Structure-function correlation of retinal photoreceptors in PRPH2-associated central areolar choroidal dystrophy patients assessed by high-resolution scanning laser imaging and microperimetry.

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.

Risk factors and management of primary giant retinal tears.

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.

The genetics and disease mechanisms of rhegmatogenous retinal detachment.

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-ß 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.

Charles Bonnet syndrome in patients with Stargardt disease: prevalence and risk factors.

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 mm2) as compared with controls (range 0-180 mm2). 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.

Air versus fluorinated gas tamponades in pars plana vitrectomy treatment for primary rhegmatogenous retinal detachment.

PURPOSE: To compare the treatment success of air with fluorinated gas (20% SF6 or 14% C3 F8 ) 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.

Low prevalence of spectacle use in the Hungarian Roma population indicates unmet health needs.

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.

Imaging diabetic retinal disease: clinical imaging requirements.

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.

Computer-assisted photoreceptor assessment on Heidelberg Engineering Spectralis™ High Magnification Module™ images.

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.

Correlation of Morphology and Function of Flecks Using Short-Wave Fundus Autofluorescence and Microperimetry in Patients With Stargardt Disease.

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.

Validation of a model for the prediction of retinopathy in persons with type 1 diabetes.

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 A1c 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.

Acute Endophthalmitis after Cataract Surgery: Clinical Characteristics and the Role of Intracameral Antibiotic Prophylaxis.

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.

Long-term outcomes of vitrectomy for proliferative diabetic retinopathy.

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.

Complement Activation Levels Are Related to Disease Stage in AMD.

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.

RETINAL HYPERREFLECTIVE FOCI IN TYPE 1 DIABETES MELLITUS.

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.

Foveal Sparing in Central Retinal Dystrophies.

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.

The identification of a RNA splice variant in TULP1 in two siblings with early-onset photoreceptor dystrophy.

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.

The absence of fundus abnormalities in Stargardt disease.

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.

Macular Dystrophy and Cone-Rod Dystrophy Caused by Mutations in the RP1 Gene: Extending the RP1 Disease Spectrum.

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.

Hyperreflective foci on optical coherence tomography associate with treatment outcome for anti-VEGF in patients with diabetic macular edema.

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.

Morphological and topographical appearance of microaneurysms on optical coherence tomography angiography.

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.