VEGF therapy., Competing Interests: The authors have declared that no competing interests exist.

Retinitis pigmentosa (RP) encompasses a group of inherited retinal dystrophies characterized by the primary degeneration of rod and cone photoreceptors. RP is a leading cause of visual disability, with a worldwide prevalence of 1:4000. Although the majority of RP cases are non-syndromic, 20-30% of patients with RP also have an associated non-ocular condition. RP typically manifests with night blindness in adolescence, followed by concentric visual field loss, reflecting the principal dysfunction of rod photoreceptors; central vision loss occurs later in life due to cone dysfunction. Photoreceptor function measured with an electroretinogram is markedly reduced or even absent. Optical coherence tomography (OCT) and fundus autofluorescence (FAF) imaging show a progressive loss of outer retinal layers and altered lipofuscin distribution in a characteristic pattern. Over the past three decades, a vast number of disease-causing variants in more than 80 genes have been associated with non-syndromic RP. The wide heterogeneity of RP makes it challenging to describe the clinical findings and pathogenesis. In this review, we provide a comprehensive overview of the clinical characteristics of RP specific to genetically defined patient subsets. We supply a unique atlas with color fundus photographs of most RP subtypes, and we discuss the relevant considerations with respect to differential diagnoses. In addition, we discuss the genes involved in the pathogenesis of RP, as well as the retinal processes that are affected by pathogenic mutations in these genes. Finally, we review management strategies for patients with RP, including counseling, visual rehabilitation, and current and emerging therapeutic options., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims: To investigate retinal microaneurysms in patients with diabetic macular oedema (DME) by optical coherence tomography angiography (OCTA) according to their location and morphology in relationship to their clinical properties, leakage on fundus fluorescein angiography (FFA) and retinal thickening on structural OCT., Methods: OCTA and FFA images of 31 eyes of 24 subjects were graded for the presence of microaneurysms. The topographical and morphological appearance of microaneurysms on OCTA was evaluated and classified. For each microaneurysm, the presence of focal leakage on FFA and associated retinal thickening on OCT was determined., Results: Of all microaneurysms flagged on FFA, 295 out of 513 (58%) were also visible on OCTA. Microaneurysms with focal leakage and located in a thickened retinal area were more likely to be detected on OCTA than not leaking microaneurysms in non-thickened retinal areas (p=0.001). Most microaneurysms on OCTA were seen in the intermediate (23%) and deep capillary plexus (22%). Of all microaneurysms visualised on OCTA, saccular microaneurysms were detected most often (31%), as opposed to pedunculated microaneurysms (9%). Irregular, fusiform and mixed fusiform/saccular-shaped microaneurysms had the highest likeliness to leak and to be located in thickened retinal areas (p<0.001, p<0.001 and p=0.001)., Conclusions: Retinal microaneurysms in DME could be classified topographically and morphologically by OCTA. OCTA detected less microaneurysms than FFA, and this appeared to be dependent on leakage activity and retinal thickening. Morphological appearance of microaneurysms (irregular, fusiform and mixed saccular/fusiform) was associated with increased leakage activity and retinal thickening., Competing Interests: Competing interests: None declared.

Background: The discussion on the use of bevacizumab is still ongoing and often doctors are deterred from using bevacizumab due to legal or political issues. Bevacizumab is an effective, safe and inexpensive treatment option for neovascular age-related macular degeneration (AMD), albeit unregistered for the disease. Therefore, in some countries ophthalmologists use the equally effective but expensive drugs ranibizumab and aflibercept. We describe the economic consequences of this dilemma surrounding AMD treatment from a societal perspective., Methods: We modelled cost-effectiveness of treatment with ranibizumab (as-needed), aflibercept (bimonthly) and bevacizumab (as-needed). Effectiveness was estimated by systematic review and meta-analysis. The drug with the most favourable cost-effectiveness profile compared to bevacizumab was used for threshold analyses. First, we determined how much we overspend per injection. Second, we calculated the required effectiveness to justify the current price and the reasonable price for a drug leading to optimal vision. Finally, we estimated how much Europe overspends if bevacizumab is not first choice., Results: Bevacizumab treatment costs €27,087 per year, about €4,000 less than aflibercept and €6,000 less than ranibizumab. With similar effectiveness for all drugs as shown by meta-analysis, bevacizumab was the most cost-effective. Aflibercept was chosen for threshold analyses. Aflibercept costs €943 per injection, but we determined that the maximum price to be cost-effective is €533. Alternatively, at its current price, aflibercept should yield about twice the visual gain. Even when optimal vision can be achieved, the maximum price for any treatment is €37,453 per year. Most importantly, Europe overspends €335 million yearly on AMD treatment when choosing aflibercept over bevacizumab., Conclusion: Bevacizumab is the most cost-effective treatment for AMD, yet is not the standard of care across Europe. The registered drugs ranibizumab and aflibercept lead to large overspending without additional health benefits. Health authorities should consider taking steps to implement bevacizumab into clinical practice as first choice., Competing Interests: The authors have declared that no competing interests exist.

Leber congenital amaurosis (LCA) is a rare inherited retinal disorder affecting approximately 1:50,000 people worldwide. So far, mutations in 25 genes have been associated with LCA, with CEP290 (encoding the Centrosomal protein of 290 kDa) being the most frequently mutated gene. The most recurrent LCA-causing CEP290 mutation, c.2991+1655A>G, causes the insertion of a pseudoexon into a variable proportion of CEP290 transcripts. We previously demonstrated that antisense oligonucleotides (AONs) have a high therapeutic potential for patients homozygously harbouring this mutation, although to date, it is unclear whether rescuing one single allele is enough to restore CEP290 function. Here, we assessed the AON efficacy at RNA, protein and cellular levels in samples that are compound heterozygous for this mutation, together with a protein-truncating mutation in CEP290 . We demonstrate that AONs can efficiently restore splicing and increase protein levels. However, due to a high variability in ciliation among the patient-derived cell lines, the efficacy of the AONs was more difficult to assess at the cellular level. This observation points towards the importance of the severity of the second allele and possibly other genetic variants present in each individual. Overall, AONs seem to be a promising tool to treat CEP290 -associated LCA, not only in homozygous but also in compound heterozygous carriers of the c.2991+1655A>G variant., Competing Interests: Rob W. J. Collin is an inventor on a filed patent (P6037013PCT) that is related to the contents of this manuscript, and which has been licensed to the pharmaceutical company ProQR Therapeutics. The authors declare no further conflict of interest.

Purpose: Choroidal endothelial cells play a central role in the pathogenesis of age-related macular degeneration (AMD). Protocols for isolating primary choroidal endothelial cells have been described but require access to human donor eyes, which is a limiting factor. Therefore, a conditionally immortalized choroidal endothelial cell (ciChEnC) line has been established., Methods: Choroidal endothelial cells were selected by magnetic-activated cell sorting and conditionally immortalized using temperature-sensitive simian virus 40 large T antigen and human telomerase. The cell line obtained was characterized based on expression of endothelial marker proteins and endothelial cell-specific responses to various stimuli. Binding of AMD-associated and non-AMD variants of complement factor H in the context of a recombinant CCP6-8 (complement control protein domains 6-8) construct was determined using ELISA., Results: ciChEnCs maintained morphology and von Willebrand factor and vascular endothelial cadherin expression for up to 27 passages. The cells internalized acetylated low-density lipoprotein, formed tubes on Matrigel, and increased intercellular adhesion molecule-1 expression in response to tumor necrosis factor-α. Cells grew into dense monolayers with barrier function and showed characteristics of choriocapillary cells, such as expression of plasmalemma vesicle-associated protein, human leukocyte antigen ABC, carbonic anhydrase IV, and membrane indentations reflecting fenestrations. ciChEnCs synthesized glycosaminoglycans chondroitin sulfate and the complement factor H ligand heparan sulfate. Interestingly, binding of the AMD-associated 402H variant of factor H to ciChEnC was significantly decreased compared to the 402Y variant., Conclusions: A novel ciChEnC cell line with choriocapillary characteristics has been established and should greatly facilitate investigation of the pathogenesis of AMD in the context of the choriocapillary microenvironment.

Background: Each inherited retinal disorder is rare, but together, they affect millions of people worldwide. No treatment is currently available for these blinding diseases, but promising new options-including gene therapy-are emerging. Arguably, the most prevalent retinal dystrophy is Stargardt disease. In each case, the specific combination of ABCA4 variants (> 900 identified to date) and modifying factors is virtually unique. It accounts for the vast phenotypic heterogeneity including variable rates of functional and structural progression, thereby potentially limiting the ability of phase I/II clinical trials to assess efficacy of novel therapies with few patients. To accommodate this problem, we developed and validated a sensitive and reliable composite clinical trial endpoint for disease progression based on structural measurements of retinal degeneration., Methods and Findings: We used longitudinal data from early-onset Stargardt patients from the Netherlands (development cohort, n = 14) and the United Kingdom (external validation cohort, n = 18). The composite endpoint was derived from best-corrected visual acuity, fundus autofluorescence, and spectral-domain optical coherence tomography. Weighting optimization techniques excluded visual acuity from the composite endpoint. After optimization, the endpoint outperformed each univariable outcome, and showed an average progression of 0.41° retinal eccentricity per year (95% confidence interval, 0.30-0.52). Comparing with actual longitudinal values, the model accurately predicted progression (R2, 0.904). These properties were largely preserved in the validation cohort (0.43°/year [0.33-0.53]; prediction: R2, 0.872). We subsequently ran a two-year trial simulation with the composite endpoint, which detected a 25% decrease in disease progression with 80% statistical power using only 14 patients., Conclusions: These results suggest that a multimodal endpoint, reflecting structural macular changes, provides a sensitive measurement of disease progression in Stargardt disease. It can be very useful in the evaluation of novel therapeutic modalities in rare disorders.

Purpose: Current standards and guidelines aimed at preventing retinal phototoxicity during intentional exposures do not specifically evaluate the contribution of endogenous photosensitizers. However, certain retinal diseases are characterized by abnormal accumulations of potential photosensitizers such as lipofuscin bisretinoids in the retinal pigment epithelium (RPE). We sought to determine these contributions by a numerical assessment of in-vivo photo-oxidative stress during irradiation of RPE lipofuscin., Methods: Based on the literature, we calculated the retinal exposure levels, optical filtering of incident radiation by the ocular lens, media, photoreceptors, and RPE melanin, light absorption by lipofuscin, and photochemical effects in the RPE in two situations: exposure to short-wavelength (λ = 488 nm) fundus autofluorescence (SW-AF) excitation light and exposure to indirect (diffuse) sunlight., Results: In healthy persons at age 20, 40, and 60, respectively, the rate of oxygen photoconsumption by lipofuscin increases by 1.3, 1.7, and 2.4 fold during SW-AF-imaging as compared to diffuse sunlight. In patients with STGD1 below the age of 30, this rate was 3.3-fold higher compared to age-matched controls during either sunlight or SW-AF imaging., Conclusions: Our results suggest that the RPE of patients with STGD1 is generally at increased risk of photo-oxidative stress, while exposure during SW-AF-imaging amplifies this risk. These theoretical results have not yet been verified with in-vivo data due to a lack of sufficiently sensitive in-vivo measurement techniques.

Purpose: To study outer retinal deterioration in relation to clinical disease activity in patients with birdshot chorioretinopathy using fundus autofluorescence and spectral-domain optical coherence tomography (OCT)., Methods: A single-centre retrospective cohort study was carried out on 42 eyes of 21 patients with birdshot disease, using a multimodal imaging approach including fundus autofluorescence, OCT, fluorescein angiography and indocyanine green angiography in combination with a patient chart review. The patients' overall clinical activity of retinal vasculitis during the follow-up period was determined by periods of clinical activity as indicated by fluorescein angiography and associated treatment decisions. Image analysis was performed to examine the spatial correspondence between autofluorescence changes and disruption of the photoreceptor inner segment ellipsoid zone on OCT., Results: Three common types of outer retinal lesions were observed in fovea-centred images of 43% of patients: circular patches of chorioretinal atrophy, ellipsoid zone disruption on OCT, and outer retinal atrophy on autofluorescence and OCT. There was good spatial correspondence between ellipsoid zone disruption and areas of diffuse hyper-autofluorescence outside the fovea. Interestingly, the ellipsoid zone disruption recovered in four out of seven patients upon intensified therapeutic immunosuppression., Conclusion: Most patients only developed peripapillary atrophy and occasional perivascular hypo-autofluorescence. A multimodal imaging approach with autofluorescence imaging and OCT may help to detect ellipsoid zone disruption in the central retina of patients with birdshot disease. Our results suggest that ellipsoid zone disruption may be related to both the activity and duration of retinal vasculitis, and could help to determine therapeutic success in birdshot disease., (© 2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: Asymmetry in disease progression between left and right eyes can occur in Stargardt disease (STGD1), and this needs to be considered in novel therapeutic trials with a fellow-eye paired controlled design. This study investigated the inter-eye discordance of best-corrected visual acuity (BCVA) and progression of RPE atrophy in STGD1., Methods: We performed a retrospective cohort study collecting 68 STGD1 patients (136 eyes) with ≥1 ABCA4 variants and ≥0.5-year follow-up on BCVA and fundus autofluorescence. We compared inter-eye correlations of RPE atrophy progression between early-onset (≤10 years), intermediate-onset (11-44), and late-onset (≥45) STGD1 and ABCA4 variant combinations by χ2 tests. We identified associations of discordant baseline BCVA and RPE atrophy with discordant RPE atrophy progression by odds ratios (OR). We defined discordance by differences >1.5 interquartile ranges ± first/third interquartiles., Results: Progression of RPE atrophy correlated moderately between eyes (ρ = 0.766), which decreased with later onset (P = 9.8 × 10-7) and lower pathogenicity of ABCA4 combinations (P = 0.007). Twelve patients (17.6%) had discordant inter-eye RPE atrophy progression, associated with baseline discordance of RPE atrophy (OR, 6.50 [1.35-31.34]), but not BCVA (OR, 0.33 [0.04-2.85])., Conclusions: Lower inter-eye correlations are more likely found in late-onset STGD1 and patients carrying low pathogenic ABCA4 combinations. To achieve the highest power in a therapeutic trial, early-phase studies should minimize inter-eye discordance by selecting early-onset STGD1 patients carrying severe ABCA4 variants without evidence of asymmetry at baseline.

Purpose: Little is known regarding the therapeutic effect of carbonic anhydrase inhibitors (CAIs) in the management of cystic macular lesions in children with X-linked juvenile retinoschisis (XLRS) despite the fact that this disease often manifests during childhood. Therefore, our goal was to determine the efficacy of CAIs in the treatment of cystic macular lesions in children with XLRS., Methods: We used CAIs to treat cystic macular lesions in 18 eyes of nine children with XLRS. We evaluated the therapeutic effect of CAI treatment with the best-corrected visual acuity and foveal zone thickness (FZT) with spectral-domain optical coherence tomography. A reduction of at least 22.4% in FZT was defined as objective evidence of response., Results: Five of nine (55.6%) XLRS patients showed a significant reduction of FZT in both eyes over a median treatment interval of 6.8 months (range, 1-23). In four of five (80.0%) patients, this reduction was already apparent after 1 month of treatment. An improvement of visual acuity was observed in five eyes (27.8%) of three patients (33.3%). Six patients (66.6%) reported minor side effects., Conclusions: Treatment with CAIs decreased FZT in more than half of the children with XLRS. This effect was observed within 1 month in the majority of patients. Carbonic anhydrase inhibitor treatment restores retinal anatomy and may contribute to creating optimal circumstances for gene therapy.

Purpose: To describe the complications associated with hydrogel explants and to describe the indications, surgical technique, and risks involved in the removal of a hydrogel explant., Design: Single-center, retrospective interventional case series., Participants: Patients who underwent surgical removal of a symptomatic, swollen hydrogel explant., Methods: We reviewed the medical records of 457 consecutive patients (467 eyes in total) who underwent surgical removal of a symptomatic, swollen episcleral MIRAgel (MIRA Inc., Waltham, MA) explant at the Radboud University Medical Center from 1998 to 2011. We reviewed the initial symptoms, clinical findings, surgical aspects, and intraoperative and postoperative complications., Main Outcome Measures: Presenting symptoms, retinal redetachment rate, and intraoperative scleral perforation., Results: The median interval between initial placement of the hydrogel explant and removal of the explant was 159 months. More than 34% of the episcleral hydrogel explants developed symptomatic swelling and required surgical removal. Intraoperative scleral perforation or retinal redetachment related to the removal of the explant occurred in 11% of patients., Conclusions: The percentage of explants that ultimately develop symptomatic swelling is considerably higher than reported previously. A swollen hydrogel explant can be removed many years after the primary detachment surgery, and 11% of cases develop intraoperative scleral perforation or retinal redetachment., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To identify mutations in FAM161A underlying autosomal recessive retinitis pigmentosa (arRP) in the Dutch and Belgian populations and to investigate whether common FAM161A-associated phenotypic features could be identified., Methods: Homozygosity mapping, amplification-refractory mutation system (ARMS) analysis, and Sanger sequencing were performed to identify mutations in FAM161A. Microsatellite and SNP markers were genotyped for haplotype analysis. Patients with biallelic mutations underwent detailed ophthalmologic examinations, including measuring best-corrected visual acuity, extensive fundus photography with reflectance and autofluorescence imaging, and optical coherence tomography., Results: Homozygosity mapping in 230 Dutch individuals with suspected arRP yielded five individuals with a homozygous region harboring FAM161A. Sanger sequencing revealed a homozygous nonsense mutation (c.1309A>T; p.[Arg437*]) in one individual. Subsequent ARMS analysis and Sanger sequencing in Dutch and Belgian arRP patients resulted in the identification of seven additional individuals carrying the p.(Arg437*) mutation, either homozygously or compound heterozygously with another mutation. Haplotype analysis identified a shared haplotype block of 409 kb surrounding the p.(Arg437*) mutation in all patients, suggesting a founder effect. Although the age of onset was variable among patients, all eight developed pronounced outer retinal loss with severe visual field defects and a bull's eye-like maculopathy, followed by loss of central vision within 2 decades after the initial diagnosis in five subjects., Conclusions: A founder mutation in FAM161A p.(Arg437*) underlies approximately 2% of arRP cases in the Dutch and Belgian populations. The age of onset of the retinal dystrophy appears variable, but progression can be steep, with almost complete loss of central vision later in life.

Objective: To determine the refractive error in patients with autosomal recessive retinitis pigmentosa (arRP) caused by RP1 mutations and to compare it with that of other genetic subtypes of RP., Methods: Twenty-six individuals had arRP with RP1 mutations, 25 had autosomal dominant RP (adRP) with RP1 mutation, 8 and 33 had X-linked RP (xlRP) with RP2 and RPGR mutations, respectively, 198 and 93 had Usher syndrome and arRP without RP1 mutations, respectively. The median of the spherical equivalent (SE) and the IQR (Q25-Q75) was determined and multiple comparisons were performed., Results: arRP patients with RP1 mutations had SE median at -4.0 dioptres (D) OD (Ocula Dextra); -3.88 D OS (Ocula Sinistra), whereas arRP patients without RP1 mutations (-0.50 D OD; -0.75 D OS) and Usher syndrome patients (-0.50 D OD; -0.38 D OS) were significantly less myopic (p<0.0001). Conversely, myopia of xlRP patients with either an RPGR mutation (-4.50 D OD; -5.25 D OS) or an RP2 mutation (-6.25 D OD; -6.88 D OS) was not significantly different from the arRP group with RP1 mutations. arRP without RP1 mutations, Usher syndrome and adRP with RP1 mutation had a narrow IQR (-9.06 to -1.13 D), whereas arRP with RP1 mutations and xlRP with RP2 or RPGR mutations had a larger range (-9.06; -1.13 D)., Conclusions: arRP patients with RP1 mutations have myopia not different from patients with xlRP with RP2 or RPGR mutations, while RP patients from other genetic subgroups were emmetropic or mildly myopic. We suggest that arRP patients with high myopic refractive error should be preferentially analysed for RP1 mutations., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Purpose: This study investigated whether pain from intravitreal injections (IVIs) can be reduced by injecting with a 33-G needle instead of the commonly used 30-G needle. Additionally, several pain-related psychological factors were explored as predictors of outcome., Methods: This randomized crossover trial included 36 patients who received injections with both needles in randomized order. After the injection, patients rated IVI pain on a 0 to 10 scale. Before injection, distress and pain expectations were assessed. Afterward, patients rated the IVI procedure and anticipated consequences. In addition, we assessed the force necessary to penetrate the sclera for both needles in porcine eyes., Results: The 33-G needle did not result in lower IVI pain (2.8 vs. 3.1, P = 0.758) but tended to cause less vitreal reflux (0 vs. 5 times, P = 0.054). Factors related to more pain were distress, expecting IVI pain and discomfort, dissatisfaction with the preparation procedure, anticipating negative consequences, and female gender. Patients regarded povidone-iodine disinfection as particularly unpleasant. Exploration of the needles' mechanical properties showed that 33-G needles penetrate the sclera more easily., Conclusion: The thinner 33-G needle does not reduce IVI pain but may limit scleral damage. Future efforts could be aimed at optimizing patient information, reducing distress, and the use of better tolerable disinfectants.

Purpose: Abnormal choroidal blood flow is considered important in the pathogenesis of chronic central serous chorioretinopathy (CSC). Optical coherence tomography (OCT) angiography can image ocular blood cell flow and could thus provide novel insights in disease mechanisms of CSC. We evaluated depth-resolved flow in chronic CSC by OCT angiography compared to fluorescein angiography (FA) and indocyanine green angiography (ICGA)., Methods: Eighteen eyes with chronic CSC, and six healthy controls, were included. Two human observers annotated areas of staining, hypofluorescence, and hotspots on FA and ICGA, and areas of abnormal flow on OCT angiography. Interobserver agreement in annotating OCT angiography and FA/ICGA was measured by Jaccard indices (JIs). We assessed colocation of flow abnormalities and subretinal fluid visible on OCT, and the distance between hotspots on ICGA from flow abnormalities., Results: Abnormal areas were most frequently annotated in late-phase ICGA and choriocapillary OCT angiography, with moderately high (median JI, 0.74) and moderate (median JI, 0.52) interobserver agreement, respectively. Abnormalities on late-phase ICGA and FA colocated with those on OCT angiography. Aberrant choriocapillary OCT angiography presented as foci of reduced flow surrounded by hyperperfused areas. Hotspots on ICGA were located near hypoperfused spots on OCT angiography (mean distance, 168 μm). Areas with current or former subretinal fluid were colocated with flow abnormalities., Conclusions: On OCT angiography, chronic CSC showed irregular choriocapillary flow patterns, corresponding to ICGA abnormalities. These results suggest focal choriocapillary ischemia with surrounding hyperperfusion that may lead to subretinal fluid leakage.

Importance: The age at which the first signs of age-related macular degeneration (AMD) manifest is variable. Better insight into factors that influence disease onset has direct implications for preventive measures and patient counseling., Objective: To identify risk factors for an earlier age at onset of neovascular AMD., Design, Setting, and Participants: Retrospective cohort study, including patient data from the European Genetic Database collected between April 2006 and July 2010. All patients had at least 1 documented visit to the outpatient AMD clinic of the Radboud University Medical Center, Nijmegen, the Netherlands, a tertiary referral center for retinal disorders. In total, 275 patients with a known age at onset of neovascular AMD and a genetic risk analysis were included., Main Outcomes and Measures: Effects of several genetic, sociodemographic, behavioral, and ocular factors on the age at onset of neovascular AMD. The mean differences in the age at onset were determined using general linear models with the age at onset as the dependent variable., Results: Past smokers and current smokers developed neovascular AMD on average 4.9 (95% CI, 3.0-6.8) and 7.7 (95% CI, 5.3-10.0) years earlier, respectively, than never smokers (P < .001 for both). Compared with the reference group, the age at onset was 5.2 (95% CI, 2.8-7.7) years earlier for homozygous carriers of the A69S risk allele in the age-related maculopathy susceptibility 2 (ARMS2) gene (P < .001). Homozygous carriers of the Y402H risk variant in the complement factor H (CFH) gene developed neovascular AMD 2.8 (95% CI, 0.5-5.0) years earlier (P = .02). Patients carrying 4 risk alleles in CFH and ARMS2 developed neovascular AMD 12.2 (95% CI, 6.2-18.3) years earlier than patients with zero risk alleles (P < .001)., Conclusions and Relevance: Genetic and environmental risk factors influence the age at onset of neovascular AMD. Individuals at risk could be identified at an early age if and when preventive or therapeutic options become available. Insight into individual risk profiles might influence patients' consideration of interventions to increase their chance of avoiding vision loss from AMD.

Purpose: To investigate whether long-term protection from light exposure affects the rate of disease progression in patients with autosomal recessive Stargardt disease (STGD1), measured using fundus autofluorescence imaging., Design: Longitudinal, retrospective, interventional case series., Methods: Five patients with Stargardt disease protected 1 eye from light exposure by applying a black contact lens during waking hours for ≥12 months. Disease progression was followed by performing autofluorescence imaging at semi-regular intervals. Longitudinal changes in autofluorescence were studied by evaluating areas of decreased autofluorescence and areas of increased autofluorescence as a measure of retinal pigment epithelium damage and lipofuscin accumulation, respectively., Results: We observed less progression of decreased autofluorescence in 4 out of 5 light-protected eyes relative to their respective nonprotected eyes. The progression of increased autofluorescence, on the other hand, was highly variable and did not respond consistently to treatment., Conclusions: Areas of decreased autofluorescence may serve as a useful biomarker for measuring the progression of Stargardt disease. The reduced progression of decreased autofluorescence in the light-protected eyes suggests that light deprivation might be beneficial in patients with Stargardt disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To determine the efficacy of multiple versions of a commercially available arrayed primer extension (APEX) microarray chip for autosomal recessive retinitis pigmentosa (arRP)., Methods: We included 250 probands suspected of arRP who were genetically analyzed with the APEX microarray between January 2008 and November 2013. The mode of inheritance had to be autosomal recessive according to the pedigree (including isolated cases). If the microarray identified a heterozygous mutation, we performed Sanger sequencing of exons and exon-intron boundaries of that specific gene. The efficacy of this microarray chip with the additional Sanger sequencing approach was determined by the percentage of patients that received a molecular diagnosis. We also collected data from genetic tests other than the APEX analysis for arRP to provide a detailed description of the molecular diagnoses in our study cohort., Results: The APEX microarray chip for arRP identified the molecular diagnosis in 21 (8.5%) of the patients in our cohort. Additional Sanger sequencing yielded a second mutation in 17 patients (6.8%), thereby establishing the molecular diagnosis. In total, 38 patients (15.2%) received a molecular diagnosis after analysis using the microarray and additional Sanger sequencing approach. Further genetic analyses after a negative result of the arRP microarray (n = 107) resulted in a molecular diagnosis of arRP (n = 23), autosomal dominant RP (n = 5), X-linked RP (n = 2), and choroideremia (n = 1)., Conclusions: The efficacy of the commercially available APEX microarray chips for arRP appears to be low, most likely caused by the limitations of this technique and the genetic and allelic heterogeneity of RP. Diagnostic yields up to 40% have been reported for next-generation sequencing (NGS) techniques that, as expected, thereby outperform targeted APEX analysis.

A growing body of evidence suggests that phototransduction can be studied in the human eye in vivo by imaging of fast intrinsic optical signals (IOS). There is consensus concerning the limiting influence of motion-associated imaging noise on the reproducibility of IOS-measurements, especially in those employing spectral-domain optical coherence tomography (SD-OCT). However, no study to date has conducted a comprehensive analysis of this noise in the context of IOS-imaging. In this study, we discuss biophysical correlates of IOS, and we address motion-associated imaging noise by providing correctional post-processing methods. In order to avoid cross-talk of adjacent IOS of opposite signal polarity, cellular resolution and stability of imaging to the level of individual cones is likely needed. The optical Stiles-Crawford effect can be a source of significant IOS-imaging noise if alignment with the peak of the Stiles-Crawford function cannot be maintained. Therefore, complete head stabilization by implementation of a bite-bar may be critical to maintain a constant pupil entry position of the OCT beam. Due to depth-dependent sensitivity fall-off, heartbeat and breathing associated axial movements can cause tissue reflectivity to vary by 29% over time, although known methods can be implemented to null these effects. Substantial variations in reflectivity can be caused by variable illumination due to changes in the beam pupil entry position and angle, which can be reduced by an adaptive algorithm based on slope-fitting of optical attenuation in the choriocapillary lamina.

Purpose: Defects in MAK, encoding a protein localized to the photoreceptor connecting cilium, have recently been associated with autosomal recessive retinitis pigmentosa (RP). The aim of this study is to describe our detailed clinical observations in patients with MAK-associated RP, including an assessment of syndromic symptoms frequently observed in ciliopathies., Methods: In this international collaborative study, 11 patients carrying nonsense or missense mutations in MAK were clinically evaluated, including extensive assessment of the medical history, slit-lamp biomicroscopy, ophthalmoscopy, kinetic perimetry, electroretinography (ERG), spectral-domain optical coherence tomography (SD-OCT), autofluorescence imaging and fundus photography. Additionally, we used a questionnaire to evaluate the presence of syndromic features and tested the olfactory function., Results: MAK-associated RP is not associated with syndromic features, not even with subclinical dysfunction of the olfactory apparatus. All patients experienced typical RP symptoms of night blindness followed by visual field constriction. Symptoms initiated between childhood and the age of 43 (mean: 23 years). Although some patients experienced vision loss, the visual acuity remained normal in most patients. ERG and ophthalmoscopy revealed classic RP characteristics, and SD-OCT demonstrated thinning of the overall retina, outer nuclear layer and photoreceptor-pigment epithelium complex., Conclusion: Nonsense and missense mutations in MAK give rise to a non-syndromic recessive RP phenotype without apparent extra-ocular features. When compared to other retinal ciliopathies, MAK-associated RP appears to be relatively mild and shows remarkable resemblance to RP1-associated RP, which could be explained by the close functional relation of these proteins., (© 2014 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)