Analysis of optical coherence tomography biomarker probability detection in central serous chorioretinopathy by using an artificial intelligence-based biomarker detector.

AIM: To adopt a novel artificial intelligence (AI) optical coherence tomography (OCT)-based program to identify the presence of biomarkers associated with central serous chorioretinopathy (CSC) and whether these can differentiate between acute and chronic central serous chorioretinopathy (aCSC and cCSC). METHODS: Multicenter, observational study with a retrospective design enrolling treatment-naïve patients with aCSC and cCSC. The diagnosis of aCSC and cCSC was established with multimodal imaging and for the current study subsequent follow-up visits were also considered. Baseline OCTs were analyzed by an AI-based platform (Discovery® OCT Fluid and Biomarker Detector, RetinAI AG, Switzerland). This software allows to detect several different biomarkers in each single OCT scan, including subretinal fluid (SRF), intraretinal fluid (IRF), hyperreflective foci (HF) and flat irregular pigment epithelium detachment (FIPED). The presence of SRF was considered as a necessary inclusion criterion for performing biomarker analysis and OCT slabs without SRF presence were excluded from the analysis. RESULTS: Overall, 160 eyes of 144 patients with CSC were enrolled, out of which 100 (62.5%) eyes were diagnosed with cCSC and 60 eyes (34.5%) with aCSC. In the OCT slabs showing presence of SRF the presence of biomarkers was found to be clinically relevant (> 50%) for HF and FIPED in aCSC and cCSC. HF had an average percentage of 81% (± 20) in the cCSC group and 81% (± 15) in the aCSC group (p = 0.4295) and FIPED had a mean percentage of 88% (± 18) in cCSC vs. 89% (± 15) in the aCSC (p = 0.3197). CONCLUSION: We demonstrate that HF and FIPED are OCT biomarkers positively associated with CSC when present at baseline. While both HF and FIPED biomarkers could aid in CSC diagnosis, they could not distinguish between aCSC and cCSC at the first visit. AI-assisted biomarker detection shows promise for reducing invasive imaging needs, but further validation through longitudinal studies is needed.

Prediction of chronic central serous chorioretinopathy through combined manual annotation and AI-assisted volume measurement of flat irregular pigment epithelium.

INTRODUCTION: The aim of this study is to investigate the role of an artificial intelligence (AI)-developed OCT program to predict the clinical course of central serous chorioretinopathy (CSC ) based on baseline pigment epithelium detachment (PED) features. METHODS: Single-center, observational study with a retrospective design. Treatment-naïve patients with acute CSC and chronic CSC were recruited and OCTs were analyzed by an AI-developed platform (Discovery OCT Fluid and Biomarker Detector, RetinAI AG, Switzerland), providing automatic detection and volumetric quantification of PEDs. Flat irregular PED presence was annotated manually and afterwards measured by the AI program automatically. RESULTS: 115 eyes of 101 patients with CSC were included, of which 70 were diagnosed with chronic CSC and 45 with acute CSC. It was found that patients with baseline presence of foveal flat PEDs and multiple flat foveal and extrafoveal PEDs had a higher chance of developing chronic form. AI-based volumetric analysis revealed no significant differences between the groups. CONCLUSIONS: While more evidence is needed to confirm the effectiveness of AI-based PED quantitative analysis, this study highlights the significance of identifying flat irregular PEDs at the earliest stage possible in patients with CSC, to optimize patient management and long-term visual outcomes.

BASELINE SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHIC RETINAL LAYER FEATURES IDENTIFIED BY ARTIFICIAL INTELLIGENCE PREDICT THE COURSE OF CENTRAL SEROUS CHORIORETINOPATHY.

PURPOSE: To identify optical coherence tomography (OCT) features to predict the course of central serous chorioretinopathy (CSC) with an artificial intelligence-based program. METHODS: Multicenter, observational study with a retrospective design. Treatment-naïve patients with acute CSC and chronic CSC were enrolled. Baseline OCTs were examined by an artificial intelligence-developed platform (Discovery OCT Fluid and Biomarker Detector, RetinAI AG, Switzerland). Through this platform, automated retinal layer thicknesses and volumes, including intaretinal and subretinal fluid, and pigment epithelium detachment were measured. Baseline OCT features were compared between acute CSC and chronic CSC patients. RESULTS: One hundred and sixty eyes of 144 patients with CSC were enrolled, of which 100 had chronic CSC and 60 acute CSC. Retinal layer analysis of baseline OCT scans showed that the inner nuclear layer, the outer nuclear layer, and the photoreceptor-retinal pigmented epithelium complex were significantly thicker at baseline in eyes with acute CSC in comparison with those with chronic CSC ( P < 0.001). Similarly, choriocapillaris and choroidal stroma and retinal thickness (RT) were thicker in acute CSC than chronic CSC eyes ( P = 0.001). Volume analysis revealed average greater subretinal fluid volumes in the acute CSC group in comparison with chronic CSC ( P = 0.041). CONCLUSION: Optical coherence tomography features may be helpful to predict the clinical course of CSC. The baseline presence of an increased thickness in the outer retinal layers, choriocapillaris and choroidal stroma, and subretinal fluid volume seems to be associated with acute course of the disease.

The role of the gut microbiome in eye diseases.

The gut microbiome is a complex ecosystem of microorganisms and their genetic entities colonizing the gastrointestinal tract. When in balanced composition, the gut microbiome is in symbiotic interaction with its host and maintains intestinal homeostasis. It is involved in essential functions such as nutrient metabolism, inhibition of pathogens and regulation of immune function. Through translocation of microbes and their metabolites along the epithelial barrier, microbial dysbiosis induces systemic inflammation that may lead to tissue destruction and promote the onset of various diseases. Using whole-metagenome shotgun sequencing, several studies have shown that the composition and associated functional capacities of the gut microbiome are associated with age-related macular degeneration, retinal artery occlusion, central serous chorioretinopathy and uveitis. In this review, we provide an overview of the current knowledge about the gut microbiome in eye diseases, with a focus on interactions between the microbiome, specific microbial-derived metabolites and the immune system. We explain how these interactions may be involved in the pathogenesis of age-related macular degeneration, retinal artery occlusion, central serous chorioretinopathy and uveitis and guide the development of new therapeutic approaches by microbiome-altering interventions for these diseases.

Central Serous Chorioretinopathy - an Overview. / Chorioretinopathia centralis serosa ­ ein Überblick.

Central serous chorioretinopathy (CSCR) is characterised by retinal serous detachment usually localised in the macular region. CSCR predominantly affects men between 30 and 50 years of age. Traditional classification differentiates between acute (duration shorter than 4 to 6 months) and chronic disease (duration longer than 4 to 6 months). The pathogenesis is multifactorial and current thinking assumes the presence of localised choroidal hyperpermeability with subsequent secondary changes in the retinal pigment epithelium (RPE). The symptoms of acute CSCR include central blurred vision, often with deterioration in visual acuity. Optical coherence tomography (OCT) reveals subretinal fluid (SRF) and/or single retinal pigment epithelial detachments. Fluorescein angiography (FA) usually shows a leaking point with absent or only minor RPE changes in the acute phase and indocyanine green angiography (ICG) highlights circumscribed areas of thickened and hyperpermeable choroid. Acute cases may show spontaneous resolution of SRF, but may also recur and/or become chronic. After the initial diagnosis, spontaneous remission is seen in about 70 to 80% of cases, with a recurrence rate of about 50%. Due to the favourable spontaneous course, it is recommended to wait for 4 to 6 months after the first symptoms manifest. Steroid therapy is considered as a major risk factor. Chronic cases are characterised by slow deterioration in visual acuity with reduced contrast and colour perception. There are extensive RPE changes, with secondary degenerative changes of the photoreceptors. The disease can by complicated by choroidal neovascularisation (CNV), especially in elderly patients. The literature lists a number of treatments: The leakage point (visible in the FA) can be treated by focal laser therapy, either micropulse laser or, if sufficiently distant from the fovea, by argon laser coagulation. Randomised trials in chronic CSCR demonstrated good outcomes with photodynamic therapy. With observation periods ranging from 3 to 6 months, several case series reports found improvement after systemic administration of mineralocorticoid receptor antagonists, carbonic anhydrase inhibitors or non-steroidal anti-inflammatory drugs. In the presence of secondary CNV, anti-VEGF treatment should be initiated. It is unclear whether the combination with PDT might be useful.

Absence of Genotype/Phenotype Correlations Requires Molecular Diagnostic to Ascertain Stargardt and Stargardt-Like Swiss Patients.

We genetically characterized 22 Swiss patients who had been diagnosed with Stargardt disease after clinical examination. We identified in 11 patients (50%) pathogenic bi-allelic ABCA4 variants, c.1760+2T>C and c.4496T>C being novel. The dominantly inherited pathogenic ELOVL4 c.810C>G p.(Tyr270*) and PRPH2-c.422A>G p.(Tyr141Cys) variants were identified in eight (36%) and three patients (14%), respectively. All patients harboring the ELOVL4 c.810C>G p.(Tyr270*) variant originated from the same small Swiss area, identifying a founder mutation. In the ABCA4 and ELOVL4 cohorts, the clinical phenotypes of "flecks", "atrophy", and "bull"s eye like" were observed by fundus examination. In the small number of patients harboring the pathogenic PRPH2 variant, we could observe both "flecks" and "atrophy" clinical phenotypes. The onset of disease, progression of visual acuity and clinical symptoms, inheritance patterns, fundus autofluorescence, and optical coherence tomography did not allow discrimination between the genetically heterogeneous Stargardt patients. The genetic heterogeneity observed in the relatively small Swiss population should prompt systematic genetic testing of clinically diagnosed Stargardt patients. The resulting molecular diagnostic is required to prevent potentially harmful vitamin A supplementation, to provide genetic counseling with respect to inheritance, and to schedule appropriate follow-up visits in the presence of increased risk of choroidal neovascularization.

Optical coherence tomography angiography findings in fellow eyes of choroidal neovascularisation associated with central serous chorioretinopathy.

AIM: To evaluate the optical coherence tomography angiography (OCTA) features of fellow eyes of patients with unilateral choroidal neovascularisation (CNV) associated with chronic central serous chorioretinopathy (CSCR). METHODS: Medical records of patients with chronic CSCR who had undergone OCT angiography of both the eyes were reviewed. Patients with evidence of unilateral CNV detected by conventional imaging (OCT, fluorescein angiography and/or indocyanine green angiography) were included in the study. The OCT and OCTA characteristics of fellow eyes were analysed. RESULTS: Forty patients (80 eyes-40 fellow eyes) with chronic CSCR with evidence of CNV in one eye were included. Mean age of the patients was 54.9±9.9 years and 82.5 % were males. Twenty-five (62.5%) fellow eyes had flat irregular pigment epithelial detachment on OCT, out of which 21 had internal hyper-reflectivity. A definite vascular network was picked up by OCTA in 9 of these 40 fellow eyes (22.5%) which was not detected on conventional imaging. In addition, two eyes had an ill-defined hyper-reflectivity, which could not be classified as a definite network at that point of time. The networks detected on OCTA in fellow eyes were mostly inactive, suggesting a subclinical neovascularisation. CONCLUSION: One-fourth of fellow eyes showed vascular network which could not be diagnosed on conventional imaging which highlights the importance of imaging both the eyes of chronic CSCR for early detection of CNV using OCTA. Further longitudinal studies are needed to assess the clinical course of such subclinical vascular networks in CSCR.

Associations of the intestinal microbiome with the complement system in neovascular age-related macular degeneration.

Age-related macular degeneration (AMD) is a leading cause of severe vision loss in the aged population. The etiology of AMD is multifactorial including nutritional factors, genetic variants mainly in the complement pathway, environmental risk factors and alterations in the intestinal microbiome. However, it remains unexplored whether there is an interdependency of these factors leading to the development of AMD. To investigate this issue, a shotgun metagenomics analysis of 57 neovascular AMD and 58 healthy controls as well as of 16 complement C3-deficient mice and 16 wildtypes was performed. Whereas the class Negativicutes was more abundant in patients, the genus Oscillibacter and species Bacteroides had a significantly higher prevalence in persons without AMD. Similar taxonomic features were identified that distinguished wildtype mice from C3-deficient mice. Moreover, several purine signaling pathways were associated with both, neovascular AMD and C3 deficiency. While SNPs within the complement factor B gene were more abundant in controls, SNPs within the high temperature requirement A serine peptidase 1 and complement factor H (CFH) genes were associated with neovascular AMD. Using a classification model, Negativicutes was identified as a potential biomarker for AMD and furthermore, it positively correlated with CFH. This study suggests an association between the intestinal microbiome and the complement system in neovascular AMD.

Comparison of Drusen Volume Assessed by Two Different OCT Devices.

To compare drusen volume between Heidelberg Spectral Domain (SD-) and Zeiss Swept-Source (SS) PlexElite Optical Coherence Tomography (OCT) determined by manual and automated segmentation methods. Thirty-two eyes of 24 patients with Age-Related Macular Degeneration (AMD) and drusen maculopathy were included. In the central 1 and 3 mm ETDRS circle drusen volumes were calculated and compared. Drusen segmentation was performed using automated manufacturer algorithms of the two OCT devices. Then, the automated segmentation was manually corrected and compared and finally analyzed using customized software. Though on SD-OCT, there was a significant difference of mean drusen volume prior to and after manual correction (mean difference: 0.0188 ± 0.0269 mm3, p < 0.001, corr. p < 0.001, correlation of r = 0.90), there was no difference found on SS-OCT (mean difference: 0.0001 ± 0.0003 mm3, p = 0.262, corr. p = 0.524, r = 1.0). Heidelberg-acquired mean drusen volume after manual correction was significantly different from Zeiss-acquired drusen volume after manual correction (mean difference: 0.1231 ± 0.0371 mm3, p < 0.001, corr. p < 0.001, r = 0.68). Using customized software, the difference of measurements between both devices decreased and correlation among the measurements improved (mean difference: 0.0547 ± 0.0744 mm3, p = 0.02, corr. p = 0.08, r = 0.937). Heidelberg SD-OCT, the Zeiss PlexElite SS-OCT, and customized software all measured significantly different drusen volumes. Therefore, devices/algorithms may not be interchangeable. Third-party customized software helps to minimize differences, which may allow a pooling of data of different devices, e.g., in multicenter trials.

Neuroprotection with rasagiline in patients with macula-off retinal detachment: A randomized controlled pilot study.

We aimed to evaluate the neuroprotective efficacy of rasagiline in pseudophakic patients who had surgery for macula-off rhegmatogenous retinal detachment (RRD). This was a 6-month, prospective, randomized, double-blind, placebo-controlled pilot study. Patients presenting with acute macula-off RRD were recruited and randomized 1:1 to receive rasagiline 1 mg/day or placebo for 7 days. Best-corrected visual acuity (BCVA) and optical coherence tomography were acquired 1 day before as well as 2 days, 3 weeks, 3 months and 6 months after surgery. We screened 26 patients with RRD whereof 23 were eventually included and randomized. The primary outcome was final BCVA. Secondary outcomes included central retinal thickness (CRT) and adverse events (AE). We evaluated photoreceptor cells (prc) recovery through morphological measurements. The baseline characteristics were comparable between groups. BCVA significantly improved in both groups (letters gained: rasagiline 61.5 ± 18.1 vs placebo 55.3 ± 29.2, p = 0.56), but no significant inter-group difference was found at any visit. CRT was stable 3 weeks after surgery onwards, with no inter-group difference. No treatment-emergent AE occurred. Significant prc restoration was observed from 3 weeks to 6 months after surgery, without inter-group difference at either visit. Ellipsoid zone integrity (ß = 0.517, p = 0.008) and foveal bulge (ß = 0.387, p = 0.038) were significant predictors of good final BCVA. In conclusion, perioperative oral treatment with rasagiline 1 mg/day for 7 days did not show significant benefits on visual or anatomical outcomes in macula-off RRD patients.

Retinal artery occlusion is associated with compositional and functional shifts in the gut microbiome and altered trimethylamine-N-oxide levels.

Retinal artery occlusion (RAO) is a sight threatening complication of cardiovascular disease and commonly occurs due to underlying atherosclerosis. As cardiovascular disease and atherosclerosis in particular has been associated with compositional alterations in the gut microbiome, we investigated this association in patients with clinically confirmed non-arteritic RAO compared to age- and sex-matched controls. On the phylum level, the relative abundance of Bacteroidetes was decreased in patients with RAO compared to controls, whereas the opposite applied for the phylum of Proteobacteria. Several genera and species such as Actinobacter, Bifidobacterium spp., Bacteroides stercoris, Faecalibacterium prausnitzii were relatively enriched in patients with RAO, whereas others such as Odoribacter, Parasutterella or Lachnospiraceae were significantly lower. Patient's gut microbiomes were enriched in genes of the cholesterol metabolism pathway. The gut derived, pro-atherogenic metabolite trimethylamine-N-oxide (TMAO) was significantly higher in patients with RAO compared to controls (p = 0.023) and a negative correlation between relative abundances of genera Parasutterella and Lachnospiraceae and TMAO levels and a positive correlation between relative abundance of genus Akkermansia and TMAO levels was found in study subjects. Our findings proposes that RAO is associated with alterations in the gut microbiome and with elevated TMAO levels, suggesting that RAO could be targeted by microbiome-altering interventions.

Optical coherence tomography angiography findings in cystoid macular degeneration associated with central serous chorioretinopathy.

AIM: To describe the optical coherence tomography (OCT) characteristics and to identify and analyse the incidence of choroidal neovascular (CNV) network seen on optical coherence tomography angiography (OCTA) in eyes with cystoid macular degeneration (CMD) associated with central serous chorioretinopathy (CSCR). METHODS: This was a retrospective, observational study of 29 eyes of 25 patients who were previously diagnosed as CSCR with CMD. Baseline patient characteristics, best-corrected visual acuity (BCVA), evidence of CNV network and its pattern on OCTA, distribution of CMD changes and OCT parameters, such as height of the neurosensory retinal detachment (NSD), presence of double layer sign, central macular thickness, were analysed. The eyes were classified into two groups depending on the presence or absence of CNV network on OCTA. BCVA, OCT parameters and CMD distribution were compared in the two groups at baseline using independent t-test. RESULT: A total of 13 (44.8 %) eyes had a CNV network, while only 9 out of the 13 eyes had pattern-I CNV. Among the eyes with CNV network (13 eyes), mean height of NSD was of 65.2±22.7 µ, whereas, among the eyes without CNV (16 eyes), it was 134.6±77.4 µ. The difference was statistically significant (p=0.013). There was no statistically significant difference between eye having a CNV and eyes without CNV in terms of other parameters. CONCLUSION: A CNV network is seen in a large subset of patients with CMD in CSCR. A shallower subretinal fluid may point towards the presence of an underlying CNV network.

VASCULAR ABNORMALITIES IN DIABETIC RETINOPATHY ASSESSED WITH SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY WIDEFIELD IMAGING.

PURPOSE: To detect vascular abnormalities in diabetic retinopathy using swept-source optical coherence tomography angiography (SS-OCTA) widefield images, and to compare the findings with color fundus photographs (CFPs) using Early Treatment Diabetic Retinopathy Study severity grading. METHODS: 3 mm × 3 mm and 12 mm × 12 mm scans were acquired to cover 70° to 80° of the posterior pole using a 100-kHz SS-OCTA instrument. Two masked graders assessed the presence of vascular abnormalities on SS-OCTA and the Early Treatment Diabetic Retinopathy Study level on CFP. The grading results were then compared. RESULTS: A total of 120 diabetic eyes (60 patients) were imaged with the SS-OCTA instrument. Cohort 1 (91 eyes; SS-OCTA grading only) showed microaneurysms in 91% (n = 83), intraretinal microvascular abnormalities in 79% (n = 72), and neovascularization in 21% (n = 19) of cases. Cohort 2 (52 eyes; CFP grading compared with SS-OCTA) showed microaneurysms on CFP in 90% (n = 47) and on SS-OCTA in 96% (n = 50) of cases. Agreement in intraretinal microvascular abnormality detection was fair (k = 0.2). Swept-source optical coherence tomography angiography detected 50% of intraretinal microvascular abnormality cases (n = 26), which were missed on CFP. Agreement in detecting neovascularization was moderate (k = 0.5). CONCLUSION: Agreement in detection of diabetic retinopathy features on CFP and SS-OCTA varies depending on the vascular changes examined. Swept-source optical coherence tomography angiography shows a higher detection rate of intraretinal microvascular abnormalities (P = 0.039), compared with Early Treatment Diabetic Retinopathy Study grading.

OCT-angiography: A qualitative and quantitative comparison of 4 OCT-A devices.

PURPOSE: To compare the quality of four OCT-angiography(OCT-A) modules. METHOD: The retina of nineteen healthy volunteers were scanned with four OCT-devices (Topcon DRI-OCT Triton Swept-source OCT, Optovue RTVue-XR, a prototype Spectralis OCT2, Heidelberg-Engineering and Zeiss Cirrus 5000-HD-OCT). The device-software generated en-face OCT-A images of the superficial (SCP) and deep capillary plexuses (DCP) were evaluated and scored by 3 independent retinal imaging experts. The SCP vessel density was assessed using Angiotool-software. After the inter-grader reliability assessment, a consensus grading was performed and the modules were ranked based on their scoring. RESULTS: There was no significant difference in the vessel density among the modules (Zeiss 48.7±4%, Optovue 47.9±3%, Topcon 48.3±2%, Heidelberg 46.5±4%, p = 0.2). The numbers of discernible vessel-bifurcations differed significantly on each module (Zeiss 2±0.9 bifurcations, Optovue 2.5±1.2, Topcon 1.3±0.7 and Heidelberg 0.5±0.6, p≤0.001). The ranking of each module differed depending on the evaluated parameter. In the overall ranking, the Zeiss module was superior and in 90% better than the median (Bonferroni corrected p-value = 0.04). Optovue was better than the median in 60%, Topcon in 40% and Heidelberg module in 10%, however these differences were not statistically significant. CONCLUSION: Each of the four evaluated OCT-A modules had particular strengths, which differentiated it from their competitors.

Association of the Intestinal Microbiome with the Development of Neovascular Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is the most frequent cause of blindness in the elderly. There is evidence that nutrition, inflammation and genetic risk factors play an important role in the development of AMD. Recent studies suggest that the composition of the intestinal microbiome is associated with metabolic diseases through modulation of inflammation and host metabolism. To investigate whether compositional and functional alterations of the intestinal microbiome are associated with AMD, we sequenced the gut metagenomes of patients with AMD and controls. The genera Anaerotruncus and Oscillibacter as well as Ruminococcus torques and Eubacterium ventriosum were relatively enriched in patients with AMD, whereas Bacteroides eggerthii was enriched in controls. Patient's intestinal microbiomes were enriched in genes of the L-alanine fermentation, glutamate degradation and arginine biosynthesis pathways and decreased in genes of the fatty acid elongation pathway. These findings suggest that modifications in the intestinal microbiome are associated with AMD, inferring that this common sight threatening disease may be targeted by microbiome-altering interventions.

FUNDUS AUTOFLUORESCENCE LIFETIMES AND CENTRAL SEROUS CHORIORETINOPATHY.

PURPOSE: To quantify retinal fluorescence lifetimes in patients with central serous chorioretinopathy (CSC) and to identify disease specific lifetime characteristics over the course of disease. METHODS: Forty-seven participants were included in this study. Patients with central serous chorioretinopathy were imaged with fundus photography, fundus autofluorescence, optical coherence tomography, and fluorescence lifetime imaging ophthalmoscopy (FLIO) and compared with age-matched controls. Retinal autofluorescence was excited using a 473-nm blue laser light and emitted fluorescence light was detected in 2 distinct wavelengths channels (498-560 nm and 560-720 nm). Clinical features, mean retinal autofluorescence lifetimes, autofluorescence intensity, and corresponding optical coherence tomography (OCT) images were further analyzed. RESULTS: Thirty-five central serous chorioretinopathy patients with a mean visual acuity of 78 ETDRS letters (range, 50-90; mean Snellen equivalent: 20/32) and 12 age-matched controls were included. In the acute stage of central serous chorioretinopathy, retinal fluorescence lifetimes were shortened by 15% and 17% in the respective wavelength channels. Multiple linear regression analysis showed that fluorescence lifetimes were significantly influenced by the disease duration (P < 0.001) and accumulation of photoreceptor outer segments (P = 0.03) but independent of the presence or absence of subretinal fluid. Prolonged central macular autofluorescence lifetimes, particularly in eyes with retinal pigment epithelial atrophy, were associated with poor visual acuity. CONCLUSION: This study establishes that autofluorescence lifetime changes occurring in central serous chorioretinopathy exhibit explicit patterns which can be used to estimate perturbations of the outer retinal layers with a high degree of statistical significance.

Next generation sequencing based identification of disease-associated mutations in Swiss patients with retinal dystrophies.

Inherited monogenic diseases of the retina and vitreous affect approximately 1 in 2000 individuals. They are characterized by tremendous genetic heterogeneity and clinical variability involving mutations in approximately 250 genes and more than 20 different clinical phenotypes. Clinical manifestations of retinal dystrophies (RDs) range from mild retinal dysfunctions to severe congenital forms of blindness. A detailed clinical diagnosis and the identification of causative mutations are crucial for genetic counseling of affected patients and their families, for understanding genotype-phenotype correlations and developing therapeutic approaches. Using whole exome sequencing (WES) we have established a reliable and efficient high-throughput analysis pipeline to identify disease-causing mutations. Our data indicate that this approach enables us to genetically diagnose approximately 64% of the patients (n = 58) with variant(s) in known disease-associated genes. We report 20 novel and 26 recurrent variants in genes associated with RDs. We also identified a novel phenotype for mutations in C2orf71 and provide functional evidence for exon skipping due to a splice-site variant identified in FLVCR1. In conclusion, WES can rapidly identify variants in various families affected with different forms of RDs. Our study also expands the clinical and allelic spectrum of genes associated with RDs in the Swiss population.

Time-Resolved Ultra-High Resolution Optical Coherence Tomography for Real-Time Monitoring of Selective Retina Therapy.

PURPOSE: Selective retina therapy (SRT) is a novel treatment for retinal pathologies, solely targeting the RPE. During SRT, the detection of an immediate tissue reaction is challenging, as tissue effects remain limited to intracellular RPE photodisruption. Time-resolved ultra-high axial resolution optical coherence tomography (OCT) is thus evaluated for the monitoring of dynamic optical changes at and around the RPE during SRT. METHODS: An experimental OCT system with an ultra-high axial resolution of 1.78 µm was combined with an SRT system and time-resolved OCT M-scans of the target area were recorded from four patients undergoing SRT. Optical coherence tomography scans were analyzed and OCT morphology was correlated with findings in fluorescein angiography, fundus photography, and cross-sectional OCT. RESULTS: In cases in which the irradiation caused RPE damage proven by fluorescein angiography, the lesions were well discernible in time-resolved OCT images but remained invisible in fundus photography and cross-sectional OCT acquired after treatment. If RPE damage was introduced, all applied SRT pulses led to detectable signal changes in the time-resolved OCT images. The extent of optical signal variation seen in the OCT data appeared to scale with the applied SRT pulse energy. CONCLUSIONS: The first clinical results proved that successful SRT irradiation induces detectable changes in the OCT M-scan signal while it remains invisible in conventional ophthalmoscopic imaging. Thus, real-time high-resolution OCT is a promising modality to monitor and analyze tissue effects introduced by selective retina therapy and may be used to guide SRT in an automatic feedback mode (www.swissmedic.ch number, 2011-MD-0006).

Selective Retina Therapy in Acute and Chronic-Recurrent Central Serous Chorioretinopathy.

PURPOSE: Selective retina therapy (SRT), the confined laser heating and destruction of retinal pigment epithelial cells, has been shown to treat acute types of central serous chorioretinopathy (CSC) successfully without damaging the photoreceptors and thus avoiding laser-induced scotoma. However, a benefit of laser treatment for chronic forms of CSC is questionable. In this study, the efficacy of SRT by means of the previously used 1.7-µs and shorter 300-ns pulse duration was evaluated for both types of CSC, also considering re-treatment for nonresponders. MATERIAL AND METHODS: In a two-center trial, 26 patients were treated with SRT for acute (n = 10) and chronic-recurrent CSC (n = 16). All patients presented with subretinal fluid (SRF) in OCT and leakage in fluorescein angiography (FA). SRT was performed using a prototype SRT laser system (frequency-doubled Q-switched Nd:YLF-laser, wavelength 527 nm) with adjustable pulse duration. The following irradiation settings were used: a train of 30 laser pulses with a repetition rate of 100 Hz and pulse durations of 300 ns and 1.7 µs, pulse energy 120-200 µJ, retinal spot size 200 µm. Because SRT lesions are invisible, FA was always performed 1 h after treatment to demonstrate laser outcome (5-8 single spots in the area of leakage). In cases where energy was too low, as indicated by missing FA leakage, energy was adjusted and the patient re-treated immediately. Observation intervals were after 4 weeks and 3 months. In case of nonimprovement of the disease after 3 months, re-treatment was considered. RESULTS: Of 10 patients with active CSC that presents focal leakage in FA, 5 had completely resolved fluid after 4 weeks and all 10 after 3 months. Mean visual acuity increased from 76.6 ETDRS letters to 85.0 ETDRS letters 3 months after SRT. Chronic-recurrent CSC was characterized by less severe SRF at baseline in OCT and weaker leakage in FA than in acute types. Visual acuity changed from baseline 71.6 to 72.8 ETDRS letters after 3 months. At this time, SRF was absent in 3 out of 16 patients (19%), FA leakage had come to a complete stop in 6 out of 16 patients (38%). In 6 of the remaining chronic CSC patients, repeated SRT with higher pulse energy was considered because of persistent leakage activity. After the re-treatment, SRF resolved completely in 5 patients (83.3%) after only 25 days. CONCLUSION: SRT showed promising results in treating acute CSC, but was less effective in chronic cases. Interestingly, re-treatment resulted in enhanced fluid resolution and dry conditions after a considerably shorter time in most patients. Therefore, SRT including re-treatment if necessary might be a valuable CSC treatment alternative even in chronic-recurrent cases.