Retinal Nerve Fiber Layer Features Identified by Unsupervised Machine Learning on Optical Coherence Tomography Scans Predict Glaucoma Progression.

Purpose:To apply computational techniques to wide-angle swept-source optical coherence tomography (SS-OCT) images to identify novel, glaucoma-related structural features and improve detection of glaucoma and prediction of future glaucomatous progression. Methods:Wide-angle SS-OCT, OCT circumpapillary retinal nerve fiber layer (cpRNFL) circle scans spectral-domain (SD)-OCT, standard automated perimetry (SAP), and frequency doubling technology (FDT) visual field tests were completed every 3 months for 2 years from a cohort of 28 healthy participants (56 eyes) and 93 glaucoma participants (179 eyes). RNFL thickness maps were extracted from segmented SS-OCT images and an unsupervised machine learning approach based on principal component analysis (PCA) was used to identify novel structural features. Area under the receiver operating characteristic curve (AUC) was used to assess diagnostic accuracy of RNFL PCA for detecting glaucoma and progression compared to SAP, FDT, and cpRNFL measures. Results:The RNFL PCA features were significantly associated with mean deviation (MD) in both SAP (R2 = 0.49, P < 0.0001) and FDT visual field testing (R2 = 0.48, P < 0.0001), and with mean circumpapillary RNFL thickness (cpRNFLt) from SD-OCT (R2 = 0.58, P < 0.0001). The identified features outperformed each of these measures in detecting glaucoma with an AUC of 0.95 for RNFL PCA compared to an 0.90 for mean cpRNFLt (P = 0.09), 0.86 for SAP MD (P = 0.034), and 0.83 for FDT MD (P = 0.021). Accuracy in predicting progression was also significantly higher for RNFL PCA compared to SAP MD, FDT MD, and mean cpRNFLt (P = 0.046, P = 0.007, and P = 0.044, respectively). Conclusions:A computational approach can identify structural features that improve glaucoma detection and progression prediction

Morphometric Optic Nerve Head Analysis in Glaucoma Patients: A Comparison between the Simultaneous Nonmydriatic Stereoscopic Fundus Camera (Kowa Nonmyd WX3D) and the Heidelberg Scanning Laser Ophthalmoscope (HRT III)

Purpose. To investigate the agreement between morphometric optic nerve head parameters assessed with the confocal laser ophthalmoscope HRT III and the stereoscopic fundus camera Kowa nonmyd WX3D retrospectively. Methods. Morphometric optic nerve head parameters of 40 eyes of 40 patients with primary open angle glaucoma were analyzed regarding their vertical cup-to-disc-ratio (CDR). Vertical CDR, disc area, cup volume, rim volume, and maximum cup depth were assessed with both devices by one examiner. Mean bias and limits of agreement (95% CI) were obtained using scatter plots and Bland-Altman analysis. Results. Overall vertical CDR comparison between HRT III and Kowa nonmyd WX3D measurements showed a mean difference (limits of agreement) of −0.06 (−0.36 to 0.24). For the CDR < 0.5 group (n=24) mean difference in vertical CDR was −0.14 (−0.34 to 0.06) and for the CDR ≥ 0.5 group (n=16) 0.06 (−0.21 to 0.34). Conclusion. This study showed a good agreement between Kowa nonmyd WX3D and HRT III with regard to widely used optic nerve head parameters in patients with glaucomatous optic neuropathy. However, data from Kowa nonmyd WX3D exhibited the tendency to measure larger CDR values than HRT III in the group with CDR < 0.5 group and lower CDR values in the group with CDR ≥ 0.5

A Clinico-Pathological Study of the Structural and Functional Changes in the Retina and Optic Nerve Following Diabetic Retinopathy Treatments

Diabetic retinopathy (DR) is the result of microvascular changes in the retina due to hyperglycemia which alter the blood-retinal barrier (BRB). The increased permeability of BRB results in the accumulation of extracellular fluid, the development of diabetic macular edema (DME) and capillary occlusion. Capillary occlusion results in retinal ischemia which increases vascular endothelial growth factor (VEGF) levels, increases vascular permeability and results in neovascularization in proliferative diabetic retinopathy (PDR) patients. The treatments clinically used for DR are panretinal photocoagulation (PRP) for PDR and injectable vascular endothelial growth factor inhibitors (anti-VEGFs) for DME. The safety of PRP and anti-VEGF therapy on the retina and optic nerve was evaluated in treatment-naïve DR patients by undergoing structural (OCT, HRT) and functional (visual field, visual acuity) diagnostic tests over a two year time period. Streptozotocin (STZ)-induced diabetic rats received different doses of intravitreal anti-VEGF injections to analyze the safety of VEGF inhibition on neuronal cells. Retinal cell cultures were exposed to different doses of anti-VEGF to assess metabolic activity, function and toxicity by colorimetric assays. This study found that patients treated with PRP, despite showing an improvement in peripheral perfusion, had a significant and progressive decline in peripheral vision. There was a discrepancy between the grading of the optic nerves post-PRP by ophthalmologists despite the absence of significant morphological changes. Anti-VEGF treatment was found to be potentially detrimental to the optic nerve by decreasing retinal nerve fiber layer thickness, increasing cup/disk ratio and cup volume over time. STZ-induced diabetic rats receiving intravitreal anti-VEGF injections had a dose-dependent increase in retinal ganglion cell death. Results from retinal cell cultures suggest that anti-VEGF treatment may be detrimental to the retina by decreasing cellular metabolic activity, and increasing cytotoxicity of retinal cells. Overall, PRP was relatively safe and improved peripheral perfusion but resulted in misdiagnosis of glaucoma based on non-morphological colouration changes of the optic nerve post-PRP. Anti-VEGF treatment appeared to be detrimental to the optic nerve by causing damage to retinal cells. In contrast to current recommendations, it is suggested to monitor both the retina and optic nerve status in patients undergoing frequent injections

Optic Nerve Head Image Analysis for Glaucoma Progression Detection

Glaucoma is a leading cause of visual disability across the world and when diagnosed the glaucoma patient will spend the rest of their life receiving treatment in managed clinical care. In the glaucoma clinic, retinal and optic nerve head (ONH) imaging can be used to help the clinician to manage patient treatment appropriately. By providing high resolution images of the optic nerve head structures and identifying changes therein related to disease onset and progression, an objective measure can be obtained as to how well or badly treatment is preventing further disease damage. This thesis contributes to the field of glaucoma progression detection by the analysis of clinical imaging data using confocal scanning laser tomography (CSLT). Primarily it is an investigation of how best to appraise and optimise current algorithms which aim to detect these glaucomatous structural changes in the optic nerve head. This is done by addressing how the performance of these methods can be best assessed in the absence of a gold standard for glaucomatous structural progression. Glaucoma expert assessment of photographs of the optic disc is the current clinical standard of assessing glaucomatous damage evident in the ONH. This is used in this thesis to act as a reference standard by which these algorithms can be compared. In addition, the statistical principles underpinning trend detection techniques are also investigated along with the performance of these techniques to detect trends in CSLT data in the presence of different types of measurement noise and image quality. A new computer model is developed and validated to simulate stable series of CSLT images, with realistic variability, which can be used to benchmark the false-positive rates of current and future progression algorithms. In conclusion, the main results reported in this thesis show that uncertainties involved in expert assessment of change in ONH photographs limits this as a reference standard for structural change in glaucoma. In addition, since stability in clinical datasets is uncertain, simulation using modelled series is shown to provide a new benchmark for comparing methods of progression detection

Stuctural and functional progression in glaucoma: some aspects

This thesis explored some aspects of the relationship between structural progression of the glaucomatous optic nerve head (ONH) and functional progression of the visual field. Sixty-one individuals with a longitudinal series of ONH images were manually identified from a database of approximately 2800 individuals attending a hospital glaucoma clinic. The ONH images obtained from the various photographic sources were equalized, for each individual, in terms of ONH size. Custom-software was designed to enable the viewing of consecutive and chronologically different ONH image-pairs under monoscopic and stereoscopic conditions, with and without sequential flicker. The efficacy, for the identification of progressive glaucomatous loss, amongst the 61 individuals, of the four viewing techniques was qualitatively evaluated by two ophthalmologists. Stereo-flicker identified the largest number of cases of progression, although little agreement was present between the two ophthalmologists. The digital characteristics of the ONH images from 27 of the 61 individuals enabled quantitative digital stereo-planimetry. A weak positive curvilinear association was present, at baseline, between the reduction in the neuroretinal rim area and the outcomes of perimetry, including residual retinal ganglion cell (RGC) count. However, little agreement was again present between the two ophthalmologists. Little association was present with either ophthalmologist between progressive structural damage and functional damage. A separate manual search of 1000 individuals with glaucoma archived in ‘Open eyes’ identified 112 individuals with a minimum of 5 visual field examinations over a minimum of 5 years. The outcomes at each stimulus location of the differential light sensitivity, expressed in decibels (dB), and of the residual RGC count, against time to follow-up, were compared using univariate linear regression analysis. In general, residual RGC count identified progression, in terms of a greater statistical significance and/ or of more stimulus locations, at an earlier stage of the disease than sensitivity expressed in dB

Expansion of retinal nerve fiber bundle narrowing in glaucoma: An adaptive optics scanning laser ophthalmoscopy study

Purpose: To investigate longitudinal changes in the retinal nerve fiber bundle in eyes with primary open angle glaucoma using adaptive optics scanning laser ophthalmoscopy. Methods: A prospective observational case series. Fourteen eyes from 12 patients with primary open angle glaucoma that exhibited retinal nerve fiber layer defects on fundus photography were imaged with adaptive optics scanning laser ophthalmoscopy over time. Results: The expansion of retinal nerve fiber bundle narrowing was observed on adaptive optics scanning laser ophthalmoscopy in 8 eyes (57.1%) over a period of 1.44 ± 0.42 years. Retinal nerve fiber bundle narrowing expanded horizontally in 2 eyes and vertically in 6 eyes. In 3 eyes, changes in the retinal nerve fiber layer were only detectable on adaptive optics scanning laser ophthalmoscopy images. Conclusions and Importance: The expansion of retinal nerve fiber bundle narrowing was observed using adaptive optics scanning laser ophthalmoscopy. Accordingly, this tool may be a useful tool for detecting glaucoma-related changes in retinal nerve fibers in a short time