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Interpreting deep learning models typically relies on post-hoc saliency map techniques. However, these techniques often fail to serve as actionable feedback to clinicians, and they do not directly explain the decision mechanism. Here, we propose an inherently interpretable model that combines the feature extraction capabilities of deep neural networks with advantages of sparse linear models in interpretability. Our approach relies on straight-forward but effective changes to a deep bag-of-local-features model (BagNet). These modifications lead to fine-grained and sparse class evidence maps which, by design, correctly reflect the model’s decision mechanism. Our model is particularly suited for tasks which rely on characterising regions of interests that are very small and distributed over the image. In this paper, we focus on the detection of Diabetic Retinopathy, which is characterised by the progressive presence of small retinal lesions on fundus images. We observed good classification accuracy despite our added sparseness constraint. In addition, our model precisely highlighted retinal lesions relevant for the disease grading task and excluded irrelevant regions from the decision mechanism. The results suggest our sparse BagNet model can be a useful tool for clinicians as it allows efficient inspection of the model predictions and facilitates clinicians’ and patients’ trust.

Zusammenfassung Hintergrund Laut WHO Malaria Report 2019 erkranken jährlich 229 Mio. Menschen an Malaria. Zwei Drittel der Todesfälle betreffen Kinder unter 5 Jahren. Ziel der Arbeit Überblick über die Fundusveränderungen im Rahmen der okulären Veränderungen bei Malaria, den Stellenwert der ophthalmologischen Diagnostik und die Bedeutung der Fundoskopie bei der Diagnose. Material und Methoden Zusammenfassende Darstellung der fundoskopisch sichtbaren Veränderungen bei zerebraler Malaria, möglicher zugrunde liegender Pathomechanismen sowie der Stellenwert der Fundoskopie in der Praxis. Ergebnisse Bei Malaria im Fundusbild erkennbar sind eine Weiß- bzw. Graufärbung der Retina („retinal whitening“), Farbveränderung retinaler Gefäße (Orange- oder Weißfärbung), Hämorrhagien, oft mit weißem Zentrum ähnlich den Roth-Flecken sowie ein Papillenödem. Diskussion Die retinalen Veränderungen bei Malaria sind charakteristisch und können helfen, Malaria von anderen Ursachen von Koma und Fieber abzugrenzen. Smartphone-basierte Fundusfotografie und künstliche Intelligenz könnten in ressourcenarmen Regionen zur Diagnose beitragen.

PurposeComparison of performance and explainability of a multi-task convolutional deep neuronal network to single-task networks for activity detection in neovascular age-dependent macular degeneration.MethodsFrom n = 70 patients (46 female, 24 male) who attended the University Eye Hospital Tübingen 3762 optical coherence tomography B-scans (right eye: 2011, left eye: 1751) were acquired with Heidelberg Spectralis, Heidelberg, Germany. B-scans were graded by a retina specialist and an ophthalmology resident, and then used to develop a multi-task deep learning model to predict disease activity in neovascular age-related macular degeneration along with the presence of sub- and intraretinal fluid. We used performance metrics for comparison to single-task networks and visualized the DNN-based decision with t-distributed stochastic neighbor embedding and clinically validated saliency mapping techniques.ResultsThe multi-task model surpassed single-task networks in accuracy for activity detection (94.2). Further-more, compared to single-task networks, visualizations via t-distributed stochastic neighbor embedding and saliency maps highlighted that multi-task networks’ decisions for activity detection in neovascular age-related macular degeneration were highly consistent with the presence of both sub- and intraretinal fluid.ConclusionsMulti-task learning increases the performance of neuronal networks for predicting disease activity, while providing clinicians with an easily accessible decision control, which resembles human reasoning.Translational RelevanceBy improving nAMD activity detection performance and transparency of automated decisions, multi-task DNNs can support the translation of machine learning research into clinical decision support systems for nAMD activity detection.

ZusammenfassungWährend zwischen 2005 und 2016 mehr als 30 000 Cochleaimplantate in Deutschland implantiert wurden, wurden nur weniger als 1% vergleichbarer Eingriffe an der Retina durchgeführt. Die beiden für den Markt zugelassenen Implantattypen haben wirtschaftlich nicht überleben können. Die vorliegende Arbeit diskutiert die Bedeutung und die Zukunft elektronischer Retinaimplantate für die Augenheilkunde.

According to the WHO Malaria Report 2019 a total of 229 million people fall ill with malaria each year and two thirds of deaths involve children under 5 years of age.To review the fundus changes in the context of malaria and the importance of ophthalmoscopy in the diagnosis.Summary of changes in cerebral malaria visible on fundus examination, possible underlying pathomechanisms and the value of ophthalmoscopy in practice.Retinal findings in malaria include white or gray staining of the retina (retinal whitening), color change of retinal vessels (orange or white staining), hemorrhages often with a white center, such as Roth's spot and papilledema.The retinal changes in malaria are specific and may help to differentiate malaria from other causes of coma and fever. Smartphone-based fundus photography and artificial intelligence could support malaria diagnostics particularly in resource-poor regions.HINTERGRUND: Laut WHO Malaria Report 2019 erkranken jährlich 229 Mio. Menschen an Malaria. Zwei Drittel der Todesfälle betreffen Kinder unter 5 Jahren.Überblick über die Fundusveränderungen im Rahmen der okulären Veränderungen bei Malaria, den Stellenwert der ophthalmologischen Diagnostik und die Bedeutung der Fundoskopie bei der Diagnose.Zusammenfassende Darstellung der fundoskopisch sichtbaren Veränderungen bei zerebraler Malaria, möglicher zugrunde liegender Pathomechanismen sowie der Stellenwert der Fundoskopie in der Praxis.Bei Malaria im Fundusbild erkennbar sind eine Weiß- bzw. Graufärbung der Retina („retinal whitening“), Farbveränderung retinaler Gefäße (Orange- oder Weißfärbung), Hämorrhagien, oft mit weißem Zentrum ähnlich den Roth-Flecken sowie ein Papillenödem.Die retinalen Veränderungen bei Malaria sind charakteristisch und können helfen, Malaria von anderen Ursachen von Koma und Fieber abzugrenzen. Smartphone-basierte Fundusfotografie und künstliche Intelligenz könnten in ressourcenarmen Regionen zur Diagnose beitragen.

Deep neural networks (DNNs) are able to predict a person’s gender from retinal fundus images with high accuracy, even though this task is usually considered hardly possible by ophthalmologists. Therefore, it has been an open question which features allow reliable discrimination between male and female fundus images. To study this question, we used a particular DNN architecture called BagNet, which extracts local features from small image patches and then averages the class evidence across all patches. The BagNet performed on par with the more sophisticated Inception-v3 model, showing that the gender information can be read out from local features alone. BagNets also naturally provide saliency maps, which we used to highlight the most informative patches in fundus images. We found that most evidence was provided by patches from the optic disc and the macula, with patches from the optic disc providing mostly male and patches from the macula providing mostly female evidence. Although further research is needed to clarify the exact nature of this evidence, our results suggest that there are localized structural differences in fundus images between genders. Overall, we believe that BagNets may provide a compelling alternative to the standard DNN architectures also in other medical image analysis tasks, as they do not require post-hoc explainability methods.

Evaluation of treatment efficacy of XEN45 gelstent for glaucoma secondary to Fuchs uveitis syndrome (FUS).This retrospective case series evaluated patients with glaucoma secondary to FUS, who underwent XEN45 implantation. Complete success was defined as IOP lowering of ≥ 20% and cutoff IOP atTwelve eyes of 12 patients were included. Qualified and complete success rates were 50% after one year (n = 10). Qualified success was achieved in 66.6% of patients with 33.3% of patients achieving complete success after two years (n = 6).XEN45 implantation had some success in the treatment of glaucoma secondary to FUS, but needling was frequently necessary to improve outcome.

Deep neural networks (DNNs) are able to predict a person’s gender from retinal fundus images with high accuracy, even though this task is usually considered hardly possible by ophthalmologists. Therefore, it has been an open question which features allow reliable discrimination between male and female fundus images. To study this question, we used a particular DNN architecture called BagNet, which extracts local features from small image patches and then averages the class evidence across all patches. The BagNet performed on par with the more sophisticated Inception-v3 model, showing that the gender information can be read out from local features alone. BagNets also naturally provide saliency maps, which we used to highlight the most informative patches in fundus images. We found that most evidence was provided by patches from the optic disc and the macula, with patches from the optic disc providing mostly male and patches from the macula providing mostly female evidence. Although further research is needed to clarify the exact nature of this evidence, our results suggest that there are localized structural differences in fundus images between genders. Overall, we believe that BagNets may provide a compelling alternative to the standard DNN architectures also in other medical image analysis tasks, as they do not require post-hoc explainability methods.

Purpose To report a new genetic mutation in the COL4A1 gene, which was identified in a baby girl with Peters anomaly (PA), a rare anterior segment mesenchymal dysgenesis, which is characterized by unilateral or bilateral corneal opacities often accompanied by glaucoma, cataract, and systemic malformations and associated with various genetic mutations. Methods Ophthalmologic examination of one baby girl and whole exome sequencing and Sanger sequencing of blood samples of the child and her biological parents were performed. Results Ophthalmologic examination led to the diagnosis of PA type I in the baby girl. Whole exome sequencing and Sanger sequencing identified the de novo mutation c.181_189delinsAGGTTTCCG; p.Gly61Arg in the COL4A1 gene in the child, whereas no other putatively causative variants in established genes associated with anterior segment dysgenesis were present. Conclusions PA might be associated with the mutation c.181_189delinsAGGTTTCCG; p.Gly61Arg in the COL4A1 gene. The COL4A1 gene encodes for collagen IVα1, an essential component of basal membranes, and mutations are associated with an increased risk for renal and cerebrovascular disorders and stroke. This should be considered when advising and monitoring patients.

Between 2005 and 2016, over 30,000 cochlear implants were implanted in Germany, while the number of retinal implants remained less than 1% of this number. The two types of retina implants that reached the market did not survive economically. The present review article discusses the impact and future of electronic retina implants in ophthalmology.Während zwischen 2005 und 2016 mehr als 30 000 Cochleaimplantate in Deutschland implantiert wurden, wurden nur weniger als 1% vergleichbarer Eingriffe an der Retina durchgeführt. Die beiden für den Markt zugelassenen Implantattypen haben wirtschaftlich nicht überleben können. Die vorliegende Arbeit diskutiert die Bedeutung und die Zukunft elektronischer Retinaimplantate für die Augenheilkunde.

Wir berichten uber eine 28-jahrige Patientin mit akuter Visusminderung nach Praeklampsie. Die Makula wies beidseits fundoskopisch nur marginale Veranderungen auf. Koharenztomographisch prasentierte sich eine bilaterale neurosensorische Abhebung. Die Fluoreszenzangiographie zeigte Fullungsdefekte der Choroidea passend zu einer Aderhautischamie nach akuter Hypertension. Die Symptome verschwanden nach 3 Monaten ohne zusatzliche Therapie vollstandig. Unklaren ophthalmologischen Befunden sollte eine umfassende internistische Abklarung folgen, um die richtige Diagnose und Therapie zu finden.

Purpose Electronic retinal implants restore some visual perception in patients blind from retinitis pigmentosa. Eye movements cause mechanical stress in intraorbital power supply cables leading to cable breaks. By using computer tomography (CT) scans at the extreme positions of the four cardinal gaze directions, this study determined in vivo, which of three surgical routing techniques results in minimal bending radius variation and favors durability. Methods Nine patients received the first-generation subretinal implant Alpha IMS (Retina Implant AG, Reutlingen, Germany) in one eye. Three techniques for intraorbital cable routing were used (straight cable route (A), parabulbar loop (B), and encircling band (C)), each in three patients. All patients underwent computer tomography of the orbital region. The bending radius of the intraorbital cable was measured with the DICOM viewer Osirix v4.1.2 (Pixmeo SARL, Bernex, Switzerland) and served as indicator for mechanical stress. Results Average bending radius variation was 87% for method A, 11% for method B, and 16% for method C. Methods A and B (P = 0.005) and methods A and C (P = 0.007) differed significantly, while method B and C showed no statistical difference (P = 0.07). Conclusions Compared to straight routes, arcuated cable routes significantly reduce cable movement and bending. Due to an easier surgical procedure, a parabulbar loop is the preferred method to minimize bending radius variation and prolong survival time of electronic subretinal implants. Translational Relevance CT analysis of cable bending of implanted medical devices allows to determine which surgical routing technique favors durability in vivo.

Background Transcranial direct current stimulation (tDCS) can polarize the cortex of the human brain. Objective/Hypothesis We sought to verify the hypothesis that posterior-anterior (PA) but not anterior-posterior (AP) tDCS of primary motor cortex (M1) produces cooperative effects with corticospinal plasticity induced by paired associative stimulation of the supplementary motor area (SMA) to M1 projection (PAS SMA→M1 ) in a highly controlled experimental design. Methods Three experimental conditions were tested in a double-blinded, randomized crossover design in 15 healthy adults: Navigated PAS SMA→M1 during PA-tDCS (35 cm 2 electrodes, anode 3 cm posterior to M1 hand area, cathode over contralateral frontopolar cortex, 1 mA, 2 × 5 min) or AP-tDCS (reversed polarity), or sham-tDCS. Effects were analyzed over 120 min post-intervention by changes of motor evoked potential (MEP) amplitude in a hand muscle. Results There was no significant effect of tDCS on PAS SMA→M1 induced plasticity in the repeated-measures ANOVA. However, post-hoc within-subject contrasts revealed a significant tDCS with PAS SMA→M1 interaction. This was explained by PA-tDCS and AP-tDCS modifying the PAS SMA→M1 effect into the same direction in 13/15 subjects (87%, p = 0.004 for deviation from equality). Sizes of the PA-tDCS and AP-tDCS effects were correlated (r s = 0.53, p = 0.044). A control experiment demonstrated that PA-tDCS and AP-tDCS alone (without PAS SMA→M1 ) had no effect on MEP amplitude. Conclusions Data point to unidirectional tDCS effects on PAS SMA→M1 induced plasticity irrespective of tDCS polarity, in contrast to our hypothesis. We propose that radial symmetry of cortical columns, gyral geometry of motor cortex, and cooperativity of plasticity induction can explain the findings.

Purpose To evaluate the motility of the eye in patients with the RETINA IMPLANT Alpha AMS. Methods Eye motility was determined in eight gaze directions in ten blind retinitis pigmentosa patients, who had received the RETINA IMPLANT Alpha AMS, before implantation of the subretinal implant and at six time-points up to one year after. Results The analysis of eye motility showed a restriction in the upgaze and gaze to the temporal side directly after surgery in eight of the nine patients included. The degree of motility restriction decreased continuously with recovery during the observation time. One year after surgery, eye motility was still restricted in the majority of patients, especially in the upgaze to the temporal side at 20° (five of seven patients). Conclusion Retinal implants with intraorbital parts (e.g. connecting cables) caused restriction in the temporal and superior viewing directions in the majority of patients. Although this restriction might be cosmetically visible, this limitation in eye motility has no effects on the monocular vision and the implant's efficacy for daily use.

A 28-year-old female patient presented with acute loss of visual acuity after pre-eclampsia. Funduscopy revealed minor alterations of the posterior pole of the macula. Optical coherence tomography displayed a bilateral neurosensory detachment. Fluorescence angiography showed filling defects of the choroid in both eyes. These findings were in line with choroidal ischemia following a hypertensive episode. The symptoms disappeared completely after 3 months without additional treatment. To clarify ambiguous pathologies the ophthalmologist should always initiate a comprehensive evaluation in internal medicine to find the right diagnosis and treatment.

Introduction Transcranial direct current stimulation (tDCS) is a widely used technique in research and clinics. However, the underlying physiological mechanisms are not yet clear. Modeling studies suggest that the electric field during tDCS is dominated by a tangential component which predominantly modifies active synaptic connections ( Radman et al., 2007 ). We have previously shown that tDCS with an increased tangential compared to the conventional montage introduced by Nitsche and Paulus (2000) , suppresses the effects of paired associative stimulation of the supplementary motor area and the primary motor cortex (PASSMA-M1) independent of tDCS polarity (Faber et al., under submission). Here, we tested the influence of tDCS with increased tangential and absolute electric field strength on M1 excitability at rest. Methods 13 healthy right-handed male subjects took part in this pseudo-randomized, double-blinded, crossover study. They received two blocks (spaced by 5 min) of 5 min of 1 mA of anodal, cathodal or sham tDCS. Modeling studies showed an increase of tangential and general electric field strength between of the electrodes ( Miranda et al., 2013 , Opitz et al., 2015 ). Therefore, we placed the electrodes 3 cm behind the primary motor cortex to maximize the tangential field strength in the hand knob area. Sessions were separated by at least three days. We evaluated M1 excitability by changes in motor-evoked potentials (MEP) in the right first dorsal interosseus muscle of the right hand at baseline versus for up to two hours after the intervention. Results The repeated measurement Analysis of Variance showed neither an effect of time, nor Condition or Time * Condition Interaction on MEP amplitude. This displays the lack of effects of tDCS in a posterior montage in a system at rest. Conclusion tDCS placed 3 cm behind the primary motor cortex with an increased absolute as well as tangential electric field strength has no effects on M1 excitability in the motor system at rest. This finding confirms experiments on slice preparation and modeling studies that showed that the tangential component of the electric field during tDCS predominantly affects active synapses.

Introduction Excitability and connectivity in the human motor network comprising the supplementary motor area (SMA) and primary motor cortex (M1) are important for voluntary movement generation and rehabilitation of lost motor function after stroke. Previously, we demonstrated that paired associative stimulation of SMA and M1 (SMA–M1-PAS) by dual coil transcranial magnetic stimulation (TMS) may induce LTP-like plasticity in this network (Arai et al., 2011. J Neurosci 31:15376–83). Here, we tested the influence of simultaneous modulation of general network excitability by transcranial direct current stimulation (tDCS) on associative SMA–M1 plasticity. Methods 12 healthy right-handed male subjects took part in this pseudo-randomized,single-blinded, crossover study. Subjects received two blocks (spaced by 5 min) of 50 pairs of neuronavigated SMA-before-M1 PAS at an interstimulus interval of 6 ms and intertrial interval of 5 s. Simultaneously we applied anodal, cathodal, or sham tDCS over the left M1 in three different sessions, at least 1 week apart. Associative SMA–M1 plasticity was quantified by changes in (i) motor-evoked potentials (MEP) in the right first dorsal interosseus muscle, and (ii) SMA-to-M1 connectivity (ratio of SMA-conditioned/unconditioned MEPs), at baseline versus for up to two hours after the intervention. Results SMA–M1-PAS resulted in an expected LTP-like MEP amplitude increase in 9 of 12 subjects in the sham tDCS condition. In 7 of these 9 SMA–M1-PAS responders, the LTP-like MEP amplitude increase was suppressed or even turned into depression both in the anodal and cathodal tDCS condition. In contrast, in all three non-responders anodal and cathodal tDCS led to less MEP suppression or even turned it into facilitation. Likewise, in 7 (anodal tDCS) and 6 (cathodal tDCS) of the 8 subjects who showed a facilitation of SMA-to-M1 connectivity in the sham tDCS condition this connectivity was reduced in the anodal and cathodal tDCS conditions, whereas it was less reduced or even facilitated in 2 (anodal tDCS) and all (cathodal tDCS) of the 4 subjects showing a reduction of SMA-to-M1 connectivity in the sham condition. Conclusion Our results demonstrate a reversing interaction between general network excitability modulation by tDCS and associative plasticity in the human SMA–M1 network, independent of the polarity of tDCS.