Predict and Protect: Evaluating the Double-Layer Sign in Age-Related Macular Degeneration.

INTRODUCTION: Advanced age-related macular degeneration (AMD) is a major cause of vision loss. Therefore, there is interest in precursor lesions that may predict or prevent the onset of advanced AMD. One such lesion is a shallow separation of the retinal pigment epithelium (RPE) and Bruch's membrane (BM), which is described by various terms, including double-layer sign (DLS). METHODS: In this article, we aim to examine and clarify the different terms referring to shallow separation of the RPE and BM. We also review current evidence on the outcomes associated with DLS: firstly, whether DLS is predictive of exudative neovascular AMD; and secondly, whether DLS has potential protective properties against geographic atrophy. RESULTS: The range of terms used to describe a shallow separation of the RPE and BM reflects that DLS can present with different characteristics. While vascularised DLS appears to protect against atrophy but can progress to exudation, non-vascularised DLS is associated with an increased risk of atrophy. Optical coherence tomography (OCT) angiography (OCTA) is the principal method for identifying and differentiating various forms of DLS. If OCTA is unavailable or not practically possible, simplified classification of DLS as thick or thin, using OCT, enables the likelihood of vascularisation to be approximated. Research is ongoing to automate DLS detection by applying deep-learning algorithms to OCT scans. CONCLUSIONS: The term DLS remains applicable for describing shallow separation of the RPE and BM. Detection and classification of this feature provides valuable information regarding the risk of progression to advanced AMD. However, the appearance of DLS and its value in predicting AMD progression can vary between patients. With further research, individualised risks can be confirmed to inform appropriate treatment.

Age-related macular degeneration (AMD) is an eye disease that may develop in older people, usually those aged over 60 years. Early in the disease, people often do not show any symptoms, but as the disease progresses, vision loss may occur. The advanced forms of AMD are called neovascular AMD (also called "wet" AMD) and advanced dry AMD (called geographic atrophy; GA). It is important to identify features and signs on eye scans that can help to predict if someone with AMD will develop an advanced form of the disease because this will help doctors plan the most appropriate treatment. One such feature on eye scans is the double-layer sign (DLS). In this article, we summarise the different names used for DLS, and assess if having a DLS increases the likelihood of someone with early AMD developing wet AMD or GA. We conclude that how DLS looks varies between people, which leads to DLS being called by various names. Someone with early AMD and a DLS containing blood vessels may be more likely to develop wet AMD; whereas someone with early AMD and a DLS without blood vessels may be more likely to develop GA. Taking photos of the eye using optical coherence tomography angiography imaging is the main method of identifying DLS and confirming whether it contains blood vessels.

Transforming the future of ophthalmology: artificial intelligence and robotics' breakthrough role in surgical and medical retina advances: a mini review.

Over the past decade, artificial intelligence (AI) and its subfields, deep learning and machine learning, have become integral parts of ophthalmology, particularly in the field of ophthalmic imaging. A diverse array of algorithms has emerged to facilitate the automated diagnosis of numerous medical and surgical retinal conditions. The development of these algorithms necessitates extensive training using large datasets of retinal images. This approach has demonstrated a promising impact, especially in increasing accuracy of diagnosis for unspecialized clinicians for various diseases and in the area of telemedicine, where access to ophthalmological care is restricted. In parallel, robotic technology has made significant inroads into the medical field, including ophthalmology. The vast majority of research in the field of robotic surgery has been focused on anterior segment and vitreoretinal surgery. These systems offer potential improvements in accuracy and address issues such as hand tremors. However, widespread adoption faces hurdles, including the substantial costs associated with these systems and the steep learning curve for surgeons. These challenges currently constrain the broader implementation of robotic surgical systems in ophthalmology. This mini review discusses the current research and challenges, underscoring the limited yet growing implementation of AI and robotic systems in the field of retinal conditions.

Angioid Streaks Remain a Challenge in Diagnosis, Management, and Treatment.

Aim: Angioid streaks (ASs) are a rare retinal condition and compromise visual acuity when complicated with choroidal neovascularization (CNV). They represent crack-like dehiscences at the level of the Bruch's membrane. This objective narrative review aims to provide an overview of pathophysiology, current treatment modalities, and future perspectives on this condition. Materials and Methods: A literature search was performed using "PubMed", "Web of Science", "Scopus", "ScienceDirect", "Google Scholar", "medRxiv", and "bioRxiv." Results: ASs may be idiopathic, but they are also associated with systemic conditions, such as pseudoxanthoma elasticum, hereditary hemoglobinopathies, or Paget's disease. Currently, the main treatment is the use of anti-vascular endothelial growth factors (anti-VEGF) to treat secondary CNV, which is the major complication observed in this condition. If CNV is detected and treated promptly, patients with ASs have a good chance of maintaining functional vision. Other treatment modalities have been tried but have shown limited benefit and, therefore, have not managed to be more widely accepted. Conclusion: In summary, although there is no definitive cure yet, the use of anti-VEGF treatment for secondary CNV has provided the opportunity to maintain functional vision in individuals with AS, provided that CNV is detected and treated early.

Treatment of age-related macular degeneration with aflibercept using a treat, extend and fixed protocol; A 4-year study of treatment outcomes, durability, safety and quality of life (An extension to the MATE randomised controlled trial).

PURPOSE: Data are limited pertaining to the long-term benefits of aflibercept treatment for neovascular age-related macular degeneration (nAMD). The aim of this study was to provide outcomes, safety, durability and quality-of-life data with aflibercept using a modified treat, extend and fixed regime over 4 years. METHODS: Prospective, multicentre, single cohort observational study of treatment-naïve nAMD participants treated with aflibercept as 2-year extension of the MATE-trial that compared early and late Treat-and-Extend for 2 years. Refracted ETDRS best corrected visual acuity (BCVA), central retinal thickness (CRT), treatment interval and adverse events were assessed. Quality-of-life was measured using the Macular Disease Dependent Quality of Life (MacDQoL) and Macular Disease Treatment Satisfaction Questionnaires (MacTSQ). RESULTS: Twenty-six of 40 participants completing the MATE-trial were enrolled with 20 completing the total 4-year study. Mean BCVA was 60.7 at Month 0 and 64.8 ETDRS letters at Month 48 while CRT decreased from 423.7 µm to 292.2 µm. Five participants discontinued treatment due to inactivity. The mean number of treatments and visits for the remaining participants was 27 and 30.0, respectively, with treatment intervals extended to 12 weeks in four participants at Month 48. Both AMD-specific QoL and treatment satisfaction remained stable between Months 0 and 48 and mean BCVA significantly correlated with AMD-specific QoL scores at Months 12, 24 and 48. CONCLUSIONS: Results suggest that BCVA can be maintained over 48 months when following a treat-extend-and-fix regimen of aflibercept with intervals out to 12 weeks, while maintaining AMD-specific QoL and treatment satisfaction.

The Double Layer Sign Is Highly Predictive of Progression to Exudation in Age-Related Macular Degeneration.

PURPOSE: The presences of a double layer sign (DLS) and a shallow irregular retinal pigment epithelium (RPE) elevation (SIRE) were investigated using spectral domain-OCT (SD-OCT) imaging to determine their ability to predict progression to exudative macular neovascularization (eMNV) in the unaffected fellow eyes (study eye) of participants with age-related macular degeneration (AMD) with newly diagnosed unilateral eMNV. DESIGN: Retrospective, reanalysis of SD-OCT scans of study eyes from the Early Detection of Neovascular AMD (EDNA) study with 3 years follow-up (FU). PARTICIPANTS: The EDNA study repository of SD-OCT scans was assessed for inclusion. Cases with incomplete data sets, low quality scans, or exhibiting other pathology were excluded, which resulted in 459 eligible cases. METHODS: Spectral domain-OCT volume scans of study eyes were graded for irregular elevation of the RPE (IE), with length, and height measurements made on the most affected B-scan. Eyes with heterogeneous reflectivity within the IE were classified as exhibiting the DLS. Eyes with DLS where the length of separation between RPE and Bruch's membrane was ≥ 1000 µm in length and < 100 µm in height were subclassified as SIRE. MAIN OUTCOME MEASURES: Hazard of progression to eMNV for DLS and SIRE. RESULTS: Of the 459 eyes, 268 had IE, of which 101 were DLS-like and 51 also fulfilled criteria for SIRE. Over the 3 years FU period, 104 (23%) eyes progressed to eMNV. After an FU of 18 months, a significantly higher proportion of study eyes (P < 0.001) with IE, DLS, and SIRE developed eMNV compared with those without these features (IE: 17% vs. no IE 6.3%; DLS: 23% vs. no DLS 9.9%; SIRE: 22% vs. no SIRE 11%). In the adjusted Cox regression models, a significantly greater hazard of progression (P < 0.001) was associated with the presence of IE (adjusted hazard ratio [HR], 3.01; 95% confidence interval [CI], 1.88-4.82), DLS (adjusted HR, 3.41; 95% CI, 2.26-5.14), or SIRE (adjusted HR, 2.83; 95% CI, 1.68-4.75). CONCLUSION: The DLS is a highly sensitive predictor of progression to eMNV, and the use of SIRE does not improve predictability. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Tyrosine Kinase Inhibitors and their role in treating neovascular age-related macular degeneration and diabetic macular oedema.

The advent of intravitreal anti-VEGF injections has revolutionised the treatment of both neovascular age-related macular degeneration (nAMD or wet AMD) and diabetic macular oedema (DMO). Despite their efficacy, anti-VEGF injections precipitate significant treatment burden for patients, caregivers and healthcare systems due to the high frequency of injections required to sustain treatment benefit. Therefore, there remains an unmet need for lower-burden therapies. Tyrosine kinase inhibitors (TKI) are a novel class of drugs that may have considerable potential in addressing this issue. This review will summarise and discuss the results of various pilot studies and clinical trials exploring the role of TKIs in treatment of nAMD and DMO, highlighting promising candidates and possible challenges in developments.

The MATE trial: a multicentre, mixed-methodology, pilot, randomised controlled trial in neovascular age-related macular degeneration.

BACKGROUND/OBJECTIVES: In healthcare research investigating complex interventions, gaps in understanding of processes can be filled by using qualitative methods alongside a quantitative approach. The aim of this mixed-methods pilot trial was to provide feasibility evidence comparing two treatment regimens for neovascular age-related macular degeneration (nAMD) to inform a future large-scale randomised controlled trial (RCT). SUBJECTS/METHODS: Forty-four treatment-naïve nAMD patients were followed over 24 months and randomised to one of two treatment regimens: standard care (SC) or treat and extend (T&E). The primary objective evaluated feasibility of the MATE trial via evaluations of screening logs for recruitment rates, nonparticipation and screen fails, whilst qualitative in-depth interviews with key study staff evaluated the recruitment phase and running of the trial. The secondary objective assessed changes in visual acuity and central retinal thickness (CRT) between the two treatment arms. RESULTS: The overall recruitment rate was 3.07 participants per month with a 40.8% non-participation rate, 18.51% screen-failure rate and 15% withdrawal/non-completion rate. Key themes in the recruitment phase included human factors, protocol-related issues, recruitment processes and challenges. Both treatment regimens showed a trend towards a visual acuity gain at month 12 which was not maintained at month 24, whilst CRT reduced similarly in both regimens over the same time period. These were achieved with one less treatment following a T&E regimen. CONCLUSION: This mixed-methodology, pilot RCT achieved its pre-defined recruitment, nonparticipation and screen failure rates, thus deeming it a success. With some minor protocol amendments, progression to a large-scale RCT will be achievable.

Development of Macular Atrophy in Patients with Wet Age-Related Macular Degeneration Receiving Anti-VEGF Treatment.

Age-related macular degeneration (AMD) is a leading cause of blindness. Late AMD can be classified into exudative (commonly known as wet AMD [wAMD]) or dry AMD, both of which may progress to macular atrophy (MA). MA causes irreversible vision loss and currently has no approved pharmacological treatment. The standard of care for wAMD is treatment with anti-vascular endothelial growth factors (VEGFs). However, recent evidence suggests that anti-VEGF treatment may play a role in the development of MA. Therefore, it is important to identify risk factors for the development of MA in patients with wAMD. For example, excessive blockade of VEGF through intense use of anti-VEGF agents may accelerate the development of MA. Patients with type III macular neovascularization (retinal angiomatous proliferation) have a particularly high risk of MA. These patients are characterized as having a pre-existing thin choroid (age-related choroidopathy), suggesting that the choroidal circulation is unable to respond to increased VEGF expression. Evidence suggests that subretinal fluid (possibly indicative of residual VEGF activity) may play a protective role. Patients receiving anti-VEGF agents must be assessed for overall risk of MA, and there is an unmet medical need to prevent the development of MA without undertreating wAMD.

TANDEM TRIAL: a factorial randomised controlled trial of dose and review schedule of bevacizumab (Avastin) for neovascular macular degeneration in the East Midlands.

OBJECTIVE: Neovascular age-related macular degeneration (nAMD) causes damage to the macula and severe vision loss. Bevacizumab is the most cost-effective nAMD treatment. The TANDEM trial was designed to determine whether, in patients with nAMD, low-dose bevacizumab is non-inferior to the standard dose in terms of visual deterioration and whether a bimonthly regimen is non-inferior to monthly, treatment as required, regimens. METHODS: This was a multicentre, 2×2 factorial, double-masked, non-inferiority randomised trial with patients considered eligible if they met the National Institute for Health and Care Excellence criteria for nAMD treatment with ranibizumab. Participants were randomly assigned to standard (1.25 mg) or low (0.625 mg) dose bevacizumab and either monthly or bimonthly review regimen. The primary outcome was time to vision deterioration, defined as reduction of ≥15 letters (three lines) during the loading phase (visual acuity scores at visits B and C compared with the initial visit A), or ≥6 letters (one line) during the maintenance phase (visual acuity scores at subsequent visits compared with mean vision at visits A-C). RESULTS: In total 812 participants (918 eyes) were randomised into the trial. The low dose showed some evidence of being non-inferior to standard dose (HR 1.07; 95% CI 0.80 to 1.42), however, there was no strong evidence of bimonthly review being non-inferior to monthly review (HR 1.45; 95% CI 1.09 to 1.94). There was no difference in visual acuity when assessed at 9 months and no major differences in the frequency of serious adverse events or reactions between the groups. CONCLUSION: The standard dose of bevacizumab can be halved without compromising efficacy. Bimonthly review cannot be considered to be no worse than monthly review.

Long-term results of intravitreal bevacizumab and dexamethasone for the treatment of punctate inner choroidopathy associated with choroidal neovascularization: A case series.

INTRODUCTION: To present a case series of three female patients with punctate inner choroidopathy. We report the outcomes after an essentially long follow-up period of up to 14 years and provide evidence of the effectiveness of intravitreal injections of bevacizumab and dexamethasone 0.7 mg in punctate inner choroidopathy patients with choroidal neovascular membrane formation. CASE SERIES PRESENTATION: This is a retrospective case series of three female patients with punctate inner choroidopathy who were treated with intravitreal injections anti-vascular endothelial growth factor agent (bevacizumab, 1.25 mg/0.05 mL). Two patients also received intravitreal dexamethasone 0.7 mg. Once a choroidal neovascular membrane developed, the outcome was poor with a best-corrected visual acuity of 6/60 or counting fingers in the affected eyes. The patients were followed up for 5, 14 and 8 years. CONCLUSION: The use of dexamethasone 0.7 mg in punctate inner choroidopathy yielded encouraging results and long periods of stability. When choroidal neovascular membrane complicates the primary disease, the prognosis is unfavourable, especially if the macula integrity has already been considerably affected. On the contrary, aggressive early therapy and continued monthly monitoring can prevent severe fibrosis, as showed in previous reports. Further larger-scale studies are needed to evaluate the efficacy of intravitreal dexamethasone 0.7 mg and bevacizumab as an alternative treatment in non-infectious uveitis.

24-month clinical outcomes of a treat-and-extend regimen with ranibizumab for wet age-related macular degeneration in a real life setting.

BACKGROUND: To evaluate the clinical effectiveness and analyze the outcomes of a treat-and-extend (T&E) treatment regimen with ranibizumab for wet age-related macular degeneration (ARMD) in real life clinical settings over the first 2 years (24 months) of treatment. METHODS: Retrospective analysis of visual acuity, spectral domain optical coherence tomography (SD-OCT) parameters and treatment burden data of 56 eyes of 54 unselected treatment naive patients diagnosed with exudative ARMD. Monthly injections were offered until no signs of disease activity such as intra-retinal (IRF) or sub-retinal fluid (SRF) were evident on SD-OCT, followed by a gradual extension of the treatment interval by 2 weeks until a maximum of 12 weeks. RESULTS: The study met its main objective, demonstrating a mean best-corrected visual acuity gain of 8.3 letters (mean 68.8 ± 11) at month 12 and 5.2 letters (mean 65.7 ± 12.3) at 24 months compared to baseline (mean 60.5 ± 8.9). Anatomical improvement was also documented with a mean reduction of central retinal thickness by 139.7 µm at 24 months (244.9 ± 48.3) compared to baseline (384.6 ± 154.9). Forty-seven eyes (83.9% N = 56) gained vision or preserved baseline vision with 23 eyes (41.1%) gaining 10 letters or more at month 12. Out of the 46 eyes that completed 24 months of treatment and monitoring, 27 (58.7% N = 46) kept a BCVA above baseline with 18 of those (39% N = 46) maintaining a 10-letter gain throughout the 24 months. Six eyes (13% N = 46) lost more than 10 letters by month 24. The mean number of injections was 12.1 ± 2.8 over the 24-month period. Twenty-seven eyes (55.1% N = 56) achieved a treatment interval of 10 weeks or more at month 12, while the respective number at month 24 was 20 eyes (43.4% N = 46) in addition though to four more patients (8.7% N = 46) who were not receiving injections at month 24 since they were placed on a Monitor & Extend regime. CONCLUSIONS: This is the first UK real-life study of a T&E treatment protocol with ranibizumab for exudative ARMD in a 24-month period and suggests that such a regimen is clinically effective and can achieve favourable outcomes with a significant reduction of the treatment burden compared to monthly PRN.

SHORT-TERM FLUCTUATION OF MACULAR EDEMA IN A PATIENT DIAGNOSED EARLY WITH IDIOPATHIC MACULAR TELANGIECTASIA TYPE 1: FOLLOW-UP WITH SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY.

PURPOSE: To present a case of idiopathic macular telangiectasia Type 1, diagnosed at early stages and its close monitoring through spectral domain optical coherence tomography. METHODS: Case report. RESULTS: A case is presented of a 43-year-old man with blurred vision in his right eye and no further symptoms. The patient did not have any history of ophthalmic disease. Imaging test with fluorescein angiography confirmed a diagnosis of idiopathic macular telangiectasia Type 1. CONCLUSION: During a close follow-up period of 6 months, spectral domain optical coherence tomography demonstrated considerable fluctuations regarding his central retinal thickness (macular edema), presence of lipid exudates, and associated visual acuity loss.

Comparing different dosing regimens of bevacizumab in the treatment of neovascular macular degeneration: study protocol for a randomised controlled trial.

BACKGROUND: Bevacizumab (Avastin®) is as effective as ranibizumab (Lucentis®) in the treatment of neovascular age-related macular degeneration (nAMD). However it has two important structural differences. First, it has two active sites instead of one; second, it retains the Fc portion of the antibody which would be expected to confer a significantly longer half-life. These agents have been associated with systemic complications including strokes, so it is desirable to use the smallest effective dose. Furthermore, the standard dosing regimen requires monthly hospital visits, which present a significant challenge both to the hospital services and to the patients (who are elderly). METHODS/DESIGN: Patients ≥50 years who are eligible for anti-vascular endothelial growth factor (VEGF) treatment of nAMD in the NHS, who are either newly referred for treatment or have reactivation of nAMD and who have not received treatment to either eye for the previous six months. We have designed a factorial multi-centre masked randomised controlled trial using bevacizumab as the intervention, with patients randomised to one of four arms: to standard or low dose and to monthly or two-monthly patient review. The aim is to recruit sufficient patients (around 1,000) to obtain 304 patients meeting the endpoint over a four-year period. The primary endpoint is time to treatment failure to be analysed using Cox regression. DISCUSSION: This randomised control trial will show if half dose and two monthly as required is as effective as full dose and monthly regimes. A two monthly as required regimen of Bevacizumab would significantly reduce both the cost and the service delivery burden for the treatment of nAMD while a reduced dose would be expected to enhance the safety profile of this treatment regime. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number: ISRCTN95654194 , registered on 22 September 2009.