Optic Disc and Fovea Localisation in Ultra-widefield Scanning Laser Ophthalmoscope Images Captured in Multiple Modalities

We propose a convolutional neural network for localising the centres of the optic disc (OD) and fovea in ultra-wide field of view scanning laser ophthalmoscope (UWFoV-SLO) images of the retina. Images captured in both reflectance and autofluorescence (AF) modes, and central pole and eyesteered gazes, were used. The method achieved an OD localisation accuracy of 99.4% within one OD radius, and fovea localisation accuracy of 99.1% within one OD radius on a test set comprising of 1790 images. The performance of fovea localisation in AF images was comparable to the variation between human annotators at this task. The laterality of the image (whether the image is of the left or right eye) was inferred from the OD and fovea coordinates with an accuracy of 99.9%

Multimodal imaging in age-related macular degeneration

Age-related macular degeneration (AMD) is a leading cause of blindness and affects approximately one in seven Australians aged 50 years and above. Currently, this complex condition is not easily and uniformly assessed. The signs of AMD differ between eyes and also occur in other macular disorders. This hinders accurate diagnosis and classification, which is fundamental to optimal patient care. Ocular imaging and visual function assessment have the potential to minimise the devastating consequences of disease through early detection. However, multiple devices are now commercially available and the impact of these technologies in clinical practice may not be straightforward. For instance, their usefulness may depend on accessibility and the operator’s knowledge and clinical skills. The impact on patient management, as well as alternative models of eye-care delivery, requires clarification. This thesis aims to explore the current and potential utility of imaging technologies (optical coherence tomography, infrared imaging, monochromatic retinal photography and fundus autofluorescence) in the assessment and management of AMD and other diseases of retinal pigment epithelium dysfunction. The findings show that optometrists self-describe high levels of practice competency and make ready use of imaging in everyday practice. However, they also unwittingly demonstrated low awareness of the evidence base in AMD. Furthermore, when their interpretation of images was tested using a series of case vignettes, their diagnostic accuracy as a group improved by only five per cent (from 61 per cent to 66 per cent); their tendency to refer increased by four per cent. These factors might be improved through education. A series of open-access, chair-side reference charts were consequently devised to help optometrists use imaging technologies more effectively in clinical practice. The additive contribution of multimodal structural and functional testing was particularly emphasised. Finally, a novel model of intermediate-tier eye-care in Australia was shown to substantially reduce the number of false positive cases or cases without a specific diagnosis. Interestingly, this model was acclaimed by reviewers as “scoring highly for originality and of international relevance”. Most excitingly, the thesis concludes with future directions regarding collaborative care and multimodal imaging, where detection of disease might be facilitated via a computational approach

Technological Advances in the Diagnosis and Management of Pigmented Fundus Tumours

Choroidal naevi are the most common intraocular tumour. They can be pigmented or non-pigmented and have a predilection for the posterior uvea. The majority remain undetected and cause no harm but are increasingly found on routine community optometry examinations. Rarely does a naevus demonstrate growth or the onset of suspicious features to fulfil the criteria for a malignant melanoma. Because of this very small risk, optometrists commonly refer these patients to hospital eye units for a second opinion, triggering specialist examination and investigation, causing significant anxiety to patients and stretching medical resources. This PhD thesis introduces the MOLES acronym and scoring system that has been devised to categorise the risk of malignancy in choroidal melanocytic tumours according to Mushroom tumour shape, Orange pigment, Large tumour size, Enlarging tumour and Subretinal fluid. This is a simplified system that can be used without sophisticated imaging, and hence its main utility lies in the screening of patients with choroidal pigmented lesions in the community and general ophthalmology clinics. Under this system, lesions were categorised by a scoring system as ‘common naevus’, ‘low-risk naevus’, ‘high-risk naevus’ and ‘probable melanoma.’ According to the sum total of the scores, the MOLES system correlates well with ocular oncologists’ final diagnosis. The PhD thesis also describes a model of managing such lesions in a virtual pathway, showing that images of choroidal naevi evaluated remotely using a decision-making algorithm by masked non-medical graders or masked ophthalmologists is safe. This work prospectively validates a virtual naevus clinic model focusing on patient safety as the primary consideration. The idea of a virtual naevus clinic as a fast, one-stop, streamlined and comprehensive service is attractive for patients and healthcare systems, including an optimised patient experience with reduced delays and inconvenience from repeated visits. A safe, standardised model ensures homogeneous management of cases, appropriate and prompt return of care closer to home to community-based optometrists. This research work and strategies, such as the MOLES scoring system for triage, could empower community-based providers to deliver management of benign choroidal naevi without referral to specialist units. Based on the positive outcome of this prospective study and the MOLES studies, a ‘Virtual Naevus Clinic’ has been designed and adapted at Moorfields Eye Hospital (MEH) to prove its feasibility as a response to the COVID-19 pandemic, and with the purpose of reducing in-hospital patient journey times and increasing the capacity of the naevus clinics, while providing safe and efficient clinical care for patients. This PhD chapter describes the design, pathways, and operating procedures for the digitally enabled naevus clinics in Moorfields Eye Hospital, including what this service provides and how it will be delivered and supported. The author will share the current experience and future plan. Finally, the PhD thesis will cover a chapter that discusses the potential role of artificial intelligence (AI) in differentiating benign choroidal naevus from choroidal melanoma. The published clinical and imaging risk factors for malignant transformation of choroidal naevus will be reviewed in the context of how AI applied to existing ophthalmic imaging systems might be able to determine features on medical images in an automated way. The thesis will include current knowledge to date and describe potential benefits, limitations and key issues that could arise with this technology in the ophthalmic field. Regulatory concerns will be addressed with possible solutions on how AI could be implemented in clinical practice and embedded into existing imaging technology with the potential to improve patient care and the diagnostic process. The PhD will also explore the feasibility of developed automated deep learning models and investigate the performance of these models in diagnosing choroidal naevomelanocytic lesions based on medical imaging, including colour fundus and autofluorescence fundus photographs. This research aimed to determine the sensitivity and specificity of an automated deep learning algorithm used for binary classification to differentiate choroidal melanomas from choroidal naevi and prove that a differentiation concept utilising a machine learning algorithm is feasible

Eye as a window to the brain: investigating the clinical utility of retinal imaging derived biomarkers in the phenotyping of neurodegenerative disease.

Background Neurodegenerative diseases, like multiple sclerosis, dementia and motor neurone disease, represent one of the major public health threats of our time. There is a clear persistent need for novel, affordable, and patient‐acceptable biomarkers of these diseases, to assist with diagnosis, prognosis and impact of interventions. And these biomarkers need to be sensitive, specific and precise. The retina is an attractive site for exploring this potential, as it is easily accessible to non‐invasive imaging. Remarkable technology revolutions in retinal imaging are enabling us to see the retina in microscopic level detail, and measure neuronal and vascular integrity. Aims and objectives I therefore propose that retinal imaging could provide reliable and accurate markers of these neurological diseases. In this project, I aimed to explore the clinical utility of retinal imaging derived measures of retinal neuronal and vessel size and morphology, and determine their candidacy for being reliable biomarkers in these diseases. I also aimed to detail the methods of retinal imaging acquisition, and processing, and the principles underlying all these stages, in relation to understanding of retinal structure and function. This provides an essential foundation to the application of retinal imaging analysis, highlighting both the strengths and potential weaknesses of retinal biomarkers and how they are interpreted. Methods After performing detailed systematic reviews and meta‐analyses of the existing work on retinal biomarkers of neurodegenerative disease, I carried out a prospective, controlled, cross‐sectional study of retinal image analysis, in patients with MS, dementia, and ALS. This involved developing new software for vessel analysis, to add value and maximise the data available from patient imaging episodes. Results From the systematic reviews, I identified key unanswered questions relating to the detailed analysis and utility of neuroretinal markers, and diseases with no studies yet performed of retinal biomarkers, such as non‐AD dementias. I recruited and imaged 961 participants over a two‐year period, and found clear patterns of significance in the phenotyping of MS, dementia and ALS. Detailed analysis has provided new insights into how the retina may yield important disease information for the individual patient, and also generate new hypotheses with relation to the disease pathophysiology itself. Conclusions Overall, the results show that retinal imaging derived biomarkers have an important and specific role in the phenotyping of neurodegenerative diseases, and support the hypothesis that the eye is an important window to neurological brain disease

Automatic extraction of retinal features to assist diagnosis of glaucoma disease

Glaucoma is a group of eye diseases that have common traits such as high eye pressure, damage to the Optic Nerve Head (ONH) and gradual vision loss. It affects the peripheral vision and eventually leads to blindness if left untreated. The current common methods of diagnosis of glaucoma are performed manually by the clinicians. Clinicians perform manual image operations such as change of contrast, zooming in zooming out etc to observe glaucoma related clinical indications. This type of diagnostic process is time consuming and subjective. With the advancement of image and vision computing, by automating steps in the diagnostic process, more patients can be screened and early treatment can be provided to prevent any or further loss of vision. The aim of this work is to develop a system called Glaucoma Detection Framework (GDF), which can automatically determine changes in retinal structures and imagebased pattern associated with glaucoma so as to assist the eye clinicians for glaucoma diagnosis in a timely and effective manner. In this work, several major contributions have been made towards the development of the automatic GDF consisting of the stages of preprocessing, optic disc and cup segmentation and regional image feature methods for classification between glaucoma and normal images. Firstly, in the preprocessing step, a retinal area detector based on superpixel classification model has been developed in order to automatically determine true retinal area from a Scanning Laser Ophthalmoscope (SLO) image. The retinal area detector can automatically extract artefacts out from the SLO image while preserving the computational effciency and avoiding over-segmentation of the artefacts. Localization of the ONH is one of the important steps towards the glaucoma analysis. A new weighted feature map approach has been proposed, which can enhance the region of ONH for accurate localization. For determining vasculature shift, which is one of glaucoma indications, we proposed the ONH cropped image based vasculature classification model to segment out the vasculature from the ONH cropped image. The ONH cropped image based vasculature classification model is developed in order to avoid misidentification of optic disc boundary and Peripapillary Atrophy (PPA) around the ONH of being a part of the vasculature area. Secondly, for automatic determination of optic disc and optic cup boundaries, a Point Edge Model (PEM), a Weighted Point Edge Model (WPEM) and a Region Classification Model (RCM) have been proposed. The RCM initially determines the optic disc region using the set of feature maps most suitable for the region classification whereas the PEM updates the contour using the force field of the feature maps with strong edge profile. The combination of PEM and RCM entitled Point Edge and Region Classification Model (PERCM) has significantly increased the accuracy of optic disc segmentation with respect to clinical annotations around optic disc. On the other hand, the WPEM determines the force field using the weighted feature maps calculated by the RCM for optic cup in order to enhance the optic cup region compared to rim area in the ONH. The combination of WPEM and RCM entitled Weighted Point Edge and Region Classification Model (WPERCM) can significantly enhance the accuracy of optic cup segmentation. Thirdly, this work proposes a Regional Image Features Model (RIFM) which can automatically perform classification between normal and glaucoma images on the basis of regional information. Different from the existing methods focusing on global features information only, our approach after optic disc localization and segmentation can automatically divide an image into five regions (i.e. optic disc or Optic Nerve Head (ONH) area, inferior (I), superior(S), nasal(N) and temporal(T)). These regions are usually used for diagnosis of glaucoma by clinicians through visual observation only. It then extracts image-based information such as textural, spatial and frequency based information so as to distinguish between normal and glaucoma images. The method provides a new way to identify glaucoma symptoms without determining any geometrical measurement associated with clinical indications glaucoma. Finally, we have accommodated clinical indications of glaucoma including the CDR, vasculature shift and neuroretinal rim loss with the RIFM classification and performed automatic classification between normal and glaucoma images. Since based on the clinical literature, no geometrical measurement is the guaranteed sign of glaucoma, the accommodation of the RIFM classification results with clinical indications of glaucoma can lead to more accurate classification between normal and glaucoma images. The proposed methods in this work have been tested against retinal image databases of 208 fundus images and 102 Scanning Laser Ophthalmoscope (SLO) images. These databases have been annotated by the clinicians around different anatomical structures associated with glaucoma as well as annotated with healthy or glaucomatous images. In fundus images, ONH cropped images have resolution varying from 300 to 900 whereas in SLO images, the resolution is 341 x 341. The accuracy of classification between normal and glaucoma images on fundus images and the SLO images is 94.93% and 98.03% respectively

The management of posterior vitreous detachment by an optometrist

Acute posterior vitreous detachment (PVD) is the most common cause of retinal detachment. The management of this condition can be variable and often undue reliance is placed upon associated signs and symptoms which can be a poor indicator of pathology. Optometrists undertake a number of extended roles, however involvement in vitreo-retinal sub-specialities appears to be limited. One objective was to directly compare an optometrist and ophthalmologist in the assessment of patients with PVD, for this a high level of agreement was found (95% sensitivity, 99% specificity, 0.94 kappa). A review of 1107 patients diagnosed with acute PVD that were re-evaluated in a PVD clinic a few weeks later was undertaken to determine whether such reviews are necessary. One-fifth of patients were found to have conditions undiagnosed at the initial assessment, overall 4% of patients had retinal breaks when examined in the PVD clinic and a total of 7% required further intervention. The sensitivity of fundus examination with +90D and 3-mirror lenses was 85-88% for detecting retinal breaks and 7-85% for pigment in the anterior vitreous for the presence of retinal breaks. Therefore patients with acute PVD should be examined by indirect ophthalmoscopy with indentation at the onset of PVD and 4-6 weeks later. The treatment of retinal breaks with laser retinopexy is performed by ophthalmologists with a primary success rate 54-85%. In a pioneering development, an optometrist undertaking this role achieved a comparable primary success rate (79%). Mid-vitreous opacities associated with PVD are described, and noted in 100% of eyes with PVD. The recognition of this sign is important in the diagnosis of PVD and retinal breaks. The importance of diagnostic imaging is also demonstrated, however the timing in relation to onset may be vital

Functional outcome of retinal oedema and its standard treatment

Macular oedema is a pathological condition of fluid accumulation in the retinal tissues. It is a nonspecific sign of several retinal diseases that in the long term can lead to permanent vision loss. The clinical aspect of macular oedema treatment and vision recovery is reduction of the amount of fluid accumulated in the retina. Due to its complex pathophysiological mechanism, macular oedema has proven challenging to manage. Many unanswered questions remain in the ophthalmology world on this subject. The development of recent diagnostic tools such as optical coherence tomography allows better understanding of the morphological changes in the retina. Now we are able to detect retinal oedema and characterise it by location, depth, and amount of fluid. Further, clinicians are now able to assess therapeutic response by examining the anatomical structures of the retina. Yet, with techniques offering objective accuracy, emerging reports have shown discrepancies between clinically examined visual acuity, anatomical changes of the retina, and patients’ self-reported visual ability. The presence of such discrepancies is also supported by the fact that results achieved by randomised clinical trials rarely align with results attained in real-world settings. Today, functional vision testing can be performed with several different methods including questionnaires, colour vision tests, reading speed tests, contrast sensitivity tests etc. Nevertheless, none of these methods are widely used in clinical settings, and their predictive capabilities have yet to be explored. Establishing precise methodology for functional vision testing is likely to provide better understanding of patients’ treatment response. This thesis aims to investigate the potential predictive capabilities of functional vision tests and to compare these capabilities with those of well-established, routine ophthalmic examinations such as visual acuity and retinal thickness tests. In the current research, I focused on the following functional examinations: the visual function questionnaire (VFQ- 25), reading speed testing, and testing of the contrast sensitivity of the macula area (examined by microperimetry). These techniques allowed very specific and sensitive testing of the functionality of the retina. In addition, I explored functional vision tests and their association to the routine ophthalmic tests and their ability to detect sub-clinical changes in vision. I believe further research in this area will offer better understanding of the functional vision changes in patients with macular oedema and potentially will help in improving visionrelated quality of life

A multifaceted approach to improving management of sight-threatening non-infectious uveitis: patient perspectives and disease phenotyping for individualised patient therapy

Non-infectious uveitis is a clinically heterogenous disease, which can cause chronic relapsing and remitting chorioretinal inflammation and vision loss. The disease is incurable but long-term clinical remission of inflammation may be induced with high dose ‘blockbuster’ systemic immunosuppression, which has multiple side effects. Personalised immunosuppressive therapy is currently not feasible, partly due to limitations in disease phenotyping. The aims of this thesis were to individualise management of patients with sight-threatening non-infectious uveitis by investigating: 1. Clinical phenotypes of two similar subtypes of sight-threatening non-infectious uveitis: multifocal choroiditis (MFC) and punctate inner choroidopathy (PIC). 2. Immunological phenotypes of patients with sight-threatening non-infectious uveitis. 3. Perspectives of patients with sight-threatening retinal disease. Clinical and imaging data from 343 eyes of 185 subjects with MFC and PIC were found have some significant differences, with PIC showing a greater predilection for young, myopic women and tendency to secondary choroidal neovascularisation. Fifty patients with intermediate uveitis, posterior uveitis and panuveitis and 10 control subjects were prospectively recruited for immunological analysis of blood samples. Patients in clinical remission had significantly higher levels of Treg, polarised towards TIGIT and T-bet, associated with higher serum cytokine levels of IL-10 of TGF-β, and significantly lower methylation levels at key Treg epigenetic sites, compared to active patients and controls. Qualitative data was collected from patients with sight-threatening retinal disease and used to design a pilot intervention to increase subjects’ capability and opportunity for healthy lifestyle change. Results suggest that the phenotyping of non-infectious uveitis could be improved and that immunological biomarkers could assist in disease management. The visual and psychosocial consequences of sight-threatening retinal disease may also be addressed with tailored behavioural interventions. These findings could improve management of patients with uveitis by supporting the transition towards a more individualised therapeutic approach

Proliferative Vitreoretinopathy; strategies to improve anatomical and visual outcomes

Proliferative vitreoretinopathy (PVR) is the most common cause of late anatomical failure of retinal detachment surgery. Efforts to modify this vitreoretinal scarring response have so far proved clinically unsuccessful, with surgical and visual outcomes remaining poor. This work is aimed at identifying strategies to improve outcomes in eyes at high risk of PVR development following open globe trauma (OGT), and those with established PVR disease. Two prospective clinical trials investigating the benefit of adjunctive corticosteroids in these two populations were conducted in a total of one hundred and eighty patients. Clinical and imaging data were collected over the course of approximately 3500 hospital attendances. The Adjunct in Ocular Trauma (AOT) Trial was a two year, pilot, single-centre prospective, participant and surgeon-masked randomized-controlled-clinical trial (RCT). Forty patients requiring vitrectomy surgery following OGT were randomized to either standard (control) or study treatment (adjuncts) in a 1:1 allocation ratio. Perioperatively, the adjunct group received intravitreal and subtenons triamcinolone acetonide, oral flurbiprofen and guttae prednisolone acetate 1%. The control group received standard care. Primary outcome was anatomical success at 6 months and showed similar results in anatomical success with 50% (10/20) in the adjunct group, compared to 47% (9/19) in the standard group (Odds Ratio 1.11, 95% Confidence Interval 0.316-3.904). Secondary outcomes included final visual acuity, occurrence of PVR, intraocular pressure (IOP) rise, number of operations and recruitment rate. Final median visual acuity was 31 ETDRS letters in the adjunct group compared to 25 ETDRS letters in the standard group. Other secondary outcomes were similar between the two groups. The hypothesis that an adjunctive slow-release dexamethasone implant (Ozurdex ®) could improve the outcomes of vitreoretinal surgery for established PVR was tested in the Ozurdex® in PVR Study. In this two year, single-centre prospective, participant and surgeon-masked RCT, 140 patients requiring vitrectomy surgery with silicone oil for retinal detachment with established PVR (Grade C) were randomized to either standard (control) or study treatment (adjunct) in a 1:1 allocation ratio. Intraoperatively, the adjunct group received an injection of 0.7mg of slow-release dexamethasone (Ozurdex) at the time of (a) vitrectomy surgery and (b) at silicone oil removal. The control group received standard care. Primary outcome measure was the proportion of patients with a stable retinal reattachment with removal of silicone oil without additional vitreoretinal surgical intervention at 6 months. Secondary outcomes included i) final visual acuity (median and ETDRS of 55 letters or better), ii) cystoid macular edema (CMO), foveal thickness and macular volume iii) development of overt PVR recurrence, iv) complete and posterior retinal reattachment, vi) tractional retinal detachment, vii) hypotony/raised IOP, viii) macula pucker/epiretinal membrane, ix) cataract, x) quality of life All 140 patients were recruited within 25 months of study commencement; 138 patients had primary outcome data. Primary outcome assessment showed similar results in anatomical success between the two groups (49.3% vs 46.3%, adjunct vs control, (Odds Ratio 0.89, 95% Confidence interval 0.46 – 1.74, p= 0.733). Mean visual acuity at 6 months was 38.3 ETDRS letters and 40.2 letters in the adjunct and control group respectively. Secondary anatomical outcomes (complete/posterior reattachment rates and PVR recurrence) were comparable between the two groups. Exploratory analysis suggested that the proportion of patients with cystoid macular oedema (CMO) or a foveal thickness of >300µm was lower in steroid-treated eyes compared to controls (42.7% and 47.6% vs 67.2% and 67.7%, respectively p= 0.004, p= 0.023). Cystoid macular oedema is a secondary cause of visual loss. At 6 months following successful surgery for PVR, eyes with evidence of external limiting membrane (ELM) disruption on Spectral Domain-Optical Coherence Tomography achieve a worse visual outcome than eyes where the ELM appears preserved (p=0.006). Provisional work using retinectomy specimens retrieved at the time of surgery in sixteen patients were studied aiming to isolate a population of Müller glia with stem cell characteristics (hMSC). This suggested that it is feasible to isolate a cell population of appropriate morphology of hMSCs, from eyes with advanced PVR. These cells survived up to ten weeks in culture but eventually terminally differentiate. The work in this thesis has shown that corticosteroids do not modify the vitreoretinal scarring response sufficiently to improve anatomical outcomes at 6 months. Further work is required to improve the outcome in eyes with PVR. Adopting visual acuity as a primary outcome, may be a plausible design in future vitreoretinal trials