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Myrte B Breukink,1,* Alexander JM Dingemans,1,* Anneke I den Hollander,1,2 Jan EE Keunen,1 Robert E MacLaren,3,4 Sascha Fauser,5 Giuseppe Querques,6 Carel B Hoyng,1 Susan M Downes,3,4 Camiel JF Boon1,7 1Department of Ophthalmology, 2Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands; 3Oxford Eye Hospital, Oxford University Hospitals NHS Trust, 4Nuffield Laboratory of Ophthalmology and NIHR Biomedical Research Centre, Department of Clinical Neurosciences, University of Oxford, Oxford, UK; 5Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany; 6Department of Ophthalmology, University Paris Est Creteil, Centre Hospitalier Intercommunal de Creteil, Creteil, France; 7Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands *These authors contributed equally to this work Purpose: To describe the clinical findings and long-term outcome of patients with chronic central serous chorioretinopathy (cCSC).Materials and methods: This was a retrospective case series in 52 eyes of 36 patients with a follow-up period of at least 1 year. Extensive ophthalmic examination and a validated questionnaire concerning vision-related quality of life (National Eye Institute Visual Function Questionnaire [NEI-VFQ]-39) were analyzed.Results: Mean visual acuity showed a significant decline over time of 0.16 logarithm of minimum angle of resolution ([logMAR] range: -0.22 to 1.3; P=0.009) after a mean follow-up period of 10.6 years. Also, patients reported lower vision-related quality of life based on the NEI-VFQ-39 for almost all categories compared to healthy controls. Macular atrophy was diagnosed more often on optical coherence tomography compared to other diagnostic entities. Retinal pigment epithelium detachments in the macula were documented on optical coherence tomography in 56% of the patients. A significant thinning of foveal thickness was measured over time compared to unaffected fellow eyes (P=0.002). On long-term follow-up, 13 eyes (37%) showed an increase in number of hot spots on fluorescein angiography.Conclusion: This study indicates that cCSC is a progressive disease in many patients, causing a progressive decline in visual acuity, accompanied by lower reported vision-related quality of life. In deciding whether or not to treat, the progressive nature of cCSC should be taken into account in this relatively young and often still professionally active patient group. Keywords: chronic central serous chorioretinopathy, micropulse laser, NEI-VFQ-39, PDT, vision-related quality of life

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]

Background: Low vision rehabilitation aims to optimise the use of residual vision after severe vision loss, but also aims to teach skills in order to improve visual functioning in daily life. Other aims include helping people to adapt to permanent vision loss and improving psychosocial functioning. These skills promote independence and active participation in society. Low vision rehabilitation should ultimately improve quality of life (QOL) for people who have visual impairment., Objectives: To assess the effectiveness of low vision rehabilitation interventions on health-related QOL (HRQOL), vision-related QOL (VRQOL) or visual functioning and other closely related patient-reported outcomes in visually impaired adults., Search Methods: We searched relevant electronic databases and trials registers up to 18 September 2019., Selection Criteria: We included randomised controlled trials (RCTs) investigating HRQOL, VRQOL and related outcomes of adults, with an irreversible visual impairment (World Health Organization criteria). We included studies that compared rehabilitation interventions with active or inactive control., Data Collection and Analysis: We used standard methods expected by Cochrane. We assessed the certainty of the evidence using the GRADE approach., Main Results: We included 44 studies (73 reports) conducted in North America, Australia, Europe and Asia. Considering the clinical diversity of low vision rehabilitation interventions, the studies were categorised into four groups of related intervention types (and by comparator): (1) psychological therapies and/or group programmes, (2) methods of enhancing vision, (3) multidisciplinary rehabilitation programmes, (4) other programmes. Comparators were no care or waiting list as an inactive control group, usual care or other active control group. Participants included in the reported studies were mainly older adults with visual impairment or blindness, often as a result of age-related macular degeneration (AMD). Study settings were often hospitals or low vision rehabilitation services. Effects were measured at the short-term (six months or less) in most studies. Not all studies reported on funding, but those who did were supported by public or non-profit funders (N = 31), except for two studies. Compared to inactive comparators, we found very low-certainty evidence of no beneficial effects on HRQOL that was imprecisely estimated for psychological therapies and/or group programmes (SMD 0.26, 95% CI -0.28 to 0.80; participants = 183; studies = 1) and an imprecise estimate suggesting little or no effect of multidisciplinary rehabilitation programmes (SMD -0.08, 95% CI -0.37 to 0.21; participants = 183; studies = 2; I 2 = 0%); no data were available for methods of enhancing vision or other programmes. Regarding VRQOL, we found low- or very low-certainty evidence of imprecisely estimated benefit with psychological therapies and/or group programmes (SMD -0.23, 95% CI -0.53 to 0.08; studies = 2; I 2 = 24%) and methods of enhancing vision (SMD -0.19, 95% CI -0.54 to 0.15; participants = 262; studies = 5; I 2 = 34%). Two studies using multidisciplinary rehabilitation programmes showed beneficial but inconsistent results, of which one study, which was at low risk of bias and used intensive rehabilitation, recorded a very large and significant effect (SMD: -1.64, 95% CI -2.05 to -1.24), and the other a small and uncertain effect (SMD -0.42, 95%: -0.90 to 0.07). Compared to active comparators, we found very low-certainty evidence of small or no beneficial effects on HRQOL that were imprecisely estimated with psychological therapies and/or group programmes including no difference (SMD -0.09, 95% CI -0.39 to 0.20; participants = 600; studies = 4; I 2 = 67%). We also found very low-certainty evidence of small or no beneficial effects with methods of enhancing vision, that were imprecisely estimated (SMD -0.09, 95% CI -0.28 to 0.09; participants = 443; studies = 2; I 2 = 0%) and multidisciplinary rehabilitation programmes (SMD -0.10, 95% CI -0.31 to 0.12; participants = 375; studies = 2; I 2 = 0%). Concerning VRQOL, low-certainty evidence of small or no beneficial effects that were imprecisely estimated, was found with psychological therapies and/or group programmes (SMD -0.11, 95% CI -0.24 to 0.01; participants = 1245; studies = 7; I 2 = 19%) and moderate-certainty evidence of small effects with methods of enhancing vision (SMD -0.24, 95% CI -0.40 to -0.08; participants = 660; studies = 7; I 2 = 16%). No additional benefit was found with multidisciplinary rehabilitation programmes (SMD 0.01, 95% CI -0.18 to 0.20; participants = 464; studies = 3; I 2 = 0%; low-certainty evidence). Among secondary outcomes, very low-certainty evidence of a significant and large, but imprecisely estimated benefit on self-efficacy or self-esteem was found for psychological therapies and/or group programmes versus waiting list or no care (SMD -0.85, 95% CI -1.48 to -0.22; participants = 456; studies = 5; I 2 = 91%). In addition, very low-certainty evidence of a significant and large estimated benefit on depression was found for psychological therapies and/or group programmes versus waiting list or no care (SMD -1.23, 95% CI -2.18 to -0.28; participants = 456; studies = 5; I 2 = 94%), and moderate-certainty evidence of a small benefit versus usual care (SMD -0.14, 95% CI -0.25 to -0.04; participants = 1334; studies = 9; I 2 = 0%). ln the few studies in which (serious) adverse events were reported, these seemed unrelated to low vision rehabilitation., Authors' Conclusions: In this Cochrane Review, no evidence of benefit was found of diverse types of low vision rehabilitation interventions on HRQOL. We found low- and moderate-certainty evidence, respectively, of a small benefit on VRQOL in studies comparing psychological therapies or methods for enhancing vision with active comparators. The type of rehabilitation varied among studies, even within intervention groups, but benefits were detected even if compared to active control groups. Studies were conducted on adults with visual impairment mainly of older age, living in high-income countries and often having AMD. Most of the included studies on low vision rehabilitation had a short follow-up, Despite these limitations, the consistent direction of the effects in this review towards benefit justifies further research activities of better methodological quality including longer maintenance effects and costs of several types of low vision rehabilitation. Research on the working mechanisms of components of rehabilitation interventions in different settings, including low-income countries, is also needed., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

In 2016 and 2017, we started an innovative learning track in the Radboudumc that combines arts and medical education, and appraised the learning processes involved. The voluntary track was followed by 32 and 30 participants respectively, mostly interns and a few residents. The initiative built upon the ideas of several American educational developments which incorporated museum visits. We extended the format by having participants join artists in their studios, to allow students to have an immersive experience of a different discipline, rather than only observing its end products. The track did not have specific learning objectives. However, participants were encouraged to set personal goals and to reflect on what they learned in terms of observation skills, creative thinking, personalized health care, and frame reflection. Here we report the rationale of the track, and illustrate preliminary conclusions with participants' quotes.

Importance: Myopia (ie, nearsightedness) is becoming the most common eye disorder to cause blindness in younger persons in many parts of the world. Visual impairment due to myopia is associated with structural changes of the retina and the globe because of elongation of the eye axis. How axial length-a sum of the anterior chamber depth, lens thickness, and vitreous chamber depth-and myopia relate to the development of visual impairment over time is unknown., Objectives: To evaluate the association between axial length, spherical equivalent, and the risk of visual impairment and to make projections of visual impairment for regions with high prevalence rates., Design, Setting, and Participants: This cross-sectional study uses population-based data from the Rotterdam Study I (1990 to 1993), II (2000 to 2002), and III (2006 to 2008) and the Erasmus Rucphen Family Study (2002 to 2005) as well as case-control data from the Myopia Study (2010 to 2012) from the Netherlands. In total, 15 404 individuals with data on spherical equivalent and 9074 individuals with data on axial length were included in the study; right eyes were used for analyses. Data were analyzed from September 2014 to May 2016., Main Outcomes and Measures: Visual impairment and blindness (defined according to the World Health Organization criteria as a visual acuity less than 0.3) and predicted rates of visual impairment specifically for persons with myopia., Results: Of the 15 693 individuals included in this study, the mean (SD) age was 61.3 (11.4) years, and 8961 (57.1%) were female. Axial length ranged from 15.3 to 37.8 mm; 819 individuals had an axial length of 26 mm or greater. Spherical equivalent ranged from -25 to +14 diopters; 796 persons had high myopia (ie, a spherical equivalent of -6 diopters or less). The prevalence of visual impairment varied from 1.0% to 4.1% in the population-based studies, was 5.4% in the Myopia Study, and was 0.3% in controls. The prevalence of visual impairment rose with increasing axial length and spherical equivalent, with a cumulative incidence (SE) of visual impairment of 3.8% (1.3) for participants aged 75 years with an axial length of 24 to less than 26 mm and greater than 90% (8.1) with an axial length of 30 mm or greater. The cumulative risk (SE) of visual impairment was 5.7% (1.3) for participants aged 60 years and 39% (4.9) for those aged 75 years with a spherical equivalent of -6 diopters or less. Projections of these data suggest that visual impairment will increase 7- to 13-fold by 2055 in high-risk areas., Conclusions and Relevance: This study demonstrated that visual impairment is associated with axial length and spherical equivalent and may be unavoidable at the most extreme values in this population. Developing strategies to prevent the development of myopia and its complications could help to avoid an increase of visual impairment in the working-age population.

Purpose: To investigate whether patients who developed chronic central serous chorioretinopathy (cCSC) in association with corticosteroid treatment respond differently to photodynamic therapy (PDT) as compared to patients who have not used corticosteroids., Methods: Clinical evaluation included visual acuity (VA), fundoscopy, optical coherence tomography (OCT), fluorescein and indocyanine green angiography. The main outcome measure was a complete resolution of subretinal fluid (SRF) on OCT after PDT., Results: One hundred and twenty-three eyes (117 patients), including 35 steroid-associated cases (29%), who received PDT treatment with reduced settings for active cCSC were included. Complete resolution of SRF on OCT was seen in 69% of the steroid-associated cases and in 50% of the controls after PDT treatment (p = 0.062). At the final follow-up moment, 74% of the cases had a complete resolution of SRF compared to 60% in the control group (p = 0.142). The VA at the first visit after therapy showed an increase in both groups (mean VA before treatment; cases: 69 ± 14 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, controls: 74 ± 13 ETDRS letters, mean VA first visit after treatment; cases: 76 ± 13 ETDRS letters, controls: 75 ± 13 ETDRS letters). No significant differences were seen in response to PDT between the patients who continued corticosteroid treatment and those who ceased the use of corticosteroids., Conclusions: Photodynamic therapy appears to be equally effective in patients suffering from steroid-associated cCSC as compared to patients with cCSC who do not use corticosteroids. Continuation of corticosteroids at the time of PDT treatment does not seem to adversely affect PDT response., (© 2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: To evaluate the outcome of a prospective protocol for the treatment of chronic central serous chorioretinopathy (CSC)., Methods: Interventional prospective case series in 59 eyes (59 patients) with active chronic CSC. All patients were first treated with indocyanine green angiography (ICGA)-guided half-dose photodynamic therapy (PDT). In case of persistent serous subretinal fluid (SRF) after a follow-up period of at least 6 weeks, ICGA-guided PDT was repeated. If the SRF persisted after two PDT treatments, additional ICGA-guided high-density subthreshold diode micropulse laser (HSML) therapy was performed. Clinical evaluation included best-corrected visual acuity (BCVA), fundoscopy, OCT, fundus autofluorescence, fluorescein angiography and ICGA., Results: After a single PDT treatment, complete resolution of SRF was seen in 37 of 59 eyes. Of the 22 eyes with no complete resolution of SRF, 19 eyes received a second PDT treatment, after which seven eyes of the 19 eyes showed a complete resolution of SRF. Ten eyes underwent HSML, of which one eye had complete resolution of SRF within 7 weeks. At final follow-up a complete resolution of SRF was present in 80% of all eyes. The mean BCVA improved from 0.28 logMAR at baseline to 0.16 logMAR at final follow-up. Improvement of BCVA was highest after the first treatment (-0.12 logMAR, p < 0.001)., Conclusions: The proposed treatment strategy using half-dose PDT and HSML in active chronic CSC resulted in an anatomical success rate of 80%. The first half-dose PDT treatment has the highest likelihood of a favourable treatment response on OCT and BCVA increase., (© 2015 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Ciliopathies are a group of human disorders caused by dysfunction of primary cilia, ubiquitous microtubule-based organelles involved in transduction of extra-cellular signals to the cell. This function requires the concentration of receptors and channels in the ciliary membrane, which is achieved by complex trafficking mechanisms, in part controlled by the small GTPase RAB8, and by sorting at the transition zone located at the entrance of the ciliary compartment. Mutations in the transition zone gene CC2D2A cause the related Joubert and Meckel syndromes, two typical ciliopathies characterized by central nervous system malformations, and result in loss of ciliary localization of multiple proteins in various models. The precise mechanisms by which CC2D2A and other transition zone proteins control protein entrance into the cilium and how they are linked to vesicular trafficking of incoming cargo remain largely unknown. In this work, we identify the centrosomal protein NINL as a physical interaction partner of CC2D2A. NINL partially co-localizes with CC2D2A at the base of cilia and ninl knockdown in zebrafish leads to photoreceptor outer segment loss, mislocalization of opsins and vesicle accumulation, similar to cc2d2a-/- phenotypes. Moreover, partial ninl knockdown in cc2d2a-/- embryos enhances the retinal phenotype of the mutants, indicating a genetic interaction in vivo, for which an illustration is found in patients from a Joubert Syndrome cohort. Similar to zebrafish cc2d2a mutants, ninl morphants display altered Rab8a localization. Further exploration of the NINL-associated interactome identifies MICAL3, a protein known to interact with Rab8 and to play an important role in vesicle docking and fusion. Together, these data support a model where CC2D2A associates with NINL to provide a docking point for cilia-directed cargo vesicles, suggesting a mechanism by which transition zone proteins can control the protein content of the ciliary compartment.

Ciliopathies are Mendelian disorders caused by dysfunction of cilia, ubiquitous organelles involved in fluid propulsion (motile cilia) or signal transduction (primary cilia). Retinal dystrophy is a common phenotypic characteristic of ciliopathies since photoreceptor outer segments are specialized primary cilia. These ciliary structures heavily rely on intracellular minus-end directed transport of cargo, mediated at least in part by the cytoplasmic dynein 1 motor complex, for their formation, maintenance and function. Ninein-like protein (NINL) is known to associate with this motor complex and is an important interaction partner of the ciliopathy-associated proteins lebercilin, USH2A and CC2D2A. Here, we scrutinize the function of NINL with combined proteomic and zebrafish in vivo approaches. We identify Double Zinc Ribbon and Ankyrin Repeat domains 1 (DZANK1) as a novel interaction partner of NINL and show that loss of Ninl, Dzank1 or both synergistically leads to dysmorphic photoreceptor outer segments, accumulation of trans-Golgi-derived vesicles and mislocalization of Rhodopsin and Ush2a in zebrafish. In addition, retrograde melanosome transport is severely impaired in zebrafish lacking Ninl or Dzank1. We further demonstrate that NINL and DZANK1 are essential for intracellular dynein-based transport by associating with complementary subunits of the cytoplasmic dynein 1 motor complex, thus shedding light on the structure and stoichiometry of this important motor complex. Altogether, our results support a model in which the NINL-DZANK1 protein module is involved in the proper assembly and folding of the cytoplasmic dynein 1 motor complex in photoreceptor cells, a process essential for outer segment formation and function.

Purpose: To analyze the clinical characteristics of a serous retinopathy associated with mitogen-activated protein kinase kinase (MEK) inhibition with binimetinib treatment for metastatic cutaneous melanoma (CM) and uveal melanoma (UM), and to determine possible pathogenetic mechanisms that may lead to this retinopathy., Design: Prospective observational, cohort-based, cross-sectional study., Participants: Thirty CM patients and 5 UM patients treated with the MEK inhibitor binimetinib (CM) or a combination of binimetinib and the protein kinase C inhibitor sotrastaurin (UM)., Methods: Extensive ophthalmic examination was performed, including Early Treatment of Diabetic Retinopathy Study best-corrected visual acuity, applanation tonometry, slit-lamp examination, indirect ophthalmoscopy, digital color fundus photography, and optical coherence tomography (OCT). In selected cases, additional examinations were performed, including visual field testing and electro-oculography (EOG). Blood samples were obtained from 3 CM patients and 3 UM patients to analyze the presence of autoantibodies against retinal and retinal pigment epithelium (RPE) proteins., Main Outcome Measures: Visual symptoms, visual acuity, fundus appearance, characteristics on OCT, fundus autofluorescence (FAF), and EOG., Results: Six CM patients (20%) and 2 UM patients (40%) reported visual symptoms during the study. The median time to the onset of symptoms, which were all mild and transient, was 3.5 days (range, <1 hour to 3 weeks). On OCT, subretinal fluid (SRF) was detected in 77% of CM patients and 60% of UM patients. In the 26 patients with SRF, the fovea was affected in 85%. After the start of the medication, an EOG was performed in 19 eyes of 11 patients; 16 of these eyes (84%) developed SRF on OCT. Fifteen of these eyes (94%) showed an abnormal Arden ratio (<1.65). A broad pattern of anti-retinal antibodies was found in 3 CM patients and 2 UM patients tested, whereas anti-RPE antibodies were detected in all 6 tested patients., Conclusions: A time-dependent and reversible serous retinopathy can develop both in patients with metastatic CM and UM treated with binimetinib. A minority of patients develop visual symptoms, which are generally mild and transient. A cause of binimetinib-associated serous retinopathy may be toxicity of medication, but autoantibodies also may be involved., (Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

To further elucidate the genetic underpinnings of uveal melanoma (UM) and identify new markers that correlate with disease outcome, archival formalin-fixed, paraffin-embedded enucleation specimens from 25 patients with UM and a mean follow-up of 14 years were analyzed for whole-genome copy-number alterations using OncoScan analysis. Copy-number alterations of chromosomes 1, 3, 6, and 8 were also analyzed in these tumors using multiplex ligation-dependent probe-amplification, and mutations in GNAQ, GNA11, and BAP1 were searched for by Sanger sequencing. Our study confirms the previously reported GNAQ and GNA11 mutation frequencies in UMs as well as the presence of monosomy 3 as a factor strongly indicating poor prognosis. Two cases with metastatic disease, but without monosomy of chromosome 3, showed loss of a small region in the distal part of chromosome 2p. Also, UMs leading to metastatic disease had more chromosomal aberrations than those without metastases. Three UMs lacking a GNAQ or a GNA11 mutation showed a gain of chromosome 8q; one of these cases showed extensive chromothripsis. Another case (with suspect lung metastasis) showed focal chromothripsis. Our whole-genome copy-number analysis shows that focal loss of chromosome 2p may be involved in the metastatic spread of UMs without monosomy 3; metastatic UMs carry more chromosomal aberrations than those without metastases; and chromothripsis may play a role in the oncogenesis of UMs, but does not necessarily indicate a poor prognosis. The clinical and particularly diagnostic utility of these findings needs to be corroborated in a larger set of patients with UM.

Purpose: In this study, single nucleotide polymorphisms (SNPs) at 19 loci, previously associated with age-related macular degeneration (AMD), were systematically tested for association in patients with chronic central serous chorioretinopathy (cCSC). In addition, we evaluated the effect of detailed phenotyping on these genetic associations., Design: Case-control study., Participants: We included 292 cCSC patients, 1147 AMD patients, and 1311 control individuals., Methods: We genotyped SNPs at 19 AMD-associated loci and 6 additional SNPs at the complement factor H (CFH) locus. Phenotyping of all patients was based on fundoscopy, spectral-domain optical coherence tomography, fluorescein angiography (FA), and indocyanine green angiography., Main Outcome Measures: We measured the allele frequencies of 25 AMD-associated SNPs and CFH haplotype frequencies in patients with cCSC and the effect of phenotypic subdivision of cCSC on genetic associations., Results: One SNP in ARMS2 (rs10490924) was significant after Bonferroni correction (Punadjusted=0.002; odds ratio [OR]=0.64). The SNPs at 3 other AMD loci (CFH, TNFRSF10A, ADAMTS9) showed a trend toward association with typical cCSC. Further analysis of the CFH locus identified 2 SNPs that significantly conferred increased risk for cCSC and 1 that was protective. The CFH-H3 haplotype was also found to be protective (P=0.01; OR=0.54). Using multimodal imaging, 197 patients were classified as having typical cCSC, 52 patients had unilateral abnormalities on FA that were otherwise typical of cCSC, and 43 patients had a clinical picture that could be compatible with cCSC, but with features that could also indicate other macular diseases. Significant differences of the minor allele frequencies of the tested SNPs were observed between these 3 phenotypic subgroups., Conclusions: Chronic CSC is associated with genetic variants in ARMS2 and CFH, indicating a genetic and pathophysiologic overlap between cCSC and AMD. Intriguingly, alleles in ARMS2 and CFH that confer risk of AMD may be protective for cCSC, and alleles in CFH that are protective for AMD confer risk for cCSC. Significant differences in allele frequencies were found among the phenotypic subgroups for several SNPs, illustrating the importance of correct clinical classification., (Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To assess the safety and efficacy of dendritic cell vaccination in metastatic uveal melanoma., Design: Interventional case series., Methods: We analyzed 14 patients with metastatic uveal melanoma treated with dendritic cell vaccination. Patients with metastatic uveal melanoma received at least 3 vaccinations with autologous dendritic cells, professional antigen-presenting cells loaded with melanoma antigens gp100 and tyrosinase. The main outcome measures were safety, immunologic response, and overall survival., Results: Tumor-specific immune responses were induced with dendritic cell vaccination in 4 (29%) of 14 patients. Dendritic cell-vaccinated patients showed a median overall survival with metastatic disease of 19.2 months, relatively long compared with that reported in the literature. No severe treatment-related toxicities (common toxicity criteria grade 3 or 4) were observed., Conclusions: Dendritic cell vaccination is feasible and safe in metastatic uveal melanoma. Dendritic cell-based immunotherapy is potent to enhance the host's antitumor immunity against uveal melanoma in approximately one third of patients. Compared with other prospective studies with similar inclusion criteria, dendritic cell vaccination may be associated with longer than average overall survival in patients with metastatic uveal melanoma., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims/hypothesis: Our study aimed to validate a model to determine a personalised screening frequency for diabetic retinopathy., Methods: A model calculating a personalised screening interval for monitoring retinopathy based on patients' risk profile was validated using the data of 3,319 type 2 diabetic patients in the Diabetes Care System West-Friesland, the Netherlands. Two-field fundus photographs were graded according to the EURODIAB coding system. Sight-threatening retinopathy (STR) was considered to be grades 3-5. Validity of the model was assessed using calibration and discrimination measures. We compared model-based time of screening with time of STR diagnosis and calculated the differences in the number of fundus photographs using the model compared with those in annual or biennial screening., Results: During a mean of 53 months of follow-up, 76 patients (2.3%) developed STR. Using the model, the mean screening interval was 31 months, leading to a reduced screening frequency of 61% compared with annual screening and 23% compared with biennial screening. STR incidence occurred after a mean of 26 months after the model-based time of screening in 67 patients (88.2%). In nine patients (11.8%), STR had developed before the model-based time of screening. The discriminatory ability of the model was good (C-statistic 0.83; 95% CI 0.74, 0.92). Calibration showed that the model overestimated STR risk., Conclusions/interpretation: A large reduction in retinopathy screening was achieved using the model in this population of patients with a very low incidence of retinopathy. Considering the number of potentially missed cases of STR, there is room for improvement in the model. Use of the model for personalised screening may eventually help to reduce healthcare use and costs of diabetes care.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly population in the Western world. AMD is a clinically heterogeneous disease presenting with drusen, pigmentary changes, geographic atrophy and/or choroidal neovascularization. Due to its heterogeneous presentation, it can be challenging to distinguish AMD from several macular diseases that can mimic the features of AMD. This clinical overlap may potentially lead to misdiagnosis. In this review, we discuss the characteristics of AMD and the macular dystrophies that can mimic AMD. The appropriate use of clinical and genetic analysis can aid the clinician to establish the correct diagnosis, and to provide the patient with the appropriate prognostic information. An overview is presented of overlapping and distinguishing clinical features., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Purpose: To report on severe HLA B27-associated anterior uveitis complicated by vitritis, hypotony, and serous retinal detachment., Methods: Retrospective case series., Results: Five patients with HLA B27-associated uveitis presented with an acute anterior uveitis complicated by vitritis, hypotony, serous retinal detachment, and ciliochoroidal effusion. Two patients had previously acute anterior uveitis and two suffered from HLA B27-associated systemic disease. Laboratory and imaging examinations did not reveal another cause of uveitis. Despite the aggressive treatment a prolonged and slow recovery followed. Four patients developed macular edema and one additional patient developed a macular pucker. Finally, 3 eyes improved, 2 eyes developed atrophy, and 1 was lost at 4-month follow-up with visual acuity of hand movements., Conclusions: The authors conclude that severe uveitis with a serous retinal detachment might develop in HLA B27-positive patients and may be complicated by protracted hypotony, macular edema, and poor visual outcome.

In the nineteen-nineties, there was much hype in the European media about presumed laser pointer maculopathy. However, the recent introduction of more powerful and therefore more dangerous laser pointers and their easy availability on the internet necessitates vigilance on the issue. This is an urgent matter, as here we report three cases of proven maculopathy due to an unsafe laser pointer. Three boys aged 13, 9 and 12 years used an unsafe laser pointer as a toy and looked repeatedly into the pointer, resulting in a permanent reduction in visual acuity due to macular damage. Laser pointers are not designed to be children's toys or instruments to annoy people in a crowd. Health authorities and the ophthalmic community should be aware of the potential danger of improper use of high-output laser pointers and warn the general public before the widespread availability of unsafe laser pointers and consequently laser pointer-induced macular damage becomes a true social problem.

Objective: To describe the clinical and genetic characteristics of patients with autosomal recessive bestrophinopathy (ARB)., Design: Retrospective case series., Participants: Ten patients with ARB from 7 different families., Methods: All patients underwent a complete ophthalmic examination, including dilated fundus examination, fundus photography, and fluorescein angiography (FA). In all probands, fundus autofluorescence (FAF) imaging, spectral-domain optical coherence tomography (OCT), full-field electroretinography (ERG), electro-oculography (EOG), and Goldmann perimetry were performed. In selected patients, multifocal ERG was performed. Blood samples were obtained to analyze the BEST1 gene for biallelic mutations that confirmed the diagnosis of ARB., Main Outcome Measures: Age at onset; visual acuity; fundus appearance; characteristics on FA, FAF, OCT, full-field ERG, and EOG; BEST1 gene mutations; and genotype-phenotype correlation., Results: The age at onset varied widely, from 2 to 54 years. A spectrum of fundus abnormalities was observed, such as multifocal yellowish subretinal deposits, subretinal fibrous scars, and cystoid intraretinal fluid collections in the macula. All ARB patients were hyperopic, and some had shallow anterior chamber angles that predisposed them to angle-closure glaucoma. The EOG results were abnormal in all patients. The full-field ERG results were abnormal in 8 ARB patients, whereas 2 patients demonstrated normal cone and rod responses on full-field ERG. Nine ARB patients carried biallelic mutations in the BEST1 gene, and in 1 patient with a characteristic ARB phenotype, only 1 mutation could be identified. Seven different mutations were detected, including 4 novel mutations., Conclusions: Autosomal recessive bestrophinopathy is a recognizable phenotype caused by autosomal recessively inherited mutations in the BEST1 gene. A differential diagnosis with other conditions can be made on the basis of marked autofluorescence changes in combination with an absent light rise on the EOG that outweighs the full-field ERG abnormalities, which point to the BEST1-related hereditary nature of the disease. A number of currently available therapeutic options should be considered in ARB, a disease that seems to be a suitable candidate for future gene therapy., (Copyright © 2013 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: Intravitreal ranibizumab injections currently are the standard treatment for neovascular age-related macular degeneration (AMD). However, a broad range of response rates have been observed, the reasons for which are poorly understood. This pharmacogenetic study evaluated the impact of high-risk alleles in CFH, ARMS2, VEGFA, vascular endothelial growth factor (VEGF) receptor KDR, and genes involved in angiogenesis (LRP5, FZD4) on the response to ranibizumab treatment and on the age of treatment onset. In contrast to previous studies, the data were stratified according to the number of high-risk alleles to enable the study of the combined effects of these genotypes on the treatment response., Design: Case series study., Participants: A cohort of 420 eyes of 397 neovascular AMD patients., Methods: The change in visual acuity (VA) between baseline and after 3 ranibizumab injections was calculated. Genotyping of single nucleotide polymorphisms in the CFH, ARMS2, VEGFA, KDR, LPR5, and FZD4 genes was performed. Associations were assessed using linear mixed models., Main Outcome Measures: The VA change after 3 ranibizumab injections and the age of neovascular disease onset., Results: After ranibizumab treatment, AMD patients without risk alleles in the CFH and ARMS2 genes (4.8%) demonstrated a mean VA improvement of 10 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, whereas no VA improvement was observed in AMD patients with 4 CFH and ARMS2 risk alleles (6.9%; P = 0.014). Patients with 4 high-risk alleles in CFH and ARMS2 were 5.2 years younger than patients with 1 or 2 risk alleles, respectively (63.5%; P<0.0001). The mean age at which the first ranibizumab treatment was carried out among AMD patients with all 6 risk alleles in CFH, ARMS2, and VEGFA was 65.9 years (2%) versus 75.3 years in patients with 0 or 1 high-risk allele (8.8%; P = 0.001). After ranibizumab treatment, patients with 6 high-risk alleles demonstrated a mean VA loss of 10 ETDRS letters (P<0.0001)., Conclusions: This study evaluated the largest pharmacogenetic AMD cohort reported to date. A cumulative effect of high-risk alleles in CFH, ARMS2, and VEGFA seems to be associated with a younger age of onset in combination with poor response rates to ranibizumab treatment., (Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To determine the genetic defect and to describe the clinical characteristics in patients with retinitis punctata albescens (RPA) and fundus albipunctatus (FAP)., Design: Case series/observational study., Participants: We included 13 patients affected by RPA or FAP., Methods: Thirteen patients were collected from 8 families with a retinal dystrophy characterized by tiny, yellow-white dots on funduscopy, typical for FAP or RPA. All patients underwent full ophthalmologic examinations, including visual field assessment. Fundus photography, and electroretinography were performed in 12 patients, and optical coherence tomography and fundus autofluorescence were performed in 4 patients. DNA samples of all patients were screened for mutations in RLBP1 and for mutations in RDH5 in patients who did not carry mutations in RLBP1. DNA samples of 2 sibling pairs of nonconsanguineous families who carried mutations neither in RLBP1 nor in RDH5 were analyzed by genome-wide homozygosity mapping. Sequence analysis was performed of LRAT, a candidate gene in a shared homozygous region., Main Outcome Measures: We assessed DNA sequence variants, best-corrected visual acuity, fundus appearance, visual field measurements, electroretinogram responses, optical coherence tomography, and fundus autofluorescence., Results: A homozygous frameshift mutation was identified in LRAT in 4 patients with RPA. Mutations in RLBP1 were identified in 7 patients with RPA and in 1 patient with FAP and cone dystrophy. One patient had compound heterozygous mutations in RDH5 and suffered from FAP with mild maculopathy., Conclusions: A genetic defect was identified in LRAT as a novel cause of RPA. LRAT is therefore the fourth gene involved in the visual cycle that may cause a white-dot retinopathy. We also revealed that mutations in RLBP1 may lead to FAP with cone dystrophy., (Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To determine the long-term effects of ruthenium-106 plaque radiation therapy for iris and iridociliary melanomas in terms of tumour regression and complications., Methods: Between 1 November 1997 and 31 December 2007, 36 patients with an iris or iridociliary melanoma were treated with Ruthenium-106 (Ru-106) ophthalmic plaque radiation therapy. The median follow-up was 6.5 years with a range of 2-11 years. The mean tumour apex dose was 151.5 Gy. Main outcome measures were local tumour control and radiation-related ocular complications., Results: The mean age of the patients at the time of treatment was 54 years (range 14-82). The tumours had a median largest basal dimension of 4.8 mm (range 3-11) and a prominence of 2.3 mm (range 0.8-5), with a median involvement of three clock hours (range 1-6). The tumours were confined to the iris in 14 patients (39%), extended into the anterior ciliary body in 12 (33%), while the anterior ciliary body tumour extended into the iris in ten patients (28%). Tumours regressed in all patients (100%) with a mean regression of 80% of the original tumour size at 7 years of follow-up. Radiation-related complications included corneal erosions on the first postoperative day in nine patients (25%), cataract in four of 11 patients free of cataract before treatment (36%) and postradiation glaucoma in one patient (3%). Visual acuity of 20/200 or worse was present in one of 20 patients (5%) at 6 years of follow-up. Local recurrences occurred in two patients (5%), 2 and 5 years after the radiation therapy respectively, and both underwent enucleation. Distant metastases occurred in one of these enucleated patients (3%) 2 years after treatment., Conclusion: Ru-106 plaque radiation therapy for iris and iridociliary melanoma resulted in good local tumour control and preservation of visual acuity with few and treatable side-effects., (© 2010 The Authors. Journal compilation © 2010 Acta Ophthalmol.)

Background: Mutations in the gene for Usher syndrome 2A (USH2A) are causative for non-syndromic retinitis pigmentosa and Usher syndrome, a condition that is the most common cause of combined deaf-blindness. To gain insight into the molecular pathology underlying USH2A-associated retinal degeneration, we aimed to identify interacting proteins of USH2A isoform B (USH2AisoB) in the retina., Results: We identified the centrosomal and microtubule-associated protein sperm-associated antigen (SPAG)5 in the retina. SPAG5 was also found to interact with another previously described USH2AisoB interaction partner: the centrosomal ninein-like protein NINLisoB. Using In situ hybridization, we found that Spag5 was widely expressed during murine embryonic development, with prominent signals in the eye, cochlea, brain, kidney and liver. SPAG5 expression in adult human tissues was detected by quantitative PCR, which identified expression in the retina, brain, intestine, kidney and testis. In the retina, Spag5, Ush2aisoB and NinlisoB were present at several subcellular structures of photoreceptor cells, and colocalized at the basal bodies., Conclusions: Based on these results and on the suggested roles for USH proteins in vesicle transport and providing structural support to both the inner ear and the retina, we hypothesize that SPAG5, USH2AisoB and NINLisoB may function together in microtubule-based cytoplasmic trafficking of proteins that are essential for cilium formation, maintenance and/or function.

Objective: To describe the mutations in the CLRN1 gene in patients from 2 consanguineous Pakistani families diagnosed with autosomal recessive retinitis pigmentosa (arRP)., Design: Case-series study., Participants: Affected and unaffected individuals of 2 consanguineous Pakistani families and 90 unaffected controls from the same population. Informed consent was obtained from participants and the protocol was approved by a local institutional review board., Methods: Patients of 2 consanguineous families were genotyped with single-nucleotide polymorphism microarrays for genome-wide linkage analysis. The search for potential candidate genes within the 8-Mb overlapping homozygous region in these families revealed the presence of CLRN1, a gene previously known to cause Usher's syndrome type III (USH3), which was analyzed by direct sequence analysis. The clinical diagnosis was based on the presence of night blindness, fundoscopic findings, and electroretinography (ERG) results. Additionally, pure tone audiometry was performed to rule out Usher's syndrome., Main Outcome Measures: Fundoscopy, single-nucleotide polymorphism microarray, DNA sequence analysis, ERG, and audiometry., Results: Sequencing of CLRN1 revealed novel missense mutations (p.Pro31Leu and p.Leu154Trp) segregating in 2 families. Analysis of fundus photographs indicated attenuation of the retinal vessels, and bone spicule pigmentation in the periphery of the retina. The ERG responses were indicative of a rod-cone pattern of the disease. Audiometric assessment revealed no hearing impairment, thereby excluding Usher's syndrome. Subcellular localization studies demonstrated the retention of the mutant proteins in the endoplasmic reticulum, whereas the wild-type protein was mainly present at the cell membrane., Conclusions: The RP-associated mutations p.Pro31Leu and p.Leu154Trp may represent hypomorphic mutations, because the substituted amino acids located in the transmembrane domains remain polar, whereas more severe changes have been detected in patients with USH3. These data indicate that mutations in CLRN1 are associated not only with USH3, but also with nonsyndromic arRP., (Copyright © 2011 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: In trans-scleral thermotherapy (TSTT), heat is applied through the sclera in order to target an intraocular uveal melanoma. Previously, it had been shown that in uveal melanoma, hyperthermia and transpupillary thermotherapy influenced expression of immunologically relevant proteins, such as S100, HLA and heat-shock proteins (HSPs). We investigated whether TSTT induced similar changes., Methods: Experimental TSTT was applied on eleven uveal melanomas prior to enucleation. Each tumour sample was processed for histopathological examination; immunohistochemical analysis was performed to determine expression of S100, HLA, HSPs and macrophage markers., Results: In TSTT-treated areas, expression of S100 and different HSPs was lost, while an upregulated expression of HSP GP96 was observed at the border of these areas. Expression levels of HLA-A and HLA-B varied between tumours and were not influenced by TSTT. The borders of the TSTT-treated areas showed high numbers of infiltrating macrophages, which were predominantly of the M2 phenotype., Conclusion: TSTT has an effect on immunological parameters with local loss of expression of HSPs and S100. The influx of M2 macrophages around the TSTT-treated areas indicates the presence of an innate immune reaction against the induced necrosis, suggesting that TSTT-treated tumour cells are removed by a macrophage-mediated tissue repair mechanism., (© 2011 The Authors. Acta Ophthalmologica © 2011 Acta Ophthalmologica Scandinavica Foundation.)

Objective: The demand for eye-care services in the Netherlands is increasing. This article indicates the causes and attempts to provide an estimate of the increase between 2010 and 2020 and to indicate what will be the consequences., Design: Descriptive study., Method: In the absence of data on the numbers of blind and visually impaired people in the Netherlands, we used data from the records of general practitioners, yearly statistics for the number of relevant activities in hospitals and a mathematical model to calculate the number of blind and visually impaired in the Netherlands. The data mentioned were extrapolated to the population of 2020. Additionally, the expected number of new treatments of neovascular age-related macular degeneration (AMD) and macular oedema in diabetic retinopathy and retinal venous occlusion were calculated by a model., Results: The number of people over 65 in the Netherlands increases by 34% between 2010 and 2020. The registrations by general practitioners show an increase of 43% of patients with eye conditions. Modelling of the new treatment methods demonstrates a threefold increase of the number of treatments. Finally, it appears that the number of blind and visually impaired people increases by 20%. The prevalence of visual impairment is the highest in elderly in health-care institutions, mentally handicapped and elderly living independently., Conclusion: The demand for eye-care services will increase by 200-300% between 2010 and 2020. The most important cause for this is the new treatment for 'wet' AMD and macular oedema using intravitreal angiogenesis inhibitors. The capacity of eye care services needs to be increased, partly by a redistribution of tasks between different professional groups within the eye care sector. Routine vision screening of elderly in care institutions and people with a mental handicap can reduce the number of Dutch people with avoidable visual impairment. For elderly living independently, provision of information and selective screening is indicated.

Purpose: To evaluate long-term outcomes of eye-conserving treatment using Ruthenium-106 plaque brachytherapy with or without transpupillary thermotherapy (TTT) for small to intermediate size choroidal melanomas., Methods: Outcomes of 425 consecutive patients were analysed. The median basal tumour diameter was 10.9 mm (range 4.8-15.9 mm), and the median apical height 4.2 mm (range 1.2-9.3 mm). Brachytherapy doses ranged from 400 to 600Gy with TTT (86%), or from 600 to 800Gy without TTT (14%), specified at the scleral surface. Kaplan-Meier survival curves, log-rank tests and Cox regression analysis were used for analysis., Results: Median follow-up was 50 months. Five-year actuarial local control was 96%. Five-year overall and metastases-free survival rates were 79.6% and 76.5%. Prognostic factors for metastasis-free survival were peripheral location (p=0.02) and smaller basal diameter (p<0.001). No dose effect relationships were found. Radiation side effects were frequent, with 2- and 5-year rates free of radiation complications of 60% and 35%. Five-year enucleation rate was 4.4% (10 for local recurrence, 7 for complications). Cosmetic and functional (visual acuity >0.10) eye preservation rates were 96% and 52% at 5 years., Conclusions: Ruthenium-106 brachytherapy for choroidal melanoma provides excellent rates of local control and eye preservation., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Usher syndrome is the most common form of hereditary deaf-blindness. It is both clinically and genetically heterogeneous. The USH2D protein whirlin interacts via its PDZ domains with other Usher-associated proteins containing a C-terminal type I PDZ-binding motif. These proteins co-localize with whirlin at the region of the connecting cilium and at the synapse of photoreceptor cells. This study was undertaken to identify novel, Usher syndrome-associated, interacting partners of whirlin and thereby obtain more insights into the function of whirlin., Methods: The database of ciliary proteins was searched for proteins that are present in both the retina and inner ear and contain a PDZ-binding motif. Interactions with whirlin were evaluated by yeast two-hybrid analyses and validated by glutathione S-transferase pull-down assays, co-immunoprecipitation, and co-localization in the retina with immunofluorescence and immunoelectron microscopy., Results: The L-type calcium channel subunit Ca(v)1.3 (alpha(1D)) specifically interacts with whirlin. In adult photoreceptors, Ca(v)1.3 (alpha(1D)) and whirlin co-localize in the region of the connecting cilium and at the synapse. During murine embryonic development, the expression patterns of the Whrn and Cacna1d genes show significant overlap and include expression in the eye, the inner ear, and the central nervous system., Conclusions: The findings indicate that Ca(v)1.3 (alpha(1D)) is connected to the Usher protein network. This conclusion leads to the hypothesis that, in the retina, whirlin scaffolds Ca(v)1.3 (alpha(1D)) and therefore contributes to the organization of calcium channels in the photoreceptor cells, where both proteins may be involved in membrane fusions.

Purpose: To estimate the magnitude and causes of blindness and low vision in The Netherlands from 2000 to 2020., Methods: Recent population-based blindness surveys in established market economies were reviewed. Age and gender specific prevalence and causes of blindness and low vision were extracted and calculated for six population subgroups in The Netherlands. A mathematical model was developed to relate the epidemiologic data with demographic data for each subgroup for each year between 2000 and 2020., Results: In 2008 an estimated 311,000 people are visually impaired in The Netherlands: 77,000 are blind and 234,000 have low vision. With the current intervention the number may increase by 18% to 367,000 in 2020. Visual impairment is most prevalent among residents of nursing homes and care institutions for the elderly, intellectually disabled persons and people aged 50+ living independently. Of all people with visual impairment 31% is male (97,000) and 69% female (214,000). More than half of all visual impairment (56%; 174,000 persons) is avoidable. A variation of around 20% might be applied to the numbers in these estimates., Conclusions: The aim of VISION 2020: The Right to Sight to reduce avoidable visual impairment is also relevant for developed countries like The Netherlands. Vision screening and awareness campaigns focusing on the identified risk groups can reduce avoidable blindness considerably. Regular updates of the model will ensure that the prognoses remain valid and relevant. With appropriate demographic data, the model can also be used in other established market economies.

Aim: To estimate the number of elderly people with visual impairment in The Netherlands, now and in the future. Possibilities for intervention are discussed., Methods and Materials: Estimates are based on a recent report on behalf of Foundation InZicht, ZonMw, in which prevalence data from population-based studies on blindness and low vision and its causes in The Netherlands, western Europe, The United States and Australia are related to the latest demographic data for The Netherlands., Results: Of the 16.4 million Dutch in 2008 2.4 million (14.7%) are 65 years of age and older. Of this last group 155,000 persons are living in nursing homes or residential homes, the others are living in their own homes. In 2008 an estimated 77,000 persons are blind and 234,000 have low vision. Of them 79% is 65 years of age or older. Of the older people in care institutions 20% is blind (32,000) and 22% has low vision (34,000). In 62% of them the visual impairment is treatable or could have been prevented ('avoidable'). Of the older people living independently 1.2% is blind (27,000) and 6.8% has low vision (154,000). In 57% of them the affliction is avoidable., Conclusion: In 2008 247,000 elderly suffer from a visual impairment that could have been treated or prevented in 143,000 (58%) of them. Screening and treatment of elderly in care institutions seems indicated, as is health education to and goal-oriented screening of elderly who live independently.

Purpose: To describe the phenotype of Best vitelliform macular dystrophy (BVMD) and to evaluate genotype-phenotype and histopathologic correlations., Methods: Retrospective analysis of patients with BVMD who underwent an extensive ophthalmic examination, including best-corrected Snellen visual acuity, fundus examination by indirect ophthalmoscopy, fundus photography, fundus autofluorescence, optical coherence tomography, fundus fluorescein angiography, and electrooculography. In addition, molecular genetic analysis of the BEST1 gene was performed in all patients., Results: We examined 40 eyes of 20 patients with BVMD. Sixteen eyes (40%) had a well-defined BVMD stage, whereas 18 eyes displayed characteristics attributable to different stages. Six eyes had an atypical form of BVMD. Fundus autofluorescence and optical coherence tomography frequently detected abnormalities that were not visible on ophthalmoscopy. All patients carried a mutation in the BEST1 gene. Molecular genetic analysis identified 8 different BEST1 mutations in 15 families, including 2 novel mutations (p.Gly299Ala and p.Ile3Thr). Genotype-phenotype correlation was limited, as we observed a broad phenotypic range in association with a single BEST1 mutation. However, the p.Ala243Val seems to cause a mild and relatively invariable BVMD phenotype., Conclusion: A broad phenotypic variability may be observed in BVMD, even with a single BEST1 mutation. Fundus autofluorescence and optical coherence tomography are valuable noninvasive imaging techniques for phenotyping and follow-up of BVMD patients.

Complement factor H (CFH) is a complement inhibitor, which is present as a soluble protein and attached to cell surfaces throughout the human body. As such, CFH is a key player in complement homeostasis, inhibiting excessive activation of the complement cascade, with an emphasis on the alternative pathway. The significance of CFH is demonstrated by the broad range of phenotypes associated with specific CFH gene variants. This phenotypic spectrum includes renal phenotypes, such as membranoproliferative glomerulonephritis and atypical hemolytic uremic syndrome, as well as ocular phenotypes, such as basal laminar drusen and age-related macular degeneration. In addition, several overlapping phenotypes have been described in association with CFH gene variants. The phenotypic outcome of these CFH variants depends on their differential impact on plasma- and surface-bound CFH function. Consequently, distinct genotype-phenotype correlations may be observed.

Bestrophin-1 is an integral membrane protein, encoded by the BEST1 gene, which is located in the basolateral membrane of the retinal pigment epithelium. The bestrophin-1 protein forms a Ca(2+) activated Cl(-) channel and is involved in the regulation of voltage-dependent Ca(2+) channels. In addition, bestrophin-1 appears to play a role in ocular development. Over 120 different human BEST1 mutations have been described to date, associated with a broad range of ocular phenotypes. The purpose of this review is to describe this spectrum of phenotypes, which includes Best vitelliform macular dystrophy and adult-onset foveomacular vitelliform dystrophy, autosomal dominant vitreoretinochoroidopathy, the MRCS (microcornea, rod-cone dystrophy, cataract, posterior staphyloma) syndrome, and autosomal recessive bestrophinopathy. The genotype-phenotype correlations that are observed in association with BEST1 mutations are discussed. In addition, in vitro studies and animal models that clarify the pathophysiological mechanisms are reviewed.

Fundus autofluorescence (FAF) is a non-invasive imaging technique that enables the visualization of lipofuscin changes in the retinal pigment epithelium. This study aims to illustrate the spectrum of FAF changes in a variety of retinal dystrophies. For this purpose, we examined patients with retinal dystrophies such as Stargardt disease, Best vitelliform macular dystrophy, and retinal dystrophies associated with mutations in the peripherin/RDS gene. All retinal dystrophies were confirmed by molecular genetic analysis. A broad range of characteristic FAF patterns was observed. Our results indicate that FAF imaging constitutes a useful additive tool in the diagnosis and follow-up of various retinal dystrophies.

Purpose: To study morphologic changes in the macula by optical coherence tomography (OCT) in patients with a crystalline macular dystrophy due to the autosomal recessive neurocutaneous Sjögren-Larsson syndrome (SLS)., Design: Retrospective observational case series., Participants: Twenty-seven eyes of 14 patients, mean age 14.6 (range, 3-24) years, with biochemically and genetically proven SLS underwent clinical and OCT investigation between September 2004 and September 2006., Methods: All patients underwent full ophthalmologic examination including slit-lamp biomicroscopy and binocular ophthalmoscopy. Optical coherence tomography of all eyes was performed using the macular thickness map protocol of Stratus OCT., Main Outcome Measures: Macular morphology in clinical examination and OCT., Results: Beside clinically visible perimacular crystalline deposits in all eyes of all study participants, macular morphology and reflectivity were significantly changed on OCT compared with healthy eyes. We found focal hyperreflectivities in all study eyes within the perifoveal ganglion cell layer and the inner plexiform layer, corresponding to the clinical localization of retinal crystals. More interestingly, a cystoid foveal degeneration on OCT was present in the majority of patients with SLS (18/27 eyes, or 67% of all eyes studied), varying from multiple microcystoid spaces to cystoid foveal atrophy. In general, patients who were severely affected on OCT showed intense changes on previously performed cerebral magnetic resonance spectroscopy., Conclusions: Patients with SLS show a childhood-onset crystalline macular dystrophy with cystoid foveal atrophy on OCT in most cases. The intraretinal deposition of lipid metabolites may lead to Müller cell degeneration with subsequent formation of cystoid spaces or atrophic changes within the fovea. Because this macular dystrophy is present in all examined patients with SLS, familiarity with this maculopathy seems important for the diagnosis of this rare systemic disease.

The differential diagnosis between primary uveal melanoma and cutaneous melanoma metastasis in the eye may be difficult, both clinically and histologically. We report successful application of combined mutational analysis of the NRAS and the CDKN2A gene to discriminate between these two entities. The patient had a history of a superficial spreading cutaneous melanoma of the left shoulder. Nine years later, she developed a lymph node metastasis in the left axilla, and 13 years later she presented with an atypical, pigmented tumor in the uvea. Histologically, the origin of the uveal melanoma could not be determined with certainty. We performed molecular analysis on the skin melanoma, the lymph node metastasis and the uveal melanoma. We detected an NRAS codon 61 mutation (c.182A>G, p.Gln61Arg) in all three tumor specimens. This mutation was absent in the normal control tissue of the patient, thereby excluding a germline mutation. To confirm a clonal relationship between the tumors, we also performed CDKN2A mutational analysis. We detected a CDKN2A mutation ((p16) c.238C>T, p.Arg80X, (p14) c.404C>T, p.Pro135Leu)) in the tumor samples, but not in the normal control tissue of the patient. We concluded that the uveal melanoma is a metastasis from the cutaneous melanoma removed 13 years before.

Background: Our study aims to identify anatomical characteristics of glaucoma filtering blebs by means of slit lamp-adapted optical coherence tomography (SL-OCT) and to identify new parameters for the functional prognosis of the filter in the early post-operative period., Methods: Patients with primary open-angle glaucoma, aged 18 years and older, scheduled for primary trabeculectomy at the Department of Ophthalmology, Radboud University Nijmegen Medical Centre, were considered for our study. All patients underwent standardized trabeculectomy with intra-operative application of mitomycin C. The filtering blebs were evaluated clinically and with SL-OCT on day 1 and 1, 2, 4 and 12 weeks following surgery. The resulting data were analysed and weighed against surgical success. To better understand the SL-OCT data a small comparative histologic study was performed., Results: The study included 20 eyes of 20 patients. After completion of our study, 15 eyes of 15 patients (mean age+/-SD 67 +/- 16 years) were eligible for data analysis and 5 eyes missed at least one follow-up visit. Filtering surgery was considered successful (intraocular pressure < or = 21 mmHg without antiglaucomatous medication) in 11 of 15 eyes. SL-OCT frequently demonstrated multiple hypo-reflective layers within Tenon's capsule ("striping" phenomenon) in the first post-operative week. Presumably, these layers corresponded with drainage channels in the histological specimen. These channels were present in functional filters but not in the failures. In addition, the visualisation of the sclera below the filtering zone was better defined in failures compared with successful filtering blebs ("shading" phenomenon). We observed no differences in the volume and clinical aspect of the blebs in the successful group compared with the unsuccessful group., Conclusions: Successful filtering blebs show characteristic optical properties on SL-OCT. These phenomena suggest a diffusely enhanced fluid content and the presence of intra-bleb drainage channels in functional filtering blebs.

Aim: Our purpose was to determine whether S-100B or melanoma inhibitory activity (MIA) concentrations in the serum of patients with large uveal melanomas were better markers for the presentation of metastases than liver function tests. We also investigated whether increased marker levels were related to known clinical and histopathological prognostic parameters., Methods: Total S-100B (A1B + BB) and MIA concentrations were measured in the sera from 104 patients with uveal melanoma prior to enucleation and in the sera from 50 healthy controls. Concentrations were also determined in the sera from 30 patients with known uveal melanoma metastases. Liaison Sangtec 100, an automated immunoluminometric assay measuring the total S-100B, and Roche MIA ELISA were used to quantify these proteins in serum. Results were compared with liver function tests [alkaline phosphatase, lactate dehydrogenase (LD), aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transpeptidase]., Results: The mean S-100B and MIA concentrations were significantly higher in patients with metastases compared to melanoma patients without metastases. At the time of enucleation, S-100B and MIA were not prognostic for metastases in uveal melanoma, but S-100B and LD were the best tests to predict the occurrence of metastatic disease during the follow-up period., Conclusions: In our study, the S-100B and MIA serum concentrations were not correlated with any tested established prognostic parameter. S-100B and LD showed better performance in identifying melanoma metastases than gamma-glutamyl transpeptidase and MIA. A prospective follow-up study is needed to evaluate S-100B and MIA in identifying early micrometastasis in uveal melanoma., (Copyright (c) 2007 S. Karger AG, Basel.)

Objectives: To determine the presence of vascular endothelial growth factor A (VEGF-A) in the aqueous humor of eyes with uveal melanoma and to identify its source., Methods: The VEGF-A concentrations were determined in aqueous humor samples obtained after enucleation from 74 eyes with untreated uveal melanoma and from 8 eyes with treated uveal melanoma. Patient survival and clinical and histopathological tumor variables were compared. In situ hybridization, Western blot analysis, and enzyme-linked immunosorbent assay were used to determine expression of VEGF-A in tumor tissue and in overlying retina., Results: Aqueous VEGF-A concentrations ranged from 18 to 826 pg/mL in 74 untreated eyes, while concentrations in 30 control eyes were significantly lower (median, 50.1 pg/mL) (P<.001). Concentrations in 8 treated eyes were much higher (median, 364 pg/mL). In situ hybridization on tissue sections and Western blot analysis and enzyme-linked immunosorbent assay on tissue extracts revealed VEGF-A in uveal melanoma tissue and in retinal tissue., Conclusions: Uveal melanoma is associated with increased concentrations of VEGF-A in aqueous humor. Aqueous VEGF-A concentration correlates with largest basal tumor diameter and with the tumor height. In eyes with uveal melanoma, tumor and retinal tissues are sources of VEGF-A.

Background: In circumscribed choroidal hemangiomas (CCH) a long observation period and decreased visual acuity before treatment are risk factors for poor visual outcome. Therefore, we studied the use of limited, single spot photodynamic therapy (PDT) with Visudyne for the timely treatment of CCH., Methods: Six consecutive patients with CCH, and metamorphopsia but (near) normal visual acuity were treated with PDT, using a single spot covering only the most prominent part of the tumour, and a radiance exposure of 50 J/cm(2). Start of treatment was 6 min following a 1-min infusion with Visudyne (6 mg/m(2) BSA), using a diode laser (692 nm)., Results: In all patients, the metamorphopsia disappeared, the OCT images returned to a normal foveal contour, and visual acuity remained 20/20 or improved to 20/20. In five patients, the tumour became ultrasonographically undetectable; in three after one PDT session, in one patient after two and in another patient after three PDT sessions. The last patient had a residual tumour height of 1.2 mm, but no metamorphopsia, a normal foveal contour on OCT, and fluorescein angiography showed no residual leakage., Conclusion: The present series demonstrates that single spot PDT might be an effective treatment for CCH with a visual acuity > or =20/30, without serious side-effects during a follow-up of at least 18 months.

Uveal melanoma develops in one of the most capillary-rich tissues of the body and is disseminated hematogenously. Knowledge of the nature and the spatiotemporal expression of angiogenic factors in uveal melanoma is essential to the development of new treatment strategies, especially with regard to improving survival. In this study, we measured the angiogenic potential of several angiogenic factors in different uveal melanoma cell lines, in an in vivo model, and in primary tumor material from patients with melanoma. Most uveal melanoma cell lines expressed vascular endothelial growth factor (VEGF)-A (isoforms 121, 165, 189), VEGF-B, VEGF-C, VEGF-D, and basic fibroblastic growth factor (b-FGF) to various extents. The expression of VEGF-A 121 was always higher than that of the other VEGF-A isoforms, suggesting that VEGF-A 121 is the most abundant VEGF-A isoform. All experimentally induced tumors expressed VEGF-A, VEGF-B, VEGF-C, VEGF-D, and basic fibroblastic growth factor (b-FGF). Similarly, significant amounts of mRNA for VEGF-B, VEGF-C, VEGF-D, and b-FGF were detected in uveal melanoma material from patients. In contrast, VEGF-A mRNA (121, 165, 189) was low (9/28) or not detectable in the tumor samples. The synthesis of VEGF-A 165 and b-FGF protein by various cell lines was measured by enzyme-linked immunosorbent assay (ELISA). Most uveal melanoma cell lines, but not normal melanocytes, strongly synthesized and secreted VEGF-A 165 and b-FGF during cell culture. Our data suggest that the expression of (lymph) angiogenic factors may play a causal role in the angiogenesis and progression of uveal melanoma and distant metastasis.

Purpose: The molecules of the HLA class I and II molecules as well as the MHC class I chain-related gene A (MICA), a polymorphic and stress-induced cell surface molecule, are involved in T-cell and natural killer-cell (NK-cell) mediated immune responses. In this study we looked for any genetic susceptibility contributed by HLA class I, class II, or MICA genes with regard to the development of uveal melanoma., Methods: Between 1998 and 2001, 159 uveal melanoma patients were typed for HLA class I and II, and 168 uveal melanoma patients were evaluated for MICA by microsatellite typing. The HLA antigen and MICA allele frequencies were compared with control groups of, respectively, 2,440 and 247 healthy Dutch individuals., Results: HLA class I, HLA class II, and MICA gene frequencies in uveal melanoma patients and healthy Dutch controls showed no significant deviations after correction for the number of comparisons., Conclusions: We conclude that there is no genetic susceptibility or increased risk attributed to any HLA class I, class II, and MICA polymorphism with regard to the development of uveal melanoma.