Classifying retinal degeneration in histological sections using deep learning

Purpose: Artificial intelligence (AI) techniques are increasingly being used to classify retinal diseases. In this study we investigated the ability of a convolutional neural network (CNN) in categorizing histological images into different classes of retinal degeneration. Methods: Images were obtained from a chemically induced feline model of monocular retinal dystrophy and split into training and testing sets. The training set was graded for the level of retinal degeneration and used to train various CNN architectures. The testing set was evaluated through the best architecture and graded by six observers. Comparisons between model and observer classifications, and interobserver variability were measured. Finally, the effects of using less training images or images containing half the presentable context were investigated. Results: The best model gave weighted-F1 scores in the range 85% to 90%. Cohen kappa scores reached up to 0.86, indicating high agreement between the model and observers. Interobserver variability was consistent with the model-observer variability in the model’s ability to match predictions with the observers. Image context restriction resulted in model performance reduction by up to 6% and at least one training set size resulted in a model performance reduction of 10% compared to the original size. Conclusions: Detecting the presence and severity of up to three classes of retinal degeneration in histological data can be reliably achieved with a deep learning classifier. Translational Relevance: This work lays the foundations for future AI models which could aid in the evaluation of more intricate changes occurring in retinal degeneration, particularly in other types of clinically derived image data.</p

A WideField Suprachoroidal Retinal Prosthesis Reliably Elicits Cortical Activity after Chronic Implantation. The Association for Research in Vision and Ophthalmology Annual Meeting. Fort Lauderdale

Citation: Villalobos J, Nayagam DAX, Allen PJ, et al. A wide-field suprachoroidal retinal prosthesis is stable and well tolerated following chronic implantation. Invest Ophthalmol Vis Sci. 2013;54:3751-3762. DOI:10.1167/ iovs.12-10843 PURPOSE. The safety of chronic implantation of a retinal prosthesis in the suprachoroidal space has not been established. This study aimed to determine the safety of a wide-field suprachoroidal electrode array following chronic implantation using histopathologic techniques and electroretinography. METHODS. A platinum electrode array in a wide silicone substrate was implanted unilaterally in the suprachoroidal space in adult cats (n ¼ 7). The lead and connector were tunneled out of the orbit and positioned subcutaneously. Postsurgical recovery was assessed using fundus photography and electroretinography (ERG). Following 3 months of passive implantation, the animals were terminated and the eyes assessed for the pathologic response to implantation. RESULTS. The implant was mechanically stable in the suprachoroidal space during the course of the study. The implanted eye showed a transient increase in ERG response amplitude at 2 weeks, which returned to normal by 3 months. Pigmentary changes were observed at the distal end of the implant, near the optic disc. Histopathologic assessment revealed a largely intact retina and a thin fibrous capsule around the suprachoroidal implant cavity. The foreign body response was minimal, with sporadic presence of macrophages and no active inflammation. All implanted eyes were negative for bacterial or fungal infections. A midgrade granuloma and thick fibrous buildup surrounded the extraocular cable. Scleral closure was maintained in six of seven eyes. There were no staphylomas or choroidal incarceration. CONCLUSIONS. A wide-field retinal prosthesis was stable and well tolerated during long-term suprachoroidal implantation in a cat model. The surgical approach was reproducible and overall safe

Preclinical safety study of a fully implantable, sub-scalp ring electrode array for long-term EEG recordings

Objective. Long-term electroencephalogram (EEG) recordings can aid diagnosis and management of various neurological conditions such as epilepsy. In this study we characterize the safety and stability of a clinical grade ring electrode arrays by analyzing EEG recordings, fluoroscopy, and computed tomography (CT) imaging with long-term implantation and histopathological tissue response. Approach. Seven animals were chronically implanted with EEG recording array consisting of four electrode contacts. Recordings were made bilaterally using a bipolar longitudinal montage. The array was connected to a fully implantable micro-processor controlled electronic device with two low-noise differential amplifiers and a transmitter-receiver coil. An external wearable was used to power, communicate with the implant via an inductive coil, and store the data. The sub-scalp electrode arrays were made using medical grade silicone and platinum. The electrode arrays were tunneled in the subgaleal cleavage plane between the periosteum and the overlying dermis. These were implanted for 3-7 months before euthanasia and histopathological assessment. EEG and impedance were recorded throughout the study. Main results. Impedance measurements remained low throughout the study for 11 of 12 channels over the recording period ranged from 3 to 5 months. There was also a steady amplitude of slow-wave EEG and chewing artifact (noise). The post-mortem CT and histopathology showed the electrodes remained in the subgaleal plane in 6 of 7 sheep. There was minimal inflammation with a thin fibrotic capsule that ranged from 4 to 101 μm. There was a variable fibrosis in the subgaleal plane extending from 210 to 3617 μm (S3-S7) due to surgical cleavage. One sheep had an inflammatory reaction due to electrode extrusion. The passive electrode array extraction force was around 1 N. Significance. Results show sub-scalp electrode placement was safe and stable for long term implantation. This is advantageous for diagnosis and management of neurological conditions where long-term, EEG monitoring is required.</p

Safety studies for a 44-channel suprachoroidal retinal prosthesis : A chronic passive study

PURPOSE. Following successful clinical outcomes of the prototype suprachoroidal retinal prosthesis, Bionic Vision Australia has developed an upgraded 44-channel suprachoroidal retinal prosthesis to provide a wider field of view and more phosphenes. The aim was to evaluate the preclinical passive safety characteristics of the upgraded electrode array. METHODS. Ten normal-sighted felines were unilaterally implanted with an array containing platinum electrodes (44 stimulating and 2 returns) on a silicone carrier near the area centralis. Clinical assessments (color fundus photos, optical coherence tomography, full-field electroretinography, intraocular pressure) were performed under anesthesia prior to surgery, and longitudinally for up to 20 weeks. Histopathology grading of fibrosis and inflammation was performed in two animals at 13 to 15 weeks. RESULTS. Eight animals showed safe electrode array insertion (good retinal health) and good conformability of the array to the retinal curvature. Eight animals demonstrated good mechanical stability of the array with only minor (<2 disc diameters) lateral movement. Four cases of surgical or stability complications occurred due to (1) bulged choroid during surgery, (2) hemorrhage from a systemic bleeding disorder, (3) infection, and (4) partial erosion of thin posterior sclera. There was no change in retinal structure or function (other than that seen at surgery) at endpoint. Histopathology showed a mild foreign body response. Electrodes were intact on electrode array removal. CONCLUSIONS. The 44-channel suprachoroidal electrode array has an acceptable passive safety profile to proceed to clinical trial. The safety profile is expected to improve in human studies, as the complications seen are specific to limitations (anatomic differences) with the feline model.</p

Chronic Electrical Stimulation with a Suprachoroidal Retinal Prosthesis: A Preclinical Safety and Efficacy Study

<div><p>Purpose</p><p>To assess the safety and efficacy of chronic electrical stimulation of the retina with a suprachoroidal visual prosthesis.</p><p>Methods</p><p>Seven normally-sighted feline subjects were implanted for 96–143 days with a suprachoroidal electrode array and six were chronically stimulated for 70–105 days at levels that activated the visual cortex. Charge balanced, biphasic, current pulses were delivered to platinum electrodes in a monopolar stimulation mode. Retinal integrity/function and the mechanical stability of the implant were assessed monthly using electroretinography (ERG), optical coherence tomography (OCT) and fundus photography. Electrode impedances were measured weekly and electrically-evoked visual cortex potentials (eEVCPs) were measured monthly to verify that chronic stimuli were suprathreshold. At the end of the chronic stimulation period, thresholds were confirmed with multi-unit recordings from the visual cortex. Randomized, blinded histological assessments were performed by two pathologists to compare the stimulated and non-stimulated retina and adjacent tissue.</p><p>Results</p><p>All subjects tolerated the surgical and stimulation procedure with no evidence of discomfort or unexpected adverse outcomes. After an initial post-operative settling period, electrode arrays were mechanically stable. Mean electrode impedances were stable between 11–15 kΩ during the implantation period. Visually-evoked ERGs & OCT were normal, and mean eEVCP thresholds did not substantially differ over time. In 81 of 84 electrode-adjacent tissue samples examined, there were no discernible histopathological differences between stimulated and unstimulated tissue. In the remaining three tissue samples there were minor focal fibroblastic and acute inflammatory responses.</p><p>Conclusions</p><p>Chronic suprathreshold electrical stimulation of the retina using a suprachoroidal electrode array evoked a minimal tissue response and no adverse clinical or histological findings. Moreover, thresholds and electrode impedance remained stable for stimulation durations of up to 15 weeks. This study has demonstrated the safety and efficacy of suprachoroidal stimulation with charge balanced stimulus currents.</p></div

Longitudinal changes in electrode impedance.

<p>Electrode impedance (kΩ) across all subjects recorded periodically over the duration of the chronic implant period. Box plots show median (midline), 1^st and 3^rd quartiles (box edges), whiskers have a maximum length 1.5 times the interquartile range and open circles denote outliers. Pre-implantation, post-explantation and post-cleaning impedance measurements were performed in normal saline. The number of individual electrode measurements that comprise each box plot ranged from 21 to 67 (maximum possible = 72; subject 505 was excluded due to a damaged lead).</p

Representative immunohistochemical stains of the chronically stimulated and control feline retina.

<p>(<b>A, B</b>) anti-glial fibrillary acidic acid (GFAP; red); Müller cells and astrocytes (supporting glial cells of the retina) can be seen in the ganglion cell layer and nerve fibre layer. No evidence of gliosis was noted in any eye in the study. (<b>C, D</b>) Glutamine synthetase (GS; green); Müller cells are evident extending through the retinal layers. (<b>E, F</b>) Neurofilament (NF-200; green); large and small ganglion cells (arrow) can be seen in the ganglion cell layer with their axons forming bundles in the nerve fibre layer (double arrowhead). Horizontal cells found in the inner nuclear layer are also stained in the feline retina. Sections are counterstained with DAPI nuclear stain (blue; panels: A, B, E and F). Variations in intensity of DAPI staining are artifactual. In all cases, normal retinal architecture was observed indicating retinal cell viability. Scale bar in panel F = 50 µm and applies to all panels. The inner retina is shown at the bottom of each image; the outer retina is shown at the top of each image. Abbreviations: GCL, ganglion cell layer; INL, inner nuclear layer; ONL, outer nuclear layer. Subject ID: 507.</p

Summary of chronic stimulation cohort.

<p><i>Stimulation mode was monopolar. Stimulation was delivered using biphasic charge balanced rectangular current pulses (phase width: 400 µs; interphase gap: 20 µs). The maximum current denotes the stimulation level at the culmination of the ramp-up period (refer <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0097182#pone-0097182-g001" target="_blank">Figure 1</a>). Charge density per phase was calculated by using the stimulation phase width of 400 µs per phase and the geometric electrode surface area of 0.2827 mm². Electrode utilisation, expressed as “X|Y|Z” denotes the number of electrodes that were stimulated maximally during the stimulation period (X); the number of electrodes that were partially stimulated, either at lower levels or for an incomplete subset of the stimulation duration (Y); and the number of unstimulated controls on the array (Z). The lead system was damaged during subject 505’s implantation; therefore it was only stimulated for 18 days (asterisk) before being disconnected from the stimulator.</i></p

Longitudinal stability of electrically-evoked visual cortex potentials (eEVCP).

<p>(<b>A</b>) Average cortical responses to increasing current are shown on the left. The stimulus is repeated twice at each current level and both response traces are displayed. The amplitude (mV) of the evoked response (within the region indicated by the blue shaded region) as a function of current (mA) is plotted on the right. In this case, evoked cortical potential threshold was 100 µA (as denoted by “T”). (<b>B</b>) eEVCP thresholds for each subject, recorded monthly, starting immediately before the initiation of chronic stimulation (0 months). Box plots show median (midline), 1^st and 3^rd quartiles (box edges), whiskers have a maximum length 1.5 times the interquartile range and open circles represent individual points. No eEVCP data was available for subject 505 due to a damaged lead. (<b>C</b>) The change in threshold, on a per-electrode basis. The changes were calculated for each electrode separately, in monthly increments, and these data were combined. Box plots show median (midline), 1^st and 3^rd quartiles (box edges), whiskers have a maximum length 1.5 times the interquartile range and open circles denote outliers. There was little variation in median change in threshold over the three time points. The 95% confidence interval comparing switch on to three months was −119.5 to 383.9 µA; this shows a range of plausible values for the overall change over time, including zero.</p

Combined rod-cone maximal full-field electroretinogram (ERG) responses at the completion of the chronic stimulation period.

<p>Examples of the ERG waveforms are shown in the inset with the a- and b-waves indicated. Dashed horizontal line indicates recording baseline. a-wave amplitude is taken from baseline to a-wave trough; b-wave amplitude is taken from a-wave trough to b-wave peak. The median and interquartile range of ERG responses from n = 7 subjects are presented in the box plots. Box plots show median (midline), 1^st and 3^rd quartiles (box edges), whiskers have a maximum length 1.5 times the interquartile range and open circles represent individual points. There was substantial overlap between the measured response amplitude of the a- and b-waves between the implanted and control eyes. The paired <i>t</i> procedures showed the mean difference (implanted minus non-implanted) for the a-wave was −14.3 µV (95% confidence interval: –50.5, 21.8, <i>p</i> = 0.37), and for the b-wave was −66.6 µV (95% confidence interval: –135.9, 2.8, <i>p</i> = 0.057). Minor differences between eyes can be attributed to electrode placement or normal biological variation.</p