Single Center Experience with Voretigene Neparvovec Gene Augmentation Therapy in RPE65 Mutation-Associated Inherited Retinal Degeneration in a Clinical Setting.

PURPOSE: To assess the impact of baseline data on psychophysical and morphological outcomes of subretinal voretigene neparvovec (VN) (Luxturna, Spark Therapeutics, Inc.) treatment. DESIGN: Single-center, retrospective, longitudinal, consecutive case series. PARTICIPANTS: Patients with RPE65-biallelic mutation-associated inherited retinal degeneration (RPE65-IRD) treated between February 2020 and March 2022 with VN and oral immunosuppression according to the manufacturer's recommendation by one surgeon (F.G.H.). METHODS: Retrospective analysis of surgical and clinical records, ancillary testing, and retinal imaging after VN therapy for RPE65-IRD. Descriptive statistics compared data at baseline up to 32 months post-treatment. MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA), low-luminance VA (LLVA), Goldmann visual fields (GVFs), chromatic full-field stimulus threshold (FST) testing (FST), scotopic and photopic 2-color threshold perimetry (2CTP), and multimodal retinal imaging. RESULTS: Thirty eyes of 19 patients were analyzed (10 pediatric patients < 20 years; 20 adult patients > 20 years of age; overall range: 8-40 years) with a median follow-up of 15 months (range, 1-32). The fovea was completely or partially detached in 16 eyes, attached in 12 eyes, and not assessable in 2 eyes on intraoperative imaging. Median BCVA at baseline was better in the pediatric group (P < 0.05) and did not change significantly independent of age. Meaningful loss of BCVA (≥ 0.3 logarithm of the minimal angle of resolution [logMAR]) occurred in 5 of 18 adult eyes, and a meaningful gain (≥-0.3 logMAR) occurred in 2 of 18 adult and 2 of 8 pediatric eyes. The LLVA and scotopic 2CTP improved considerably in pediatric patients. Scotopic blue FST improved at all ages but more in pediatric patients (8/8 eyes gained ≥ 10 decibels [dB]; P < 0.05). In pediatric patients, median GVF improved by 20% for target V4e and by 50% for target III4e (target I4e not detected). Novel atrophy developed in 13 of 26 eyes at the site of the bleb or peripheral of vascular arcades. Improvements in FST did not correlate with development of chorioretinal atrophy at 12 months. Mean central retinal thickness was 165.87 µm (± 26.26) at baseline (30 eyes) and 157.69 µm (± 30.3) at 12 months (26 eyes). Eight adult patients were treated unilaterally. The untreated eyes did not show meaningful changes during follow-up. CONCLUSIONS: These data in a clinical setting show the effectiveness of VN therapy with stable median BCVA and mean retinal thickness and improvements of LLVA, FST, and 2CTP up to 32 months. Treatment effects were superior in the pediatric group. We observed new chorioretinal atrophy in 50% of the treated eyes. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Interpretation of SD-OCT imaging data in real-life conditions versus standardized reading centre analysis in eyes with diabetic macular oedema or macular oedema secondary to retinal vein occlusion: 24-month follow-up of the ORCA study.

PURPOSE: As part of the prospective, non-interventional OCEAN study, the ORCA module evaluated physicians' spectral domain optical coherence tomography (SD-OCT) image interpretations in the treatment of diabetic macular oedema (DME) or macular oedema (ME) secondary to retinal vein occlusion (RVO). METHODS: Presence of intraretinal fluid (IRF) and/or subretinal fluid (SRF) was evaluated independently by physicians and reading centres (RCs) on 1612 SD-OCT scans of 133 patients diagnosed with either DME or ME secondary to RVO. Agreement between physicians and RCs was calculated for both cohorts individually and as a combined ME cohort. Physicians' treatment decisions were analysed related to the results of the OCT-evaluations. RESULTS: For the combined ME cohort, presence of IRF/SRF was recorded by RCs in 792/1612 (49.1%) visits and by physicians in 852/1612 (52.9%) visits, with an agreement regarding presence or absence of foveal fluid in 70.4% of cases. In 64.4% (510/792) of visits with RC-detected foveal IRF and/or SRF no injection was given. In 30.3% of these visits with foveal fluid no reason was identified for a 'watch and wait' approach indicating possible undertreatment. BCVA deterioration was seen in a quarter of these eyes at the following visit. CONCLUSION: Despite good agreement between physicians and RCs to recognize SRF and IRF, our data indicate that omitting injections despite foveal involvement of fluid is frequent in routine clinical practice. This may put patients at risk of undertreatment, which may negatively impact real-life BCVA outcomes. TRIAL REGISTRATION: www. CLINICALTRIALS: gov , identifier NCT02194803.

Surgical site infections are independently associated with the development of postoperative acute-on-chronic liver failure in liver cirrhosis.

Acute-on-chronic liver failure (ACLF) is associated with organ failure and high short-term mortality. Bacterial infections and surgery have been reported as major precipitants for ACLF. However, detailed characterization of postoperative infections after elective surgery in patients with liver cirrhosis and their impact on the development of ACLF have not been investigated yet. A total of 235 patients with cirrhosis without ACLF and proven bacterial infections undergoing elective surgery were included. The primary end point was the development of ACLF within 28 days after surgery, and secondary end points were infection development within 28 days and 3-month ACLF-related mortality. Cox regression analysis was used for identification of risk factors associated with ACLF development, infection development, and mortality. A total of 86 patients (37%) developed ACLF within 28 days after surgery. Patients with new postoperative infections had significantly higher rates of associated ACLF episodes within 28 days (51% vs. 24%, p < 0.001) and higher 3-month mortality ( p < 0.05) than patients without postoperative infections. New infections after surgery [HR: 2.43 (1.59-3.71), p < 0.001] and organ/space surgical site infections [HR: 2.46 (1.26-4.80), p = 0.01] in particular were independent risk factors associated with ACLF development 28 days after surgery. Extensive procedures were associated with the development of new postoperative infection episodes within 28 days. Infections treated with initial appropriate empirical antibiotic strategies showed significantly improved survival. This study characterizes and identifies bacterial infections in general and organ/space surgical site infection in particular as precipitating events for the development of ACLF after elective surgery in patients with cirrhosis. Postoperative ACLF combined with infections leads to higher postoperative short-term mortality than each condition separately, especially in extensive procedures. Interdisciplinary care, early identification of postoperative ACLF and infections, and adequate, broad, and early treatment strategies are needed to improve postoperative outcome.

[Use of artificial intelligence in geographic atrophy in age-related macular degeneration]. / Einsatz von künstlicher Intelligenz bei der geographischen Atrophie bei der altersabhängigen Makuladegeneration.

The first regulatory approval of treatment for geographic atrophy (GA) secondary to age-related macular degeneration in the USA constitutes an important milestone; however, due to the nature of GA as a non-acute, insidiously progressing pathology, the ophthalmologist faces specific challenges concerning risk stratification, making treatment decisions, monitoring of treatment and patient education. Innovative retinal imaging modalities, such as fundus autofluorescence (FAF) and optical coherence tomography (OCT) have enabled identification of typical morphological alterations in relation to GA, which are also suitable for the quantitative characterization of GA. Solutions based on artificial intelligence (AI) enable automated detection and quantification of GA-specific biomarkers on retinal imaging data, also retrospectively and over time. Moreover, AI solutions can be used for the diagnosis and segmentation of GA as well as the prediction of structure and function without and under GA treatment, thereby making a valuable contribution to treatment monitoring and the identification of high-risk patients and patient education. The integration of AI solutions into existing clinical processes and software systems enables the broad implementation of informed and personalized treatment of GA secondary to AMD.

[Use of artificial intelligence for recognition of biomarkers in intermediate age-related macular degeneration]. / Einsatz von künstlicher Intelligenz zur Erkennung von Biomarkern bei der intermediären altersabhängigen Makuladegeneration.

Advances in imaging and artificial intelligence (AI) have revolutionized the detection, quantification and monitoring for the clinical assessment of intermediate age-related macular degeneration (iAMD). The iAMD incorporates a broad spectrum of manifestations, which range from individual small drusen, hyperpigmentation, hypopigmentation up to early stages of geographical atrophy. Current high-resolution imaging technologies enable an accurate detection and description of anatomical features, such as drusen volumes, hyperreflexive foci and photoreceptor degeneration, which are risk factors that are decisive for prediction of the course of the disease; however, the manual annotation of these features in complex optical coherence tomography (OCT) scans is impractical for the routine clinical practice and research. In this context AI provides a solution by fully automatic segmentation and therefore delivers exact, reproducible and quantitative analyses of AMD-related biomarkers. Furthermore, the application of AI in iAMD facilitates the risk assessment and the development of structural endpoints for new forms of treatment. For example, the quantitative analysis of drusen volume and hyperreflective foci with AI algorithms has shown a correlation with the progression of the disease. These technological advances therefore improve not only the diagnostic precision but also support future targeted treatment strategies and contribute to the prioritized target of personalized medicine in the diagnostics and treatment of AMD.

[Digital remote monitoring of chronic retinal conditions-A clinical future tool? : Remote monitoring of chronic retinal conditions]. / Digitale Telemedizin zur Überwachung chronischer Netzhauterkrankungen ­ ein klinisches Werkzeug für die Zukunft? : Fernüberwachung chronischer Netzhauterkrankungen.

BACKGROUND: In view of the predicted increase in incidence and prevalence of chronic retinal diseases and undersupply of care in the population, telemedicine could contribute to reducing access barriers to healthcare and improving the results of treatment. OBJECTIVE: A literature review on remote monitoring of chronic retinal diseases was carried out. MATERIAL AND METHODS: The medical literature was searched for publications on remote monitoring of chronic retinal diseases. The results were compiled in a narrative overview. RESULTS: The four main topics in the literature are: validation studies, implementation strategies, acceptance/target group analyses and health economic analyses. Remote monitoring systems are based on visual function tests, imaging or patient reports and have been particularly investigated in age-related macular degeneration (AMD) and diabetic eye disease (DED). Studies indicate positive effects regarding an optimization of clinical care and a favorable safety profile but randomized controlled trials are lacking for the majority of monitoring tools. CONCLUSION: Remote monitoring could complement existing care structures for patients with chronic retinal diseases, especially AMD and DED. Promising systems are based on hyperacuity or optical coherence tomography, while patient-reported data are not commonly used; however, there is currently insufficient evidence justifying the use of remote monitoring systems in chronic retinal diseases in Europe and more research on the validation of remote monitoring systems is needed.

Characteristics and Spatial Distribution of Structural Features in Age-Related Macular Degeneration: A MACUSTAR Study Report.

PURPOSE: To report the prevalence and topographic distribution of structural characteristics in study participants with age-related macular degeneration (AMD) and controls in the cross-sectional study part of the MACUSTAR study (ClinicalTrials.gov Identifier: NCT03349801). DESIGN: European, multicenter cohort study. SUBJECTS: Overall, 301 eyes of 301 subjects with early (n = 34), intermediate (n = 168), and late AMD (n = 43), as well as eyes without any AMD features (n = 56). METHODS: In study eyes with intermediate AMD (iAMD), the presence of structural AMD biomarkers, including pigmentary abnormalities (PAs), pigment epithelium detachment (PED), refractile deposits, reticular pseudodrusen (RPD), hyperreflective foci (HRF), incomplete/complete retinal pigment epithelium (RPE), and outer retinal atrophy (i/cRORA), and quiescent choroidal neovascularization (qCNV) was systematically determined in the prospectively acquired multimodal retinal imaging cross-sectional data set of MACUSTAR. Retinal layer thicknesses and the RPE drusen complex (RPEDC) volume were determined for the total study cohort in spectral-domain (SD) OCT imaging using a deep-learning-based algorithm. MAIN OUTCOME MEASURES: Prevalence and topographic distribution of structural iAMD features. RESULTS: A total of 301 study eyes of 301 subjects with a mean (± standard deviation) age of 71.2 ± 7.20 years (63.1% women) were included. Besides large drusen, the most prevalent structural feature in iAMD study eyes were PA (57.1%), followed by HRF (51.8%) and RPD (22.0%). Pigment epithelium detachment lesions were observed in 4.8%, vitelliform lesions in 4.2%, refractile deposits in 3.0%, and qCNV in 2.4%. Direct precursor lesions for manifest retinal atrophy were detected in 10.7% (iRORA) and 4.2% (cRORA) in iAMD eyes. Overall, the highest RPEDC volume with a median of 98.92 × 10-4 mm³ was found in iAMD study eyes. Spatial analysis demonstrated a predominant distribution of RPD in the superior and temporal subfields at a foveal eccentricity of 1.5 to 2 mm, whereas HRF and large drusen had a distinct topographic distribution involving the foveal center. CONCLUSIONS: Detailed knowledge of the prevalence and distribution of structural iAMD biomarkers is vital to identify reliable outcome measure for disease progression. Longitudinal analyses are needed to evaluate their prognostic value for conversion to advanced disease stages. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

OCT Signs of Early Atrophy in Age-Related Macular Degeneration: Interreader Agreement: Classification of Atrophy Meetings Report 6.

PURPOSE: To determine the interreader agreement for incomplete retinal pigment epithelium (RPE) and outer retinal atrophy (iRORA) and complete RPE and outer retinal atrophy (cRORA) and their related features in age-related macular degeneration (AMD). DESIGN: Interreader agreement study. PARTICIPANTS: Twelve readers from 6 reading centers. METHODS: After formal training, readers qualitatively assessed 60 OCT B-scans from 60 eyes with AMD for 9 individual features associated with early atrophy and performed 7 different annotations to quantify the spatial extent of OCT features within regions of interest. The qualitative and quantitative features were used to derive the presence of iRORA and cRORA and also in an exploratory analysis to examine if agreement could be improved using different combinations of features to define OCT atrophy. MAIN OUTCOME MEASURES: Interreader agreement based on Gwet's first-order agreement coefficient (AC1) for qualitatively graded OCT features and classification of iRORA and cRORA, and smallest real difference (SRD) for quantitatively graded OCT features. RESULTS: Substantial or better interreader agreement was observed for all qualitatively graded OCT features associated with atrophy (AC1 = 0.63-0.87), except for RPE attenuation (AC1 = 0.46) and disruption (AC1 = 0.26). The lowest SRD for the quantitatively graded horizontal features was observed for the zone of choroidal hypertransmission (± 190.8 µm). Moderate agreement was found for a 3-category classification of no atrophy, iRORA, and cRORA (AC1 = 0.53). Exploratory analyses suggested a significantly higher level of agreement for a 3-category classification using (1) no atrophy; (2) presence of inner nuclear layer and outer plexiform layer subsidence, or a hyporeflective wedge-shaped band, as a less severe atrophic grade; and (3) the latter plus an additional requirement of choroidal hypertransmission of 250 µm or more for a more severe atrophic grade (AC1 = 0.68; P = 0.013). CONCLUSIONS: Assessment of iRORA and cRORA, and most of their associated features, can be performed relatively consistently and robustly. A refined combination of features to define early atrophy could further improve interreader agreement.

[Baseline diagnostics and initial treatment decision for anti-vascular endothelial growth factor treatment in retinal diseases : Comparison between results by study physician and reading centers (ORCA/OCEAN study)]. / Initiale Diagnostik und Indikationsstellung zur Anti-Vascular-Endothelial Growth-Factor-Therapie bei Netzhauterkrankungen : Vergleich der Befundung durch Studienarzt versus Reading Center (ORCA/OCEAN-Studie).

BACKGROUND: The ORCA module of the non-interventional OCEAN study investigated the use of retinal imaging diagnostics in the clinical treatment of patients undergoing vascular endothelial growth factor (VEGF) inhibitor treatment as part of routine clinical care. This article analyzes the agreement between the diagnosis documented by the treating ophthalmologist and the evaluation of reading centers at baseline as well as the effect on the response to treatment during the course. METHODS: A total of 396 patients (age 75.4 years) were enrolled in which ranibizumab treatment was indicated by the treating ophthalmologist due to either diabetic macular edema (DME), neovascular age-related macular degeneration (nvAMD) or retinal venous occlusion (RVO). Over a period of 24 months, patient and examination data, treatments and interpretation of retinal imaging data by the treating ophthalmologist were systematically recorded. Furthermore, retinal imaging data were also evaluated by three reading centers. RESULTS: In 338 out of 396 (85.4%) study eyes, the baseline diagnosis of the treating ophthalmologist was confirmed by the reading centers (DME 87.5%, nvAMD 82.3%, RVO 94.9%). In 17 of the remaining 58 eyes with a discrepant diagnosis, there was at least a consensus with respect to the indications for VEGF inhibitor therapy. The differential diagnoses included a variety of different retinal diseases. During follow-up of up to 3 months, eyes with a consistent diagnosis showed a clear increase in visual acuity (6.4 versus 2.7 letters, p = 0.05) and greater decrease in central retinal thickness (-112.3 versus -24.4 µm, p < 0.0001). DISCUSSION: The initial treatment decision for anti-VEGF therapy with consideration of the differential diagnoses can be challenging. Accurate evaluation of the clinical and imaging findings along with appropriate expertise appear to be important. The observation of superior initial response in eyes with a consensus of the diagnosis at baseline underlines the relevance of an adequate initial assessment for a successful treatment outcome.

Comparison of Green Versus Blue Fundus Autofluorescence in ABCA4-Related Retinopathy.

PURPOSE: To investigate the interreader and intermodality agreement for grading of retinal pigment epithelium (RPE) atrophy lesion size in ABCA4-related retinopathy using green (GAF) and blue fundus autofluorescence (BAF) imaging. METHODS: In this cross-sectional case series, 97 eyes of 49 patients with RPE atrophy secondary to ABCA4-related retinopathy underwent GAF- (518 nm excitation light) and BAF- (488 nm excitation light) imaging using confocal scanning laser ophthalmoscopy (Spectralis HRA, Heidelberg Engineering, Heidelberg, Germany). Lesions with definitely decreased autofluorescence (DDAF) and questionably decreased autofluorescence (QDAF) in GAF and BAF imaging were analyzed separately by five independent readers using semiautomated software (RegionFinder, Heidelberg Engineering). Intermodality and interreader agreements were assessed for the square-root lesion size, lesion perimeter, and circularity. RESULTS: GAF- and BAF-based measurements of DDAF and QDAF showed high intermodality and interreader agreement concerning square-root lesion size, as well as shape descriptive parameters (perimeter and circularity). Interreader agreement of square-root lesion size was slightly, hence not significantly higher for GAF-based grading ([95% coefficients of repeatability, intraclass correlation coefficient] DDAF: 0.215 mm, 0.997; QDAF: 0.712 mm, 0.981) compared to BAF-based grading (DDAF: 0.232 mm, 0.997; QDAF: 0.764 mm, 0.978). However, DDAF-measurements revealed distinctly more reproducible results than QDAF-measurements. Foveal sparing did not interfere with intermodality agreement. CONCLUSIONS: Both GAF- and BAF-based quantification of RPE atrophy showed very reliable results with possible superiority of GAF in the context of less energetic excitation light. TRANSLATIONAL RELEVANCE: The high interreader agreement qualifies the use of DDAF progression in GAF and BAF imaging as potential morphologic outcome measure for interventional clinical trials and disease monitoring.

Calculating the individual probability of successful ocriplasmin treatment in eyes with VMT syndrome: a multivariable prediction model from the EXPORT study.

BACKGROUND/AIMS: To evaluate predictive factors for the treatment success of ocriplasmin and to use these factors to generate a multivariate model to calculate the individual probability of successful treatment. METHODS: Data were collected in a retrospective, multicentre cohort study. Patients with vitreomacular traction (VMT) syndrome without a full-thickness macular hole were included if they received an intravitreal injection (IVI) of ocriplasmin. Five factors (age, gender, lens status, presence of epiretinal membrane (ERM) formation and horizontal diameter of VMT) were assessed on their association with VMT resolution. A multivariable logistic regression model was employed to further analyse these factors and calculate the individual probability of successful treatment. RESULTS: 167 eyes of 167 patients were included. Univariate analysis revealed a significant correlation to VMT resolution for all analysed factors: age (years) (OR 0.9208; 95% CI 0.8845 to 0.9586; p<0.0001), gender (male) (OR 0.480; 95% CI 0.241 to 0.957; p=0.0371), lens status (phakic) (OR 2.042; 95% CI 1.054 to 3.958; p=0.0344), ERM formation (present) (OR 0.384; 95% CI 0.179 to 0.821; p=0.0136) and horizontal VMT diameter (µm) (OR 0.99812; 95% CI 0.99684 to 0.99941, p=0.0042). A significant multivariable logistic regression model was established with age and VMT diameter. CONCLUSION: Known predictive factors for VMT resolution after ocriplasmin IVI were confirmed in our study. We were able to combine them into a formula, ultimately allowing the calculation of an individual probability of treatment success with ocriplasmin in patients with VMT syndrome without FTHM.

Analysis of Peripapillary Atrophy in Relation to Macular Geographic Atrophy in Age-Related Macular Degeneration.

PURPOSE: The purpose of this study was to investigate the presence, configuration, and progression of peripapillary atrophy (PPA) relative to macular geographic atrophy (GA) in AMD. METHODS: Confocal scanning laser ophthalmoscopy images of 413 eyes of 413 patients with GA secondary to AMD (median age, 77.0 years) were evaluated for the presence and configuration of PPA at baseline. In addition, the progression of PPA and the regression of the shortest linear dimension between PPA and GA ("buffer zone") were assessed in 164 eyes that had completed 12 months of follow-up. RESULTS: At baseline, PPA was present in 357 (86.4%) of 413 eyes, of which 330 eyes (79.9%) were classified as nonconfluent and 27 eyes (6.5%) as confluent PPA. At month 12, eight eyes had transformed from nonconfluent to confluent PPA. The median buffer zone at baseline was significantly smaller in these latter eyes than in eyes where the PPA remained nonconfluent (168.46 vs. 1451.64 µm; P < 0.001). The mean regression rate of the buffer zone was 163.0 µm/y (interquartile range, 77.2-281.3). CONCLUSIONS: Peripapillary atrophy is highly prevalent in eyes with GA due to AMD. Assessment of the buffer zone in eyes with nonconfluent PPA at baseline may be helpful to identify subjects at risk for the progression to confluent PPA. In future interventional clinical trials, it may be useful to exclude any eyes both with confluent PPA at baseline and at risk for development of confluent PPA over time to improve the accuracy of GA lesion size quantification and its enlargement over time.

Topography of geographic atrophy in age-related macular degeneration.

PURPOSE: To determine the topographic distribution and progression of geographic atrophy (GA) in patients with AMD. METHODS: Fundus autofluorescence images (excitation 488, emission 500-700 nm) from 413 eyes of 413 subjects (median age, 77.0 years; inter quartile range [IQR], 72.0-82.0 years) of the Geographic Atrophy Progression (GAP) study were retrospectively analyzed. Using a modified Early Treatment Diabetic Retinopathy Study grid to divide the posterior pole into nine different subfields plus periphery, the localization, size, and progression of atrophic patches were determined. Subfields, zones (center, inner and outer), and slices (nasal, temporal, inferior, superior) were compared using the Friedman test. RESULTS: The center and inner zones were involved in almost all eyes (>95%), while atrophy was less common in the outer zone subfields (76%). Inner zone atrophy size (median 4.00 mm(2)) and progression rate (0.67 mm(2)/year) were significantly greater than in the outer zone (0.60 mm(2) and 0.42 mm(2)/year; P < 0.001). There was a trend toward outer zone subfield and periphery involvement with increasing total size of atrophy. In addition, the superior outer subfield was significantly more affected by atrophy as compared with the other three outer subfields of the grid (P < 0.001). CONCLUSIONS: Distribution and progression of existing GA patches depended both on the eccentricity from the center and total GA size. Central macular areas appeared most susceptible for the occurrence and expansion of GA. Refined analysis of distribution and directional spread is important to understand the natural history of the disease. This information will likely be helpful to design interventional GA clinical trials and associated anatomical outcome measures. (ClinicalTrials. gov number, NCT00599846.).