Using texture based features from the continuous wavelet transform of the electroretinogram to predict glaucoma.

Glaucoma is an optic neuropathy resulting in the progressive loss of retinal ganglion cells (RCGs). The photopic negative response (PhNR) of the electroretinogram (ERG) has been used to objectively measure RCG function. This study sought to explore whether the usage of textural features extracted from the continuous wavelet transform of the ERG combined with ERG amplitude markers were more effective at predicting glaucoma severity than using the ERG markers alone. One-hundred and three eyes of 55 participants were included in this study, who underwent ERG testing with a protocol targeted at the PhNR. Predictive models for glaucoma severity based on the estimated RGC count were fitted using multiadaptive regression splines (MARS). The models informed by a combination of amplitude markers and texture analysis had a better predictive performance; R2 = 0.492, compared to models informed by markers alone having an R2 = 0.349 (p = 0.009).Clinical Relevance- As a direct measure of retinal function, the ERG has potential to determine the health of RGCs. This study demonstrates there is additional data within the ERG available to clinicians, which has the potential to improve the diagnosis and management of glaucoma.

Time-Frequency Analysis of ERG With Discrete Wavelet Transform and Matching Pursuits for Glaucoma.

Purpose: To examine the performance of two time-frequency feature extraction techniques applied to electroretinograms (ERGs) for the prediction of glaucoma severity. Methods: ERGs targeting the photopic negative response were obtained in 103 eyes of 55 patients with glaucoma. Features from the ERG recordings were extracted using two time-frequency extraction techniques based on the discrete wavelet transform (DWT) and the matching pursuit (MP) decomposition. Amplitude markers of the time-domain signal were also extracted. Linear and multivariate adaptive regression spline (MARS) models were fitted using combinations of these features to predict estimated retinal ganglion cell counts, a measure of glaucoma disease severity derived from standard automated perimetry and optical coherence tomography imaging. Results: Predictive models using features from the time-frequency analyses-using both DWT and MP-combined with amplitude markers outperformed predictive models using the markers alone with linear (P = 0.001) and MARS (P ≤ 0.011) models. For example, the proportions of variance (R2) explained by the MARS model using the DWT and MP features with amplitude markers were 0.53 and 0.63, respectively, compared to 0.34 for the model using the markers alone (P = 0.011 and P = 0.001, respectively). Conclusions: Novel time-frequency features extracted from the photopic ERG substantially added to the prediction of glaucoma severity compared to using the time-domain amplitude markers alone. Translational Relevance: Substantial information about retinal ganglion cell dysfunction exists in the time-frequency domain of ERGs that could be useful in the management of glaucoma.

Repeatability and Reproducibility of Retinal Fractal Dimension Measured with Swept-Source Optical Coherence Tomography Angiography in Healthy Eyes: A Proof-of-Concept Study.

The retinal vascular network fractal dimension (FD) could be a promising imaging biomarker. Our objective was to evaluate its repeatability and reproducibility in healthy eyes. A cross-sectional study was undertaken with young, healthy volunteers who had no reported cardiac risk factors or ocular disease history. For each participant, three SS-OCTA images (12 × 12 mm) were acquired using the Plex Elite 9000 (Carl Zeiss Meditec AG, Jena, Germany) by two ophthalmologists. Automated segmentation was obtained from both the superficial and deep capillary plexuses. FD was estimated by box counting. The intraclass correlation coefficients (ICC) were used as measures for repeatability and reproducibility. A total of 43 eyes of healthy volunteers were included. The mean ± standard deviation (SD) age was 30 ± 6.2 years. The results show good repeatability. The ICC was 0.722 (95% CI, 0.541-0.839) in the superficial capillary plexus and 0.828 (95% CI, 0.705-0.903) in the deep capillary plexus. For reproducibility, the ICC was 0.651 (95% CI, 0.439-0.795) and 0.363 (95% CI, 0.073-0.596) at the superficial and deep capillary plexus, respectively. In this study, the FD of the vascular network measured via SS-OCTA showed good repeatability and reproducibility in healthy participants.

Prediction of glaucoma severity using parameters from the electroretinogram.

Glaucoma is an optic neuropathy that results in the progressive loss of retinal ganglion cells (RGCs), which are known to exhibit functional changes prior to cell loss. The electroretinogram (ERG) is a method that enables an objective assessment of retinal function, and the photopic negative response (PhNR) has conventionally been used to provide a measure of RGC function. This study sought to examine if additional parameters from the ERG (amplitudes of the a-, b-, i-wave, as well the trough between the b- and i-wave), a multivariate adaptive regression splines (MARS; a non-linear) model and achromatic stimuli could better predict glaucoma severity in 103 eyes of 55 individuals with glaucoma. Glaucoma severity was determined using standard automated perimetry and optical coherence tomography imaging. ERGs targeting the PhNR were recorded with a chromatic (red-on-blue) and achromatic (white-on-white) stimulus with the same luminance. Linear and MARS models were fitted to predict glaucoma severity using the PhNR only or all ERG markers, derived from chromatic and achromatic stimuli. Use of all ERG markers predicted glaucoma severity significantly better than the PhNR alone (P ≤ 0.02), and the MARS performed better than linear models when using all markers (P = 0.01), but there was no significant difference between the achromatic and chromatic stimulus models. This study shows that there is more information present in the photopic ERG beyond the conventional PhNR measure in characterizing RGC function.

Pupillometric recordings to detect glaucoma.

Objective. Glaucoma is the second cause of vision loss with early diagnosis having significantly better prognosis. We propose the use of hippus, the steady-state pupil oscillations, obtained from an eye-tracker for computerised detection of glaucoma.Approach. Pupillary data were recorded using a commercial eye-tracker device directly to the laptop. A total of 40 glaucoma patients and 30 age-matched controls were recruited for the study. The signals were de-noised, and the entropy of the steady-state oscillations was obtained for two light intensities, 34 and 100 cd m-2.Main results. The results show that at 100 cd m-2, there was significant difference (p < 0.05) between the sample entropy of the healthy eyes (0.55 ± 0.017) and glaucoma eyes (0.7 ± 0.034). The results at 34 cd m-2were also significantly different, though to a lesser extent.Significance. Entropy of the pupillary oscillations, or hippus, obtained using an eye-tracking device showed a significant difference between glaucoma and healthy eyes. The method used commercially available inexpensive hardware and thus has the potential for wide-scale deployment for computerized detection of glaucoma.

Sample entropy analysis of pupillary signals in glaucoma patients and control via light-induced pupillometry.

This paper evaluated the pupillary light reflex of glaucomatous eyes in the presence of constant lighting via light-induced pupillometry using sample entropy. The study used 20 patients and 15 controls, applied three different light intensities to their eyes, and recorded the behavior of the pupil. This study has validated that there is a difference in the entropy of pupillary data in glaucoma and healthy eyes. We concluded that entropy analysis is an excellent method to differentiate glaucoma eyes with the control through light-induced pupillometry. Hence, pupillometry has potential clinical applications in glaucoma investigation.

Association between Optical Coherence Tomography and Fluorescein Angiography based retinal features in the diagnosis of Macular Edema.

The association between optical coherence tomography (OCT) and the geometrical vascular parameters obtained from the fluorescein angiography (FA) of the eyes with macular edema (ME) was investigated. Data from 82 untreated eyes with ME were studied. Fractal dimension (FD), simple tortuosity, branching angle, total angle count and vessel to background ratio were the five vasculature parameters from FA that were studied. The four OCT features measured were central retinal/foveal thickness, average para-fovea thickness, average peri-fovea thickness and OCT volume. The four OCT parameters showed a significant difference between ME requiring treatment (MERT) and non-MERT eyes with the central retinal thickness (threshold at 300 µm) and average para-fovea thickness (threshold at 338.5 µm) as most significant. The results also indicate that FD from the FA of retinal vessels in the macular region was associated with the changes in retinal thickness and that OCT parameters can potentially be used for directly identifying ME.

Agreement study between color and IR retinal images based on retinal vasculature morphological parameters.

BACKGROUND: Color fundus photography have been extensively used to explore the link between retinal morphology changes associated with various disease i.e. Diabetic Retinopathy, Glaucoma. The development of multimodal imaging system that integrates Infrared Scanning Laser Ophthalmoscope (IR-SLO) and Optical Coherence Tomography (OCT) could help in studying these diseases at an early stage. The aim of this study was to test the agreement between the retinal vasculature parameters from the Infrared images obtained from optical coherence tomography and color fundus imaging. METHODS: The IR and Color retinal images were obtained from 16 volunteer participants and seven retinal vessel parameters, i.e. Fractal Dimension (FD), Average Angle (ABA), Total Angle Count (TAC), Tortuosity (ST), Vessel/Background ratio (VBR), Central Retinal Arteriolar Equivalent (CRAE) and Central Retinal Venular Equivalent (CRVE) were extracted from these retinal images using Retinal Image Vasculature Assessment software (RIVAS) and Integrative Vessel Analysis (IVAN). RESULTS: The Bland Altman plot was used to investigate the agreement between the two modalities. The paired sample t-test was used to assess the presence of fixed bias and the slope of Least Square Regression (LSR) line for the presence of proportional bias. The paired sample t-test showed that there was no statistically significant difference between Color and IR based on retinal vessel features (all p values > 0.05). LSR also revealed no statistically significant difference in the retinal vessel features between Color and IR. CONCLUSION: This study has revealed that there is a fair agreement between Color and IR images based on retinal vessel features. This research has shown that it is possible to use IR images of the retina to measure the retinal vasculature parameters which has the advantage of being flash-less, can be used even if there is opacity due to cataract, and can be performed along with OCT on the same device.

Relation Between Retinal Vasculature and Retinal Thickness in Macular Edema.

This study has investigated the relationship of the retinal vasculature and the retinal thickness for Macular Edema (ME) subjects. Ninety sets of Fluorescein Angiograph (FA) and Optical Coherence Tomography (OCT) of 54 participants were analyzed. Multivariate analysis using the binary logistic regression model was used to study the association between vessel parameters and retinal thickness. The results reveal retinal vessel feature i.e. fractal dimension (FD) as the most sensitive parameter to the changes in retinal thickness associated with ME. Thus, indicating a direct relationship between the retinal vasculature and retinal thickness which is caused due to neovascular causing exudates, leakages and hemorrhages, with applications for alternate modality for detection of ME.

More than blindsight: Case report of a child with extraordinary visual capacity following perinatal bilateral occipital lobe injury.

Injury to the primary visual cortex (V1, striate cortex) and the geniculostriate pathway in adults results in cortical blindness, abolishing conscious visual perception. Early studies by Larry Weiskrantz and colleagues demonstrated that some patients with an occipital-lobe injury exhibited a degree of unconscious vision and visually-guided behaviour within the blind field. A more recent focus has been the observed phenomenon whereby early-life injury to V1 often results in the preservation of visual perception in both monkeys and humans. These findings initiated a concerted effort on multiple fronts, including nonhuman primate studies, to uncover the neural substrate/s of the spared conscious vision. In both adult and early-life cases of V1 injury, evidence suggests the involvement of the Middle Temporal area (MT) of the extrastriate visual cortex, which is an integral component area of the dorsal stream and is also associated with visually-guided behaviors. Because of the limited number of early-life V1 injury cases for humans, the outstanding question in the field is what secondary visual pathways are responsible for this extraordinary capacity? Here we report for the first time a case of a child (B.I.) who suffered a bilateral occipital-lobe injury in the first two weeks postnatally due to medium-chain acyl-Co-A dehydrogenase deficiency. At 6 years of age, B.I. underwent a battery of neurophysiological tests, as well as structural and diffusion MRI and ophthalmic examination at 7 years. Despite the extensive bilateral occipital cortical damage, B.I. has extensive conscious visual abilities, is not blind, and can use vision to navigate his environment. Furthermore, unlike blindsight patients, he can readily and consciously identify happy and neutral faces and colors, tasks associated with ventral stream processing. These findings suggest significant re-routing of visual information. To identify the putative visual pathway/s responsible for this ability, MRI tractography of secondary visual pathways connecting MT with the lateral geniculate nucleus (LGN) and the inferior pulvinar (PI) were analysed. Results revealed an increased PI-MT pathway in the left hemisphere, suggesting that this pulvinar relay could be the neural pathway affording the preserved visual capacity following an early-life lesion of V1. These findings corroborate anatomical evidence from monkeys showing an enhanced PI-MT pathway following an early-life lesion of V1, compared to adults.

ISCEV extended protocol for the photopic negative response (PhNR) of the full-field electroretinogram.

The International Society for Clinical Electrophysiology of Vision (ISCEV) Standard for full-field electroretinography (ERG) describes a minimum procedure, but encourages more extensive testing. This ISCEV extended protocol describes an extension to the ERG Standard, namely the photopic negative response (PhNR) of the light-adapted flash ERG, as a well-established technique that is broadly accepted by experts in the field. The PhNR is a slow negative-going wave after the b-wave that provides information about the function of retinal ganglion cells and their axons. The PhNR can be reduced in disorders that affect the innermost retina, including glaucoma and other forms of optic neuropathy. This document, based on existing literature, provides a protocol for recording and analyzing the PhNR in response to a brief flash. The protocol includes full-field stimulation, a frequency bandwidth of the recording in which the lower limit does not exceed 0.3 Hz, and a spectrally narrowband stimulus, specifically, a red flash on a rod saturating blue background. Suggested flash strengths cover a range up to and including the minimum required to elicit a maximum amplitude PhNR. This extended protocol for recording the PhNR provides a simple test of generalized retinal ganglion cell function that could be added to standard ERG testing.

A Comparison of the RETeval Sensor Strip and DTL Electrode for Recording the Photopic Negative Response.

PURPOSE: To compare the RETeval sensor strip and Dawson-Trick-Litzkow (DTL) electrodes for recording the photopic negative response (PhNR) using a portable electroretinogram (ERG) device in eyes with and without glaucoma. METHODS: Twenty-six control and 31 glaucoma or glaucoma-suspect participants were recruited. Photopic ERGs were recorded with sensor strip and DTL electrodes in random order using the LKC RETeval device. Stimuli consisted of brief, red flashes (1.7 cd.s/m2) on a blue background (photopic 10 cd/m2). The PhNR amplitude was measured from baseline to trough and also expressed as a ratio over the b-wave amplitude. RESULTS: The sensor strip-recorded PhNR amplitude was significantly attenuated (mean ± standard deviation [SD], 4.8 ± 2.1 vs. 12.7 ± 4.8 µV, P < 0.0001), with lower signal-to-noise ratio (SNR; 5.5 ± 2.1 vs. 8.1 ± 3.9, P < 0.0001), and a trend toward a larger PhNR/b-wave ratio compared with DTL electrodes. The PhNR amplitude, implicit time and PhNR/b-wave ratio correlated with visual field mean light sensitivity, although this fell short of significance for the sensor strip recorded PhNR amplitude. The electrodes demonstrated similar intersession repeatability with a coefficient of repeatability of ±27% and ±28% for the DTL and sensor strip, respectively. CONCLUSIONS: Sensor strip electrodes are a viable alternative for recording reproducible PhNRs, especially when values are normalized to the b-wave. However, DTL electrodes should be considered in cases of attenuated PhNR, or in elevated noise levels, due to its better signal-to-noise quality. TRANSLATIONAL RELEVANCE: Sensor strip electrodes can simplify PhNR recordings in the clinic, potentially eliminating the need for an experienced operator.

Photopic Negative Response Obtained Using a Handheld Electroretinogram Device: Determining the Optimal Measure and Repeatability.

PURPOSE: To determine the measure of the photopic negative response (PhNR) of the full-field electroretinogram (ERG) that exhibits the optimal level of test-retest repeatability, and examine its repeatability under different conditions using a handheld, nonmydriatic ERG system and self-adhering skin electrodes. METHODS: Multiple ERG recordings (using 200 sweeps each) were performed in both eyes of 20 normal participants at two different sessions to compare its coefficient of repeatability (CoR; where 95% of the test-retest difference is expected to lie) between different PhNR measures and under different testing conditions (within and between examiners, and between sessions). RESULTS: The ratio between the PhNR trough to b-wave peak and b-wave peak to a-wave trough amplitude (PhNR/B ratio) exhibited the lowest CoR relative to its effective dynamic range (30 ± 4%) when including three recordings. There were no significant changes in the PhNR/B ratio over seven measurements (4 right and 3 left eyes) at either session (P ≥ 0.100), or significant difference in its CoR between different testing conditions (P = 0.314). CONCLUSION: The PhNR/B ratio was the measure that minimized variability, and its measurements using a novel handheld ERG system with self-adhering skin electrodes and the protocols described in this study were comparable under different testing conditions and over multiple recordings. TRANSLATIONAL RELEVANCE: The PhNR can be measured for clinical and research purposes using a simple-to-implement technique that is consistent within and between visits, and also between examiners.

Test-Retest Variability of Fundus-Tracked Perimetry at the Peripapillary Region in Open Angle Glaucoma.

PURPOSE: To examine the association between the measured level and local gradient of visual sensitivity on the magnitude of test-retest variability of its measurements at the peripapillary region using fundus-tracked perimetry in eyes with glaucoma. METHODS: A total of 30 participants with open angle glaucoma underwent three examinations in one eye on fundus-tracked perimetry using a stimulus pattern that sampled the peripapillary region densely. Factors associated with the magnitude of test-retest variability at each location were examined. RESULTS: There was no significant change in average pointwise sensitivity (PWS) between tests 1 and 2 (P = 0.855), but a significant reduction between tests 2 and 3 (P < 0.001). Therefore, all subsequent analyses were performed only between tests 1 and 2. Multivariate analyses revealed that the magnitude of test-retest variability at a given location was significantly associated with its average sensitivity and gradient of sensitivity relative to the immediately adjacent locations (P ≤ 0.001), meaning that locations with low levels of sensitivity (4-18 dB) with low gradients of sensitivity (<2 dB/location) had a 90% test-retest limit of ±5.83 dB, compared to a limit of ±10.65 dB in areas of high gradients of sensitivity (>4 dB/location). CONCLUSIONS: On a pointwise basis, the test-retest variability of visual sensitivity in glaucoma is not just related to its measured level, but also its local gradient when using fundus-tracked perimetry. Locations with low sensitivity do not necessarily demonstrate very high test-retest variability, depending on the local uniformity of visual field damage.

Application-Dedicated Selection of Filters (ADSF) using covariance maximization and orthogonal projection.

Visible and near-infrared (Vis-NIR) spectra are generated by the combination of numerous low resolution features. Spectral variables are thus highly correlated, which can cause problems for selecting the most appropriate ones for a given application. Some decomposition bases such as Fourier or wavelet generally help highlighting spectral features that are important, but are by nature constraint to have both positive and negative components. Thus, in addition to complicating the selected features interpretability, it impedes their use for application-dedicated sensors. In this paper we have proposed a new method for feature selection: Application-Dedicated Selection of Filters (ADSF). This method relaxes the shape constraint by enabling the selection of any type of user defined custom features. By considering only relevant features, based on the underlying nature of the data, high regularization of the final model can be obtained, even in the small sample size context often encountered in spectroscopic applications. For larger scale deployment of application-dedicated sensors, these predefined feature constraints can lead to application specific optical filters, e.g., lowpass, highpass, bandpass or bandstop filters with positive only coefficients. In a similar fashion to Partial Least Squares, ADSF successively selects features using covariance maximization and deflates their influences using orthogonal projection in order to optimally tune the selection to the data with limited redundancy. ADSF is well suited for spectroscopic data as it can deal with large numbers of highly correlated variables in supervised learning, even with many correlated responses.

Measuring the Photopic Negative Response: Viability of Skin Electrodes and Variability Across Disease Severities in Glaucoma.

PURPOSE: The purpose of this study was to determine the feasibility of measuring the photopic negative response (PhNR) of the full-field electroretinogram (ERG) using skin electrodes compared to conjunctival electrodes and its test-retest variability over a range of disease severities in open-angle glaucoma. METHODS: Recordings were performed twice (100 sweeps each) within the same session in 43 eyes of 23 participants with glaucoma to determine its intrinsic variability. The ratio between the PhNR and B-wave amplitude (PhNR/B ratio) was determined for each trace and computed across 5 to 100 sweeps of each recording. Spectral-domain optical coherence tomography was used to measure the average peripapillary retinal nerve fiber layer (RNFL) thickness. RESULTS: The PhNR/B ratio and its magnitude of variability were not significantly different between skin and conjunctival electrodes (P ≤ 0.197), and the degree of variability decreased substantially with increasing number of sweeps. For skin electrodes, the intraclass correlation coefficient was 0.89 and 0.91 for right and left eyes, respectively. The variability of the PhNR/B ratio decreased with lower RNFL thickness values and larger B-wave amplitudes (P ≤ 0.002). CONCLUSIONS: Skin electrodes are a viable alternative to conjunctival electrodes when measuring the PhNR in open angle glaucoma, and increasing the number of sweeps substantially reduced its intrinsic variability; the extent of variability was also lower with worsening disease severity. TRANSLATIONAL RELEVANCE: The feasibility of performing ERG recordings widely across a range of disease severities in glaucoma can be achieved through using skin electrodes and increasing the number of sweeps performed to improve measurement repeatability.

Neuronal activity-dependent regulation of retinal blood flow.

Blood flow in the retina is intrinsically regulated to meet the metabolic demands of its constituent cells. Flickering light or stationary contrast reversals induce an increase in blood flow within seconds of the stimulus onset. This phenomenon is thought to compensate for an increase in ganglion cell activity and energy consumption. Ganglion cell activity is in turn dependent on signals from photoreceptors, bipolar cells, horizontal cells and amacrine cells. The physiological properties of these neurons determine how each type is affected by a particular light characteristic. Neuronal activity then triggers the release of signalling molecules that dilate local blood vessels and increase blood flow. Nitric oxide has been implicated as an important mediator, but metabolites of arachidonic acid may also be involved. Detailed elucidation of these mechanisms, together with advances in imaging technology, may facilitate the use of neurovascular tests to improve the detection of retinal damage in pathological conditions.

Vitamin A Deficiency Presenting with 'Itchy Eyes'.

We present the case of an 88-year-old female living in metropolitan Melbourne, Australia who developed vitamin A deficiency manifesting as 'itchy eyes' due to a bizarre dietary habit. Slit lamp examination revealed Bitot's spots and a subsequent vitamin A serum level test revealed severe deficiency. An electroretinogram showed grossly reduced a- and b-wave amplitudes consistent with generalised rod and cone dysfunction - these parameters showed marked improvement 5 months post supplementation. This case highlights the presence of vitamin A deficiency in the developed world and that a careful dietary history should be taken when assessing a patient complaining of 'itchy eyes'. Timely diagnosis and treatment may result in dramatic resolution of symptoms and signs as well as prevention of serious morbidity.

Relationship between diabetes and grayscale fractal dimensions of retinal vasculature in the Indian population.

BACKGROUND: Diabetes mellitus is rapidly increasing in the Indian population. The purpose of this study was to identify changes in the retinal vasculature of diabetic people, ahead of visual impairments. Grayscale Fractal Dimension (FD) analysis of retinal images was performed on people with type 2 diabetes from an Indian population. METHODS: A cross-sectional study comprising 189 Optic Disc (OD) centred retinal images of healthy and diabetic individuals aged 14 to 73 years was conducted. Grayscale Box Counting FD of these retinal photographs was measured without manual supervision. Statistical analysis was conducted to determine the difference in the FD between diabetic and healthy (non-diabetic) people. RESULTS: The results show that grayscale FD values for diabetic cases are higher compared to controls, irrespective of the gender. It was also observed that FD was higher for male compared with females. CONCLUSIONS: There is difference in the grayscale fractal dimension of retinal vasculature of diabetic patients and healthy subjects, even when there is no reported retinopathy.