Management of neovascular age-related macular degeneration with ranibizumab: Long-term outcomes and second eye outcomes

Background: Intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents are the established standard of care for neovascular age related macular degeneration (nAMD), however there are currently limited data on long-term outcomes of this therapy. Ranibizumab is one such anti-VEGF agent administered to treat nAMD. Patients diagnosed with nAMD undergo regular clinic based follow-up as part of their treatment, often on a monthly basis. Assessment during these appointments includes optical coherence tomography (OCT) scans, which can contribute to the detection of nAMD in the second eye. There is limited data on the symptomatic status, clinical presentation and outcomes of second eye nAMD whilst undergoing regular assessment for the first treatment eye under these conditions. Aims: The first aim of this thesis is to evaluate the long-term (5-year) outcomes of intravitreal ranibizumab (an anti-VEGF agent) in treating nAMD by examining a cohort within a real life clinic setting. The second aim is to compare the clinical presentation and treatment outcomes between the first and second treated eyes in patients that developed nAMD in both eyes, whilst under regular review for unilateral nAMD. Methods: A total of 208 patients (208 eyes) were included in a retrospective case series assessing the 5-year outcomes of nAMD treated with ranibizumab, entitled the long-term ranibizumab study (LTRS) (Chapter 3). Intervention was an individualised treatment model after three initial monthly loading doses. Visual acuity (VA), central macular thickness (CMT), qualitative OCT features, and adverse events (AE) were determined for each visit. Snellen VA was converted to Early Treatment Diabetic Retinopathy Study (ETDRS) letters for analysis. To assess outcomes of second eyes diagnosed with nAMD, a retrospective case series entitled second-eye ranibizumab study (SERS) forms the second part of this thesis (Chapter 4). Forty-five consecutive patients fulfilled the inclusion criteria of commencing treatment with ranibizumab in the first eye for nAMD between July 2007 and March 2011,and subsequently developing nAMD in the second eye with at least 12-months of follow-up in each eye. Treatment was administered under the same conditions as the LTRS. Snellen VA was measured, and OCT examination of both eyes at each visit assessed the presence of intra-retinal fluid (IRF) and sub-retinal fluid (SRF). Patient reported symptoms were recorded at every clinic visit. Paired t-tests were used to assess changes in VA and CMT over the study duration of the LTRS and SERS and two sample t- tests were used to evaluate VA differences between groups. Changes in VA compared to baseline were classified into the three categories: stable VA (loss or gain of ≤15 letters), improved VA (gain of >15 letters), or worse VA (loss of >15 letters). Linear regression was used to assess the effects of age, gender, number of injections, previous treatment, medical history, medications, and baseline VA on both VA and CMT changes. Chi-square test or Fisher’s exact test were used to measure proportions of patients with visual stability and OCT fluid free status at 12-months in the SERS. Results: In the LTRS, mean VA improved by 1.9 letters after 1 year (p=0.020) and decreased by 2.4 letters over 5-years of the treatment (p=0.040). At the end of year 5, 11.1% (23/208) of patients improved VA by more than 15 letters and 68.8% (143/208) of patients had stable VA, while 20.2% (42/208) patients lost more than 15 letters. Patients with VA less than 35 letters (approximate Snellen VA 6/60) at baseline showed significant VA improvement after 5-years of treatment (mean increase 11.5 letters, p=0.01), whilst those that were between 70 and 85 letters (approximate Snellen VA 6/12 to 6/6) at baseline showed a mean decrease (-12.9 letters, p=76 letters, or Snellen VA approximately 6/9)) showed greater stability of vision at 12-months vs. first treated eyes (p=0.05). There was no significant difference in mean VA change between first and second treated eyes. The proportion of OCT - fluid free eyes was higher amongst second treated eyes compared with first treated eyes at 12-months (70% vs. 40%, p=0.02). Intra-retinal fluid (IRF) was seen in 54% of second treated eyes at baseline compared with 84% in first treated eyes (p=0.01). Symptoms were absent in 54% of second treated eyes at baseline. The most common symptoms were “blurred vision” (28% of all patients) and metamorphopsia (11% of all patients). Conclusions: The visual gains achieved were not as significant as clinical trials, likely reflecting the differences in inclusion criteria of patients, and less rigorous follow-up and treatment. Intravitreal ranibizumab was effective in maintaining vision in patients with nAMD and reducing macula thickness over 5-years using an individualised treatment regime in a real-world setting.. Ranibizumab is a safe drug to use over 5-years in a real-world clinical setting. In patients undergoing treatment for nAMD in the first eye, OCT screening of the second eye at each visit may be necessary to detect second eye nAMD in this at-risk population. A large proportion of patients are asymptomatic at diagnosis of second eye disease, and a significant proportion of patients were detected to have treatable subfoveal nAMD with OCT alone. Second eye disease detected and treated by such a protocol showed a lower rate of IRF at baseline, suggesting early detection had occurred. Second eyes showed a higher rate of fluid free status at 12-months compared to the first treated eye, suggesting that early detection and treatment led to improved anatomical outcomes, potentially explaining superior VA outcomes. Patients commencing treatment in their second eye with good VA had better visual outcomes compared to those with worse VA

UOLO - automatic object detection and segmentation in biomedical images

We propose UOLO, a novel framework for the simultaneous detection and segmentation of structures of interest in medical images. UOLO consists of an object segmentation module which intermediate abstract representations are processed and used as input for object detection. The resulting system is optimized simultaneously for detecting a class of objects and segmenting an optionally different class of structures. UOLO is trained on a set of bounding boxes enclosing the objects to detect, as well as pixel-wise segmentation information, when available. A new loss function is devised, taking into account whether a reference segmentation is accessible for each training image, in order to suitably backpropagate the error. We validate UOLO on the task of simultaneous optic disc (OD) detection, fovea detection, and OD segmentation from retinal images, achieving state-of-the-art performance on public datasets.Comment: Publised on DLMIA 2018. Licensed under the Creative Commons CC-BY-NC-ND 4.0 license: http://creativecommons.org/licenses/by-nc-nd/4.0

Improving the economic value of photographic screening for optical coherence tomography-detectable macular oedema : a prospective, multicentre, UK study

Peer reviewedPublisher PD

The role of standard automated perimetry in age-related macular degeneration

Standard automated perimetry (SAP) is a well-established test of visual function, Goldmann size III (GIII) being the standard stimulus size used. Studies have shown that using GIII across the visual field (VF) may however result in lower separability between normals and those with optic nerve disease, as loss of visual function is greater within complete spatial summation. In contrast, GII operates largely within complete spatial summation for most of the conventional VF test grid thus may perform better than GIII in detecting visual function loss, particularly in optic nerve disease. It is not known if a similar issue is present when SAP is used to assess age-related macular degeneration (AMD), which exhibits abnormal sensitivity measurements in the central VF. Reports on the use of SAP in AMD however are limited. Understanding of the normal spatial summation characteristics of the central VF is also unclear. This thesis measured contrast sensitivity in the central 20° VF using GIII and other Goldmann stimulus sizes in normal and AMD cohorts. From this, it was found that GIII did not operate within complete spatial summation in the central 20° VF whereas GI and GII did. Thus they may be more suitable for testing this region. An additional surprising finding was that the AMD cohort showed increased sensitivity with GV relative to normals, also suggesting large stimulus sizes may be useful in assessing early to intermediate AMD. This thesis also explored the use of contrast sensitivity isocontours (CSIs) in reducing test variability. CSIs are groups of test locations with statistically similar sensitivities identified by pattern recognition. This thesis established normal CSIs within the central 20° VF and showed that CSI guided analysis returned a greater defect depth than standard clinical pointwise analysis in assessing the AMD cohort, suggesting that CSIs may be useful in minimising test variability in SAP. The outcomes of this thesis may provide guidance in devising an optimum test paradigm and analysis technique for assessing AMD. This work may also aid future studies investigating function-structure correlation in AMD and developing a better understanding of the overall functional characteristics of the central 20° VF

End-to-End Fovea Localisation in Colour Fundus Images with a Hierarchical Deep Regression Network

Accurately locating the fovea is a prerequisite for developing computer aided diagnosis (CAD) of retinal diseases. In colour fundus images of the retina, the fovea is a fuzzy region lacking prominent visual features and this makes it difficult to directly locate the fovea. While traditional methods rely on explicitly extracting image features from the surrounding structures such as the optic disc and various vessels to infer the position of the fovea, deep learning based regression technique can implicitly model the relation between the fovea and other nearby anatomical structures to determine the location of the fovea in an end-to-end fashion. Although promising, using deep learning for fovea localisation also has many unsolved challenges. In this paper, we present a new end-to-end fovea localisation method based on a hierarchical coarse-to-fine deep regression neural network. The innovative features of the new method include a multi-scale feature fusion technique and a self-attention technique to exploit location, semantic, and contextual information in an integrated framework, a multi-field-of-view (multi-FOV) feature fusion technique for context-aware feature learning and a Gaussian-shiftcropping method for augmenting effective training data. We present extensive experimental results on two public databases and show that our new method achieved state of- the-art performances. We also present a comprehensive ablation study and analysis to demonstrate the technical soundness and effectiveness of the overall framework and its various constituent components

Clinical outcomes of ranibizumab treatment in diabetic eye disease

Background: The vascular endothelial growth factor (VEGF) inhibitor ranibizumab is emerging as an efficacious treatment for diabetic macular oedema. Large clinical trials have shown improvements in visual acuity and reduced central retinal thickness. Details of its effect on other retinal functional parameters are lacking. There is a concern that repeated ranibizumab treatment could exacerbate macular ischaemia or lead to global retinal dysfunction by inhibiting physiological isoforms of VEGF. Outcomes of surgery for advanced proliferative retinopathy remain variable and post-operative complications including recurrent haemorrhage can limit visual recovery. VEGF is strongly implicated in the pathogenesis of advanced retinopathy, so VEGF inhibition prior to surgery may improve outcomes. Trials have failed to demonstrate a clear benefit for bevacizumab, so investigation of the licensed intraocular agent ranibizumab represents a logical next step. Aims: To investigate the effects of ranibizumab and laser treatment in diabetic macular oedema on the following parameters: visual acuity, protan and tritan colour contrast sensitivity, 4° and 12° macular sensitivity by microperimetry, electrophysiological indices from pattern and full field electroretinograms. To report structural retinal changes following ranibizumab and laser treatment in terms of qualitative and quantitative optical coherence tomography outcomes, and to quantify macular ischaemia by fluorescein angiography. To investigate the effect on visual acuity at three months post-surgery of ranibizumab pre-treatment in patients undergoing vitrectomy for advanced proliferative diabetic retinopathy. Methods: Randomised clinical trial of intravitreal ranibizumab vs. laser in 36 subjects with centre-involving diabetic macular oedema (The LUCIDATE study). Randomised clinical trial of pre-operative intravitreal ranibizumab vs. subconjunctival saline injection in 30 subjects undergoing vitrectomy-delamination for advanced proliferative diabetic retinopathy (The RaDiVit study). Results: Thirty six subjects with diabetic macular oedema were recruited and 33 completed the trial. Ranibizumab treated subjects gained a mean of 6 letters compared with 0.9 letter loss for laser at 48 weeks. Retinal sensitivity improved in the central macular 4° and 12° in both groups but to a greater extent with ranibizumab. There was no evidence of worsening global retinal dysfunction by electroretinograms in either group. Retinal thickness decreased in both groups: there was a 132 µm reduction in central macular thickness with ranibizumab compared with 103 µm for laser. Fluorescein angiography showed no evidence of significantly increased macular ischaemia in either group. Thirty subjects with advanced proliferative diabetic retinopathy were recruited, underwent surgery, and completed the study. At three months post-surgery, visual acuity in the ranibizumab group was 53 letters compared with 47 letters in the control group. Conclusion: In diabetic macular oedema, there is evidence that ranibizumab leads to greater improvements in visual acuity and retinal sensitivity than laser, with a corresponding greater reduction in retinal thickness. There is no evidence that it worsens macular ischaemia or indices of global retinal electrophysiological function, but larger trials designed to address each of the outcomes investigated here would be required to confirm these findings. In proliferative diabetic retinopathy, there is evidence from this small pilot study that ranibizumab treatment leads to better visual acuity at 3 months post-surgery. An appropriately powered trial would be required to confirm this

Loss of chromatic sensitivity in patients with age-related maculopathy - correlation with structural changes in the retina

Purpose: To assess colour vision in Age-related macular degeneration (AMD) while relating chromatic sensitivity to the severity of AMD and AMD morphologies such as drusen and reticular pseudodrusen. To evaluate if chromatic functional loss precedes structural changes in initial stages of AMD, and if it can be a valuable risk stratification tool for advanced AMD. Methods: Chromatic sensitivity was tested using the Colour Assessment and Diagnosis (CAD) test developed by City, University of London and correlated to the structural changes from fundus photography and spectral domain OCT. All patients were asymptomatic with a visual acuity of 6/12 or better. CAD thresholds were compared to clinical classification in all AMD eyes (Ferris et al., 2013); Soft drusen and Reticular drusen (RPD); Central macular thickness (CMT); Fundus autofluorescence (FAF) pattern (Einbock et al., 2005; Wong et al., 2014) and Soft drusen characteristics (Bird et al., 1995). Cases of conversion to ‘Wet’ AMD were identified through a repeat clinical assessment after the first 12 months. Chromatic sensitivity in early onset drusen (EOD) included comparing their colour thresholds to AMD eyes. Student t-test were used for correlation and P200 μm was statistically significant with P<0.01 for RG and <0.002 for YB. Review of baseline CAD thresholds in cases converted to wet AMD at the end of 12 months, revealed six eyes had converted to wet AMD. The baseline CAD thresholds of these eyes were not conclusive of being predictive of the impending change to wet AMD. Conclusions: The visual acuity and hence the integrity of cone photoreceptors remains relatively unaffected in early and intermediate stages of AMD. The processing of cone signals in the retina can however be heavily disrupted with subsequent loss of both YB and RG chromatic sensitivity in the eyes. The greatest losses relate to eyes with reticular pseudodrusen. Chromatic sensitivity change was indicative in early macular thinning but failed to herald the onset of wet AMD in our study sample

En face OCT imaging for the assessment of glaucoma

Glaucoma is a leading cause of irreversible vision loss globally, and demands early and accurate diagnosis. OCT has become a key investigative technique in glaucoma, and, although it provides invaluable clinical support, detection of early glaucoma remains imperfect. Recent OCT developments enabled direct assessment of retinal nerve fibre bundle (RNFB) reflectance in en face OCT images. The technique has considerable potential in the assessment of glaucoma, yet it has limited clinical usability due to an incomplete understanding of RNFB features in healthy and glaucoma eyes and the lack of accepted methods to identify reflectance defects. This thesis aimed to better understand characteristics of RNFB reflectance in en face OCT imaging and to develop objective methods to extract defects in this domain. Structural and functional measures of glaucoma changes were collected in eyes with established glaucoma and age-similar controls. Results showed that the healthy configuration of RNFB varies across the retina and between different eyes. We developed a method for automated and objective examination of reflectivity changes in en face images. This method considers individual anatomy and varying RNFB configuration, and found more abnormalities than previous approaches. Measures of en face reflectance and conventional retinal nerve fibre layer thickness were strongly related. The agreement between changes of reflectance and visual function was moderate-to-good, and both testing domains presented concordant abnormalities in all tested eyes. Following further minimisation of artefacts in en face images, direct use of reflectance analysis or its combination with perimetry appear viable and with significant potential for clinical examination of glaucoma