Multitask Learning for Activity Detection in Neovascular Age-Related Macular Degeneration.

Purpose: The purpose of this study was to provide a comparison of performance and explainability of a multitask convolutional deep neuronal network to single-task networks for activity detection in neovascular age-related macular degeneration (nAMD). Methods: From 70 patients (46 women and 24 men) who attended the University Eye Hospital Tübingen, 3762 optical coherence tomography B-scans (right eye = 2011 and 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 multitask 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 deep neural network (DNN)-based decision with t-distributed stochastic neighbor embedding and clinically validated saliency mapping techniques. Results: The multitask model surpassed single-task networks in accuracy for activity detection (94.2% vs. 91.2%). The area under the curve of the receiver operating curve was 0.984 for the multitask model versus 0.974 for the single-task model. Furthermore, compared to single-task networks, visualizations via t-distributed stochastic neighbor embedding and saliency maps highlighted that multitask networks' decisions for activity detection in neovascular age-related macular degeneration were highly consistent with the presence of both sub- and intraretinal fluid. Conclusions: Multitask 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 Relevance: By improving nAMD activity detection performance and transparency of automated decisions, multitask DNNs can support the translation of machine learning research into clinical decision support systems for nAMD activity detection.

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.

Expert-validated estimation of diagnostic uncertainty for deep neural networks in diabetic retinopathy detection.

Deep learning-based systems can achieve a diagnostic performance comparable to physicians in a variety of medical use cases including the diagnosis of diabetic retinopathy. To be useful in clinical practice, it is necessary to have well calibrated measures of the uncertainty with which these systems report their decisions. However, deep neural networks (DNNs) are being often overconfident in their predictions, and are not amenable to a straightforward probabilistic treatment. Here, we describe an intuitive framework based on test-time data augmentation for quantifying the diagnostic uncertainty of a state-of-the-art DNN for diagnosing diabetic retinopathy. We show that the derived measure of uncertainty is well-calibrated and that experienced physicians likewise find cases with uncertain diagnosis difficult to evaluate. This paves the way for an integrated treatment of uncertainty in DNN-based diagnostic systems.

Photodynamic therapy with double duration for circumscribed choroidal haemangioma: functional and anatomical results based on initial parameters.

IMPORTANCE: Pre-treatment symptoms longer than 12 months and foveal cystoid changes are indicators for poor anatomical and functional outcome after photodynamic therapy (PDT). BACKGROUND: To evaluate the prognostic factors on the effectiveness of PDT with double duration for treatment of exudative circumscribed choroidal haemangioma. DESIGN: Retrospective study. PARTICIPANTS: Twenty-seven patients with symptomatic exudative circumscribed choroidal haemangioma treated with PDT. METHODS: Clinical charts of patients with exudative circumscribed choroidal haemangioma treated with PDT were analysed with regard to visual acuity, duration of symptoms, subfoveal fluid, foveal cystoid changes and foveal thickness in optical coherence tomography. MAIN OUTCOME MEASURES: Change of best-corrected visual acuity, sub- and intrafoveal fluid and foveal thickness measured with optical coherence tomography from baseline to last follow-up. RESULTS: Mean visual acuity improved by 0.05 from 0.42 logMAR (standard deviation [SD] 0.34) to 0.37 logMAR (SD 0.47). In 70% of the patients, PDT stopped exudation and revealed a dry fovea. The recurrence or persistence of sub- or intrafoveal fluid was significantly associated with pre-therapeutic symptoms existing for more than 12 months (P = 0.046). Mean foveal thickness in optical coherence tomography decreased from 324 µm (SD 223 µm) to 209 µm (SD 109 µm). CONCLUSIONS AND RELEVANCE: PDT proved to be a safe and effective treatment procedure for exudative circumscribed choroidal haemangioma in our series, with few side effects. We observed a more successful treatment with regard to anatomical and functional results in cases with pre-existing symptoms less than 12 months and in cases without pre-therapeutic foveal cystoid changes.

Visualization and follow-up of acute macular neuroretinopathy with the Spectralis HRA+OCT device.

BACKGROUND: Acute macular neuroretinopathy (AMNR) is a rare disease entity, the diagnosis of which is frequently complicated by the subtlety of biomicroscopic findings. METHODS: Two cases of AMNR are presented, in which the diagnosis and follow-up was enabled using the Spectralis HRA+OCT in the absence of clear biomicroscopic findings. RESULTS: The typical lesions were visualized by hyporeflexion during infrared imaging and faded over time. With spectral domain optical coherence tomography, changes in the outer retina in the affected regions were documented, with no change over time. CONCLUSION: The broader availability of this technology may enhance the diagnosis and follow-up of AMNR.

Bevacizumab for choroidal neovascularization secondary to pathologic myopia: Is there a decline of the treatment efficacy after 2 years?

BACKGROUND: The Verteporfin in Photodynamic Therapy (VIP) Study failed to prove a statistically significant benefit for myopic choroidal neovascularization (CNV) at the end of the second year. Therefore, we wanted to evaluate whether the early effects seen under anti-VEGF treatment can be maintained over longer follow-up intervals. METHODS: This consecutive case series included all patients at the Centre for Ophthalmology, Tuebingen, with a 2-year follow-up after treatment with 1.25 mg of bevacizumab alone or in combination with photodynamic therapy. Twenty-one eyes from 19 patients were analyzed in the retrospective evaluation of best-corrected visual acuity (BCVA) and central foveal thickness (CFT). RESULTS: Mean logMAR BCVA improved from 0.64 at baseline to 0.55 after 1 year (p = 0.32) and remained 0.55 at 2 years (p = 0.23). A subgroup analysis showed that mean logMAR BCVA in the monotherapy group improved from 0.7 to 0.5 at 2 years (n = 11, p = 0.06). In the combined therapy group, mean logMAR BCVA changed from 0.55 to 0.59 at 2 years (n = 10, p = 0.69). Mean CFT decreased significantly in both groups by 168 microm (p < 0.001) and 76 microm (p < 0.05) in the monotherapy and in the combined groups, respectively. No complications or adverse effects were observed. CONCLUSION: Although the limitations of the study design have to be acknowledged and carefully discussed, we found no obvious superiority of a combined treatment for myopic CNV, at least in terms of the functional outcome and the injection frequency. The results indicate that bevacizumab might be beneficial in the treatment of patients with CNV secondary to pathologic myopia.

Chorioretinal neovascularization after radial optic neurotomy for central retinal vein occlusion.

Radial optic neurotomy was recently introduced for the treatment of central retinal vein occlusion. Two patients developed chorioretinal neovascularization through the radial cut of the optic disc after pars plana vitrectomy, radial optic neurotomy, and endophotocoagulation. Patients undergoing radial optic neurotomy should be closely observed to minimize the risk of this complication.

Comparison of early retreatment with the standard regimen in verteporfin therapy of neovascular age-related macular degeneration.

PURPOSE: To compare the efficacy and safety of early retreatment with verteporfin therapy with that of approved standard verteporfin therapy in neovascular age-related macular degeneration. DESIGN: Prospective, randomized, multicenter clinical trial. PARTICIPANTS: Two hundred three patients with predominantly classic choroidal neovascularization secondary to age-related macular degeneration. METHODS: Throughout the first 6 months of follow-up, patients received retreatment with verteporfin therapy either every 2 months (group A) or 3 months (group B). From 6 to 12 months, both groups received retreatment at 3-month intervals. MAIN OUTCOME MEASURES: The primary outcome of the study was best-corrected mean visual acuity as measured using the Early Treatment Diabetic Retinopathy Study protocol. The secondary outcomes were percentage of patients losing at least 3 lines of vision, percentage of patients gaining at least 1 line of vision, and lesion size based on the greatest linear dimension (GLD) documented by fluorescein angiography, impact of initial lesion size, and retreatment rate as well as safety. RESULTS: Visual acuity was similar in both groups at baseline with a mean visual acuity of 20/100(-1). During the 12 months of follow-up, mean visual acuity was better in the early retreatment group at all intervals; however, no statistically significant benefit was seen in the overall population at any time (P>0.1). At month 12, mean visual acuity was 20/160(+1) in group A and 20/160(-1) in group B. There was a trend for better outcomes in the early retreatment group with regard to loss of less than 3 lines of vision at 12 months (61% vs. 51.7%). No statistically significant difference was seen with regard to lesion size for either group throughout follow-up with a final GLD of the lesion of 2790 microm (group A) and 2996 microm (group B). However, subgroup analysis indicated a statistically relevant benefit (P< or =0.004) for patients with small lesions (GLD<2000 microm) at baseline receiving early retreatment. CONCLUSIONS: Early retreatment in 2-month intervals did not show a significant overall benefit at 1 year of follow-up compared with the standard regimen. However, smaller lesions seemed to benefit from early retreatment with verteporfin therapy in contrast to larger lesions.

Characteristics of visual field defects by scanning laser ophthalmoscope microperimetry after radial optic neurotomy for central retinal vein occlusion.

PURPOSE: To evaluate visual field defects after radial optic neurotomy (RON) for the treatment of central retinal vein occlusion (CRVO) by using scanning laser ophthalmoscope microperimetry. METHODS: Thirteen eyes of 13 patients with severe vision loss (< or = 20/200) from CRVO who underwent pars plana vitrectomy and RON had postoperative Goldmann kinetic perimetry, scanning laser ophthalmoscope microperimetry, and fluorescein angiographic evaluation. RESULTS: After a mean follow-up of 8 months, 6 of the 13 patients had visual improvement by > or = 2 lines. Eight patients developed an anastomosis at the radial cut. Postoperatively, sectorial visual field loss arising from the optic head was found by Goldmann perimetry in six patients, and a thin nerve fiber bundle defect was found in three patients. Four patients had no detectable visual field defect shown by Goldmann perimetry, but microperimetry demonstrated an absolute nerve fiber bundle defect arising from the radial cut at the optic disk for three of these patients. CONCLUSION: Visual field loss after RON for the treatment of CRVO is a frequent complication. The etiology of this visual loss appears to be a combination of mechanical trauma to the nerve fiber layers and ischemia of the optic disk circulation.

Pigment epithelial detachments with retinal vascular anomalous complex in age-related macular degeneration.

PURPOSE: To analyze and compare the angiographic features of retinal vascular anomalous complex (RVAC) in patients with a vascularized pigment epithelial detachment (PED) secondary to age-related macular degeneration. METHODS: Retrospective evaluation of fluorescein and indocyanine green angiographies of 180 patients with occult choroidal neovascularization and PED. RESULTS: On indocyanine green angiography (ICGA), RVAC demonstrated as a focal hyperfluorescence in connection with retinal choroidal anastomosis was identified in 12 of the 180 eyes (6.7%) with a vascularized PED. In comparison, fluorescein angiography revealed RVAC in 6 of the 12 eyes. Associated clinical and angiographic features were intraretinal hemorrhage in all 12 eyes, cystoid macular edema in 6 eyes and preretinal hemorrhage in 4 eyes. CONCLUSIONS: RVAC is better delineated on ICGA than on fluorescein angiography. In clinically suspected cases with a vascularized PED in connection with intraretinal hemorrhage and/or cystoid macular edema, ICGA should be performed to enhance management considerations.

Lack of long-term cortical reorganization after macaque retinal lesions.

Several aspects of cortical organization are thought to remain plastic into adulthood, allowing cortical sensorimotor maps to be modified continuously by experience. This dynamic nature of cortical circuitry is important for learning, as well as for repair after injury to the nervous system. Electrophysiology studies suggest that adult macaque primary visual cortex (V1) undergoes large-scale reorganization within a few months after retinal lesioning, but this issue has not been conclusively settled. Here we applied the technique of functional magnetic resonance imaging (fMRI) to detect changes in the cortical topography of macaque area V1 after binocular retinal lesions. fMRI allows non-invasive, in vivo, long-term monitoring of cortical activity with a wide field of view, sampling signals from multiple neurons per unit cortical area. We show that, in contrast with previous studies, adult macaque V1 does not approach normal responsivity during 7.5 months of follow-up after retinal lesions, and its topography does not change. Electrophysiology experiments corroborated the fMRI results. This indicates that adult macaque V1 has limited potential for reorganization in the months following retinal injury.

Natural course of occult choroidal neovascularization in age-related macular degeneration: development of classic lesions in fluorescein angiography.

PURPOSE: To analyse the frequency of conversion from occult with no classic choroidal neovascularization (CNV) and occult with minimally classic CNV into predominantly classic CNV secondary to age-related macular degeneration. METHODS: Retrospective evaluation of baseline and repeat angiograms of 54 eyes with a follow-up of 6-12 months. RESULTS: In the group with initially occult with no classic CNV, nine of 40 eyes (23%) progressed to a predominantly classic lesion, whereas in the group of occult with a minimally classic CNV, 10 of 14 eyes (71%) eyes developed a predominantly classic CNV. CONCLUSIONS: The proportion of eyes that develop predominantly classic CNV is much higher in eyes with initially occult and minimally classic CNV, compared with eyes with initially occult and no classic CNV. Our data suggest that the natural course of CNV secondary to AMD begins as occult and progresses to classic CNV.

Subfoveal hemorrhage after verteporfin photodynamic therapy in treatment of choroidal neovascularization.

BACKGROUND: To identify the frequency of new subfoveal hemorrhage and its impact on visual acuity 2 weeks following verteporfin photodynamic therapy (PDT) in the treatment of predominantly classic subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). METHODS: Retrospective, noncomparative, consecutive, interventional case series. At a tertiary retinal referral center, 104 eyes of 97 consecutive patients with predominantly classic subfoveal CNV were treated by PDT. Morphological outcomes include new subfoveal hemorrhage assessed on the photo review (pretreatment, 2 and 12 weeks after PDT). Visual acuity outcomes include moderate (3-5 ETDRS lines) and severe (6 and more ETDRS lines) loss of visual acuity at 2 weeks after PDT. RESULTS: In this study, 104 eyes of 97 patients were analyzed. CNV in all eyes was secondary to AMD. New subfoveal hemorrhage was found in 22% (23/104) of the eyes 2 weeks following PDT. 17.4% (4/23) of the eyes with new subfoveal hemorrhage had moderate or severe loss of visual acuity. In such eyes the 12-week examination revealed considerable resorption of the new subfoveal hemorrhage with some improvement of visual acuity. CONCLUSIONS: In 3.8% of the eyes that underwent PDT for predominantly classic subfoveal CNV secondary to AMD, new subfoveal hemorrhage may result in moderate or severe loss of visual acuity within 2 weeks. In all eyes with new subfoveal hemorrhage, considerable resorption of the hemorrhage and some improvement of the visual acuity were seen at 12 weeks. Candidates for PDT should be informed about the low risk of this complication.

Verteporfin photodynamic therapy for extrafoveal choroidal neovascularisation in pathologic myopia.

BACKGROUND: To report long-term functional and morphological outcome of verteporfin photodynamic therapy (PDT) for classic extrafoveal choroidal neovascularisation (CNV) secondary to pathologic myopia. METHODS: This retrospective case series included three eyes of three consecutive patients with classic extrafoveal CNV secondary to pathologic myopia, who underwent PDT at a tertiary retinal referral centre. Change in visual acuity and fluorescein leakage was the main outcome criteria. RESULTS: The patients were followed up an average of 36 months (33-40 months). In all eyes increase of visual acuity (one eye 1 ETDRS line, two eyes 2 ETDRS line) and no fluorescein leakage of the CNV were seen. CONCLUSIONS: PDT can achieve long-term improvement of the visual acuity and morphological stability in selected cases with classic extrafoveal CNV in pathologic myopia. Large scale randomised studies are warranted for assessment of the benefit of PDT in such eyes.

In vivo assessment of subretinally implanted microphotodiode arrays in cats by optical coherence tomography and fluorescein angiography.

BACKGROUND: Following multiple promising investigations into restoration of vision in degenerative retinal disease by implantation of a sub- or epiretinal prosthesis, the step to clinical use in humans is impending. In this study we intended to establish optical coherence tomography (OCT) and fluorescein angiography (FA) first in research animals for noninvasive assessment of the condition of the posterior pole of eyes after intraocular implant surgery. METHODS: Three adult cats that had undergone subretinal implant surgery were evaluated by OCT and FA between 1 and 470 days postoperatively. Eight adult cats served as control. In addition histology was performed. RESULTS: In all three cats OCT demonstrated stable positioning of the implants in the subretinal space during the complete examination period. Transient retinal edema was found in the early postoperative period but decreased during follow-up. The retina over the implants was well attached at all times in cats 1 and 2; however, in cat 3 localized retinal detachment was demonstrated. FA showed intact retinal vasculature over the subretinal implant in high detail without interference from choroidal background fluorescence. CONCLUSIONS: OCT and FA have been fruitfully applied to cats to assess the morphological and circulatory conditions of the neuroretina and of its interface with the subretinal implant. The techniques may therefore provide a tool for objective, noninvasive in vivo evaluation of eyes that have undergone subretinal implant surgery, both in research animals and in humans.

Immunohistopathologic evaluation of choroidal neovascular membranes following verteporfin-photodynamic therapy.

PURPOSE: To evaluate the vascularization and proliferative activity in choroidal neovascular membranes due to age-related macular degeneration after verteporfin photodynamic therapy and submacular removal. DESIGN: Interventional case series. METHODS: In a retrospective review of seven patients who underwent removal of subfoveal classic choroidal neovascular membranes after treatment with photodynamic therapy 3 to 146 days earlier, membranes were stained for CD 34, CD 105, and Ki-67 and correlated with clinical pictures and fluorescein angiography. RESULTS: Fluorescein angiography performed on the day of surgery disclosed nonperfusion of the treated area 3 days after photodynamic therapy, but perfusion and leakage were seen at greater post-photodynamic therapy intervals. Membranes excised 3 days after photodynamic therapy showed CD34 and CD105 positive, mostly occluded vessels. The endothelial cells appeared damaged. Ki-67 activity was low. In membranes excised 34 to 146 days after photodynamic therapy, all vessels appeared patent and were lined by healthy endothelial cells with strong expression of CD34 and CD105. Ki-67 expression was elevated after 34 days but decreased thereafter. CONCLUSION: Photodynamic therapy did not cause a general or complete occlusion of vessels within the choroidal neovascular membranes, as suggested by fluorescein angiography 3 days postintervention, but the endothelial cells appeared to be severely damaged. Proliferative activity within these specimens was reduced. At longer intervals after photodynamic therapy, the fibrovascular tissue seemed to recover; perfusion, hyperfluorescence, and leakage of the choroidal neovascular membranes could be detected by fluorescein angiography. The clinical appearance showed a correlation with the immunohistologic characteristics of an increased proliferative activity and patent vascularization.

Massive retinal gliosis: a late complication of retinal detachment surgery.

PURPOSE: Massive retinal gliosis is a rare, benign, intraocular tumor. It develops mostly in long-standing ocular disease such as chronic inflammation, vascular disorders, glaucoma, trauma, or congenital abnormalities. We report on a case of massive retinal gliosis, which developed 17 years following retinal detachment surgery. METHODS: Case report. RESULTS: A 64-year-old woman developed a peripheral fundus tumor 17 years after successful retinal detachment surgery. Follow-up examination demonstrated growth of the mass. The tumor was treated by pars plana vitrectomy and local endoresection. Histopathological study revealed massive reactive gliosis of the retina. CONCLUSIONS: To our knowledge, this is the first histopathologically proven case of a massive retinal gliosis, which developed after a non-drainage retinal detachment surgery. Endoresection is a therapeutic option in suspected massive retinal gliosis. It provides material for histological diagnosis which obviates unnecessary intervention in a functioning eye.

Indocyanine green angiography in a case of unilateral recurrent posterior acute multifocal placoid pigment epitheliopathy.

PURPOSE: To report a case of unilateral recurrent acute posterior multifocal placoid pigment epitheliopathy (APMPPE) imaged by indocyanine green (ICG) angiography. METHODS: A complete ophthalmological evaluation, including fluorescein and ICG angiography, was performed. RESULTS: Acute posterior multifocal placoid pigment epitheliopathy recurred 3 months after the initial disease in a 23-year-old male patient. On ICG angiography, both new, active and healed, inactive lesions demonstrated hypofluorescence throughout the study. The healed lesions were smaller in size and irregularly shaped, whereas the new, active lesions were larger in size, round and more confluent. CONCLUSION: New, active and healed, inactive lesions in APMPPE can both be imaged and differentiated by ICG angiography.