Clinical and Genetic Findings in a Cohort of Patients with PRPF31-associated Retinal Dystrophy.

PURPOSE: The purpose of our study was to assess the phenotypic and genotypic spectrum in a large cohort of patients with PRPF31-associated retinal dystrophy. DESIGN: Retrospective cohort study METHODS: In this retrospective chart review study, we collected cross-sectional data on the phenotype and genotype of patients with PRPF31-associated retinal dystrophy from the clinics for inherited retinal dystrophies at the University of Tuebingen and the local RetDis database and biobank. Patients underwent thorough ophthalmological examinations and genetic testing. RESULTS: Eighty-six patients from 61 families were available for clinical assessment, while genomic DNA was available for 111 individuals (index patients and family members). Fifty-three different disease-associated variants were observed in our cohort. Point mutations were the most common class. All but two patients exhibited features of a typical Retinitis pigmentosa (RP). One patient showed a cone-rod-dystrophy pattern. One mutation carrier revealed no signs of a retinal dystrophy. There was a statistically significant better visual acuity for patients with large deletions in the 20-39 age group. Cystoid macular edema was common in those with preserved central retina and showed an association with female sex. CONCLUSION: Our study confirms high phenotypic variability in disease onset and age at which legal blindness is reached in PRPF31-linked RP. Non-penetrance is commonly documented in family history, although poorly represented in our study, possibly indicating that true asymptomatic mutation carriers are rare if followed-up over lifetime with thorough ophthalmologic workup.

Clinical validation of saliency maps for understanding deep neural networks in ophthalmology.

Deep neural networks (DNNs) have achieved physician-level accuracy on many imaging-based medical diagnostic tasks, for example classification of retinal images in ophthalmology. However, their decision mechanisms are often considered impenetrable leading to a lack of trust by clinicians and patients. To alleviate this issue, a range of explanation methods have been proposed to expose the inner workings of DNNs leading to their decisions. For imaging-based tasks, this is often achieved via saliency maps. The quality of these maps are typically evaluated via perturbation analysis without experts involved. To facilitate the adoption and success of such automated systems, however, it is crucial to validate saliency maps against clinicians. In this study, we used three different network architectures and developed ensembles of DNNs to detect diabetic retinopathy and neovascular age-related macular degeneration from retinal fundus images and optical coherence tomography scans, respectively. We used a variety of explanation methods and obtained a comprehensive set of saliency maps for explaining the ensemble-based diagnostic decisions. Then, we systematically validated saliency maps against clinicians through two main analyses - a direct comparison of saliency maps with the expert annotations of disease-specific pathologies and perturbation analyses using also expert annotations as saliency maps. We found the choice of DNN architecture and explanation method to significantly influence the quality of saliency maps. Guided Backprop showed consistently good performance across disease scenarios and DNN architectures, suggesting that it provides a suitable starting point for explaining the decisions of DNNs on retinal images.

Interim Results of a Multicenter Trial with the New Electronic Subretinal Implant Alpha AMS in 15 Patients Blind from Inherited Retinal Degenerations.

Purpose: We assessed the safety and efficacy of a technically advanced subretinal electronic implant, RETINA IMPLANT Alpha AMS, in end stage retinal degeneration in an interim analysis of two ongoing prospective clinical trials. The purpose of this article is to describe the interim functional results (efficacy). Methods: The subretinal visual prosthesis RETINA IMPLANT Alpha AMS (Retina Implant AG, Reutlingen, Germany) was implanted in 15 blind patients with hereditary retinal degenerations at four study sites with a follow-up period of 12 months (www.clinicaltrials.gov NCT01024803 and NCT02720640). Functional outcome measures included (1) screen-based standardized 2- or 4-alternative forced-choice (AFC) tests of light perception, light localization, grating detection (basic grating acuity (BaGA) test), and Landolt C-rings; (2) gray level discrimination; (3) performance during activities of daily living (ADL-table tasks). Results: Implant-mediated light perception was observed in 13/15 patients. During the observation period implant mediated localization of visual targets was possible in 13/15 patients. Correct grating detection was achieved for spatial frequencies of 0.1 cpd (cycles per degree) in 4/15; 0.33 cpd in 3/15; 0.66 cpd in 2/15; 1.0 cpd in 2/15 and 3.3 cpd in 1/15 patients. In two patients visual acuity (VA) assessed with Landolt C- rings was 20/546 and 20/1111. Of 6 possible gray levels on average 4.6 ± 0.8 (mean ± SD, n = 10) were discerned. Improvements (power ON vs. OFF) of ADL table tasks were measured in 13/15 patients. Overall, results were stable during the observation period. Serious adverse events (SAEs) were reported in 4 patients: 2 movements of the implant, readjusted in a second surgery; 4 conjunctival erosion/dehiscence, successfully treated; 1 pain event around the coil, successfully treated; 1 partial reduction of silicone oil tamponade leading to distorted vision (silicon oil successfully refilled). The majority of adverse events (AEs) were transient and mostly of mild to moderate intensity. Conclusions: Psychophysical and subjective data show that RETINA IMPLANT Alpha AMS is reliable, well tolerated and can restore limited visual functions in blind patients with degenerations of the outer retina. Compared with the previous implant Alpha IMS, longevity of the new implant Alpha AMS has been considerably improved. Alpha AMS has meanwhile been certified as a commercially available medical device, reimbursed in Germany by the public health system.