Ranibizumab 0.5 mg for Diabetic Macular Edema with Bimonthly Monitoring after a Phase of Initial Treatment: 18-Month, Multicenter, Phase IIIB RELIGHT Study.

PURPOSE: To evaluate ranibizumab 0.5 mg using bimonthly monitoring and individualized re-treatment after monthly follow-up for 6 months in patients with visual impairment due to diabetic macular edema (DME). DESIGN: A phase IIIb, 18-month, prospective, open-label, multicenter, single-arm study in the United Kingdom. PARTICIPANTS: Participants (N = 109) with visual impairment due to DME. METHODS: Participants received 3 initial monthly ranibizumab 0.5 mg injections (day 0 to month 2), followed by individualized best-corrected visual acuity (BCVA) and optical coherence tomography-guided re-treatment with monthly (months 3-5) and subsequent bimonthly follow-up (months 6-18). Laser was allowed after month 6. MAIN OUTCOME MEASURES: Mean change in BCVA from baseline to month 12 (primary end point), mean change in BCVA and central retinal thickness (CRT) from baseline to month 18, gain of ≥10 and ≥15 letters, treatment exposure, and incidence of adverse events over 18 months. RESULTS: Of 109 participants, 100 (91.7%) and 99 (90.8%) completed the 12 and 18 months of the study, respectively. The mean age was 63.7 years, the mean duration of DME was 40 months, and 77.1% of the participants had received prior laser treatment (study eye). At baseline, mean BCVA was 62.9 letters, 20% of patients had a baseline BCVA of >73 letters, and mean baseline CRT was 418.1 µm, with 32% of patients having a baseline CRT <300 µm. The mean change in BCVA from baseline to month 6 was +6.6 letters (95% confidence interval [CI], 4.9-8.3), and after institution of bimonthly treatment the mean change in BCVA at month 12 was +4.8 letters (95% CI, 2.9-6.7; P < 0.001) and +6.5 letters (95% CI, 4.2-8.8) at month 18. The proportion of participants gaining ≥10 and ≥15 letters was 24.8% and 13.8% at month 12 and 34.9% and 19.3% at month 18, respectively. Participants received a mean of 6.8 and 8.5 injections over 12 and 18 months, respectively. No new ocular or nonocular safety findings were observed during the study. CONCLUSIONS: The BCVA gain achieved in the initial 6-month treatment period was maintained with an additional 12 months of bimonthly ranibizumab PRN treatment.

Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus.

Idiopathic congenital nystagmus is characterized by involuntary, periodic, predominantly horizontal oscillations of both eyes. We identified 22 mutations in FRMD7 in 26 families with X-linked idiopathic congenital nystagmus. Screening of 42 singleton cases of idiopathic congenital nystagmus (28 male, 14 females) yielded three mutations (7%). We found restricted expression of FRMD7 in human embryonic brain and developing neural retina, suggesting a specific role in the control of eye movement and gaze stability.

An eye on equity: faricimab-driven health equity improvements in diabetic macular oedema using a distributional cost-effectiveness analysis from a UK societal perspective.

BACKGROUND/OBJECTIVES: Diabetic macular oedema (DMO) is a leading cause of blindness in developed countries, with significant disease burden associated with socio-economic deprivation. Distributional cost-effectiveness analysis (DCEA) allows evaluation of health equity impacts of interventions, estimation of how health outcomes and costs are distributed in the population, and assessments of potential trade-offs between health maximisation and equity. We conducted an aggregate DCEA to determine the equity impact of faricimab. METHODS: Data on health outcomes and costs were derived from a cost-effectiveness model of faricimab compared with ranibizumab, aflibercept and off-label bevacizumab using a societal perspective in the base case and a healthcare payer perspective in scenario analysis. Health gains and health opportunity costs were distributed across socio-economic subgroups. Health and equity impacts, measured using the Atkinson inequality index, were assessed visually on an equity-efficiency impact plane and combined into a measure of societal welfare. RESULTS: At an opportunity cost threshold of £20,000/quality-adjusted life year (QALY), faricimab displayed an increase in net health benefits against all comparators and was found to improve equity. The equity impact increased the greater the concerns for reducing health inequalities over maximising population health. Using a healthcare payer perspective, faricimab was equity improving in most scenarios. CONCLUSIONS: Long-acting therapies with fewer injections, such as faricimab, may reduce costs, improve health outcomes and increase health equity. Extended economic evaluation frameworks capturing additional value elements, such as DCEA, enable a more comprehensive valuation of interventions, which is of relevance to decision-makers, healthcare professionals and patients.

Improved Structure and Function in Early-Detected Second-Eye Neovascular Age-Related Macular Degeneration: FASBAT/Early Detection of Neovascular Age-Related Macular Degeneration Report 1.

PURPOSE: Visual acuity (VA) and structural biomarker assessment before and 24-months after early detection and routine treatment of second-eye involvement with neovascular age-related macular degeneration (nAMD) and additional comparison with the first eye affected. DESIGN: Prospective, 22-center observational study of participants with unilateral nAMD in the Early Detection of Neovascular AMD (EDNA) study, coenrolled into the Observing Fibrosis, Macular Atrophy and Subretinal Highly Reflective Material, Before and After Intervention with anti-VEGF Treatment (FASBAT) study for an additional 2-year follow-up. PARTICIPANTS: Older adults (> 50 years) with new onset nAMD in the first eye. METHODS: Assessment of both eyes with OCT, color fundus photography (CFP), clinic-measured VA, and quality of life (QoL). MAIN OUTCOME MEASURES: Prevalence of atrophy, subretinal hyperreflective material (SHRM), intraretinal fluid (IRF), subretinal fluid (SRF), and changes in VA over the study duration in both the first and second eyes affected with nAMD. Composite QoL scores over time. RESULTS: Of 431 participants recruited to the FASBAT study, the second eye converted to nAMD in 100 participants at a mean of 18.9 months. Visual acuity was 18 letters better at the time of early diagnosis in the second eye compared with conventional diagnosis in the first eye (72.9 vs. 55.6 letters). Visual acuity remained better in the second eye 24.9 months postconversion, at 69.5 letters compared with 59.7 letters at a similar matched time point in the first eye (18.9 months). A greater proportion of participants had vision > 70 letters in the second eye versus the first eye, 24.9 months postconversion (61 vs. 35). Prevalence of SHRM and IRF was lower in the second eye compared with the first eye 24.9 months postconversion. However, SRF prevalence was greater in the second eye 24.9 months postconversion. The development and progression of total area of atrophy appears similar in both eyes. Mean composite QoL scores increased over time, with a significant correlation between VA for the second eye only 24.9 months postconversion. CONCLUSION: This study has shown that early detection of exudative AMD in the second eye is associated with reduced prevalence of SHRM and IRF and greater VA, which is significantly correlated with maintained QoL. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

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 UK clinical eye research strategy: refreshing research priorities for clinical eye research in the UK.

OBJECTIVES: To validate and update the 2013 James Lind Alliance (JLA) Sight Loss and Vision Priority Setting Partnership (PSP)'s research priorities for Ophthalmology, as part of the UK Clinical Eye Research Strategy. METHODS: Twelve ophthalmology research themes were identified from the JLA report. They were allocated to five Clinical Study Groups of diverse stakeholders who reviewed the top 10 research priorities for each theme. Using an online survey (April 2021-February 2023), respondents were invited to complete one or more of nine subspecialty surveys. Respondents indicated which of the research questions they considered important and subsequently ranked them. RESULTS: In total, 2240 people responded to the survey (mean age, 59.3 years), from across the UK. 68.1% were female. 68.2% were patients, 22.3% healthcare professionals or vision researchers, 7.1% carers, and 2.1% were charity support workers. Highest ranked questions by subspecialty: Cataract (prevention), Cornea (improving microbial keratitis treatment), Optometric (impact of integration of ophthalmic primary and secondary care via community optometric care pathways), Refractive (factors influencing development and/or progression of refractive error), Childhood onset (improving early detection of visual disorders), Glaucoma (effective and improved treatments), Neuro-ophthalmology (improvements in prevention, diagnosis and treatment of neurodegeneration affecting vision), Retina (improving prevention, diagnosis and treatment of dry age-related macular degeneration), Uveitis (effective treatments for ocular and orbital inflammatory diseases). CONCLUSIONS: A decade after the initial PSP, the results refocus the most important research questions for each subspecialty, and prime targeted research proposals within Ophthalmology, a chronically underfunded specialty given the substantial burden of disability caused by eye disease.

Optical coherence tomography imaging biomarkers associated with neovascular age-related macular degeneration: a systematic review.

The aim of this systematic literature review is twofold, (1) detail the impact of retinal biomarkers identifiable via optical coherence tomography (OCT) on disease progression and response to treatment in neovascular age-related macular degeneration (nAMD) and (2) establish which biomarkers are currently identifiable by artificial intelligence (AI) models and the utilisation of this technology. Following the PRISMA guidelines, PubMed was searched for peer-reviewed publications dated between January 2016 and January 2022. POPULATION: Patients diagnosed with nAMD with OCT imaging. SETTINGS: Comparable settings to NHS hospitals. STUDY DESIGNS: Randomised controlled trials, prospective/retrospective cohort studies and review articles. From 228 articles, 130 were full-text reviewed, 50 were removed for falling outside the scope of this review with 10 added from the author's inventory, resulting in the inclusion of 90 articles. From 9 biomarkers identified; intraretinal fluid (IRF), subretinal fluid, pigment epithelial detachment, subretinal hyperreflective material (SHRM), retinal pigmental epithelial (RPE) atrophy, drusen, outer retinal tabulation (ORT), hyperreflective foci (HF) and retinal thickness, 5 are considered pertinent to nAMD disease progression; IRF, SHRM, drusen, ORT and HF. A number of these biomarkers can be classified using current AI models. Significant retinal biomarkers pertinent to disease activity and progression in nAMD are identifiable via OCT; IRF being the most important in terms of the significant impact on visual outcome. Incorporating AI into ophthalmology practice is a promising advancement towards automated and reproducible analyses of OCT data with the ability to diagnose disease and predict future disease conversion. SYSTEMATIC REVIEW REGISTRATION: This review has been registered with PROSPERO (registration ID: CRD42021233200).

The management of neovascular age-related macular degeneration: A systematic literature review of patient-reported outcomes, patient mental health and caregiver burden.

PURPOSE: The aim of this systematic literature review was to describe patient-reported outcomes, mental health and caregiver burden in patients with neovascular age-related macular degeneration (nAMD) treated with anti-vascular endothelial growth factor (VEGF) agents in routine clinical practice. METHODS: Electronic searches were conducted in Embase and MEDLINE according to pre-defined criteria. RESULTS: Of 856 records identified, 63 met inclusion criteria. Depression or depressive symptoms were reported in up to 42% of patients with nAMD. Of 25/63 (40%) studies evaluating quality of life (QoL) and using various tools, eight studies reported composite National Eye Institute Visual Functioning Questionnaire scores following anti-VEGF treatment. Of these, seven reported a statistically significant improvement at the earliest time point measured (Month 3-12) and approximately 50% reported sustained QoL benefits at 12 months. In studies comparing the attributed or different regimens, the most important factor from the patient's perspective was the likelihood that a particular regimen would maintain vision. There was a preference towards treat and extend, which was associated with a perceived reduction in patient and caregiver burden, compared to fixed dosing. CONCLUSIONS: A coordinated holistic approach to patient care is key to optimizing patient well-being as well as visual outcomes. Further research regarding the patient-reported impact of nAMD management outside the trial setting (particularly international longitudinal studies) is warranted. Standardization of QoL studies would assist in establishing whether sustained QoL improvement, rather than prevention of QoL decline, should be a realistic expectation of treatment of nAMD in the longer term.

Assessing the structure of the posterior visual pathway in bilateral macular degeneration.

Macular degeneration (MD) embodies a collection of disorders causing a progressive loss of central vision. Cross-sectional MRI studies have revealed structural changes in the grey and white matter in the posterior visual pathway in MD but there remains a need to understand how such changes progress over time. To that end we assessed the posterior pathway, characterising the visual cortex and optic radiations over a ~ 2-year period in MD patients and controls. We performed cross-sectional and longitudinal analysis of the former. Reduced cortical thickness and white matter integrity were observed in patients compared to controls, replicating previous findings. While faster, neither the rate of thinning in visual cortex nor the reduction in white matter integrity during the ~ 2-year period reached significance. We also measured cortical myelin density; cross-sectional data showed this was higher in patients than controls, likely as a result of greater thinning of non-myelinated tissue in patients. However, we also found evidence of a greater rate of loss of myelin density in the occipital pole in the patient group indicating that the posterior visual pathway is at risk in established MD. Taken together, our results revealed a broad decline in grey and white matter in the posterior visual pathway in bilateral MD; cortical thickness and fractional anisotropy show hints of an accelerated rate of loss also, with larger effects emerging in the occipital pole.

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.

Cortical Atrophy Predicts Visual Performance in Long-Term Central Retinal Disease; GCL, pRNFL and Cortical Thickness Are Key Biomarkers.

Purpose: The aim of this study was to assess both retinal and cortical structure in a cohort of patients with long-term acquired central retinal disease in order to identify potential disease biomarkers and to explore the relationship between the anterior and posterior visual pathways. Methods: Fourteen participants diagnosed with long-term central retinal disease underwent structural assessments of the retina using spectral-domain optical coherence tomography, including macular ganglion cell layer (GCL) and peripapillary retinal nerve fiber layer (pRNFL) thickness. Structural magnetic resonance imaging was used to measure visual cortex, including cortical volume of the entire occipital lobe and cortical thickness of the occipital pole and calcarine sulcus, representing the central and peripheral retina, respectively. Results: Mean thickness was significantly reduced in both the macular GCL and the inferior temporal pRNFL across patients. Cortical thickness was significantly reduced in both the occipital pole and calcarine sulcus, representing the central and peripheral retina, respectively. Disease duration significantly correlated with GCL thickness with a large effect size, whereas a medium effect size suggests the possibility that cortical thickness in the occipital pole may correlate with visual acuity. Conclusions: Long-term central retinal disease is associated with significant structural changes to both the retina and the brain. Exploratory analysis suggests that monitoring GCL thickness may be a sensitive biomarker of disease progression and reductions in visual cortical thickness may be associated with reduced visual acuity. Although this study is limited by its heterogeneous population, larger cohort studies would be needed to better establish some of the relationships detected between disease dependent structural properties of the anterior and posterior visual pathway given the effect sizes reported in our exploratory analysis.

An Introduction to Biosimilars for the Treatment of Retinal Diseases: A Narrative Review.

Biological therapies have revolutionized the treatment of disease across a number of therapeutic areas including retinal diseases. However, on occasion, such treatments may be relatively more expensive compared to small molecule therapies. This can restrict patient access and treatment length leading to suboptimal clinical outcomes. Several biosimilar candidates of ranibizumab and aflibercept are currently in development and the first biosimilar of ranibizumab received EMA approval in August and FDA approval in September 2021. Biosimilars are biological medicines that are highly similar to an already-approved biological medicine (reference product). The physicochemical and clinical similarity of a biosimilar is determined by a rigorous analytical and clinical program, including extensive pharmacokinetic and pharmacodynamic analysis with phase III equivalence studies where appropriate. These phase III studies are carried out in a patient population that is representative of all of the potential approved therapeutic indications of the originator product and the most sensitive for detecting potential differences between the biosimilar and the reference product. Biosimilars have been used successfully across a wide range of therapeutic areas for the past 15 years where they have achieved substantial cost savings that can be reinvested into healthcare systems without affecting the quality of patient care. The current review provides an introduction to biosimilars with the aim of preparing retinal specialists for discussing these products with their patients.

Efficacy Outcomes of Brolucizumab Versus Aflibercept in Neovascular Age-Related Macular Degeneration Patients with Early Residual Fluid.

OBJECTIVE: To compare the outcomes of brolucizumab versus aflibercept in patients with neovascular age-related macular degeneration with early residual fluid in the HAWK and HARRIER studies. DESIGN: Post hoc analysis using pooled data from the phase 3 studies HAWK (NCT02307682) and HARRIER (NCT02434328). PARTICIPANTS: The early residual fluid cohort for this post hoc analysis consisted of patients treated with either brolucizumab 6 mg (n = 730 patients) or aflibercept 2 mg (n = 729 patients) and who had the presence of intraretinal fluid (IRF), subretinal fluid (SRF), or both verified by spectral-domain OCT at the week 12 clinic visit. METHODS: After 3 initial monthly doses, patients treated with brolucizumab received injections every 12 weeks (q12w) or every 8 weeks (q8w), depending on the neovascular age-related macular degeneration disease activity, whereas patients treated with aflibercept received fixed q8w dosing. MAIN OUTCOME MEASURES: The mean change in best-corrected visual acuity and central subfield thickness (CST) from the baseline to that at weeks 48 and 96, the proportion of patients treated with brolucizumab remaining on q12w dosing to week 96, and the change in fluid status at weeks 48 and 96. RESULTS: All analyses were based on 149 of 730 (20.4%) patients treated with brolucizumab and 217 of 729 (29.8%) patients treated with aflibercept with spectral-domain OCT-verified IRF, SRF, or both at their week 12 visit. The best-corrected visual acuity improvements from baseline at weeks 48 and 96 were numerically better for brolucizumab than for aflibercept (least square mean [standard error] 7.9 ± 1.1 vs. 4.6 ± 0.9 and 7.4 ± 1.3 vs. 2.9 ± 1.1 letters, respectively). The CST reductions from baseline at weeks 48 and 96 were consistently greater with brolucizumab than with aflibercept (least square mean [standard error], µm: -194.9 ± 13.7 vs. -123.9 ± 11.3; and -201.1 ± 14.5 vs. -134.2 ± 12.0, respectively). At weeks 48 and 96, patients treated with brolucizumab had a 40.4% and 31.3% probability of remaining on q12w dosing intervals, respectively. Fewer patients treated with brolucizumab had remaining IRF, SRF, or both at weeks 48 and 96 than patients treated with aflibercept (59.1% vs. 75.1% and 49.0% vs. 60.4%, respectively). CONCLUSIONS: In patients with early residual fluid, defined as spectral-domain OCT-verified IRF, SRF, or both at the week 12 clinic visit, brolucizumab resolved the early residual fluid and reduced CST more effectively than aflibercept, resulting in greater best-corrected visual acuity improvements through week 96 of anti-VEGF treatment.

Assessing functional reorganization in visual cortex with simulated retinal lesions.

Macular degeneration (MD) causes central vision loss, removing input to corresponding representations in the primary visual cortex. There is disagreement concerning whether the cortical regions deprived of input can remain responsive, and the source of reported cortical responses is still debated. To simulate MD in controls, normally sighted participants viewed a bright central disk to adapt the retina, creating a transient 'retinal lesion' during a functional MRI experiment. Participants viewed blocks of faces, scrambled faces and uniform grey stimuli, either passively or whilst performing a one-back task. To assess the impact of the simulated lesion, participants repeated the paradigm using a more conventional mean luminance simulated scotoma without adaptation. Our results suggest our attempt to create a more realistic simulation of a lesion did not impact on responses in the representation of the simulated lesion. While most participants showed no evidence of stimulus-driven activation within the lesion representation, a few individuals (22%) exhibited responses similar to a participant with juvenile MD who completed the same paradigm (without adaptation). Reliability analysis showed that responses in the representation of the lesion were generally consistent irrespective of whether positive or negative. We provide some evidence that peripheral visual stimulation can also produce responses in central representations in controls while performing a task. This suggests that the 'signature of reorganization of visual processing', is not found solely in patients with retinal lesions, consistent with the idea that activity may be driven by unmasked top-down feedback.

Demographic and Clinical Factors that Influence the Visual Response to Anti-Vascular Endothelial Growth Factor Therapy in Patients with Neovascular Age-Related Macular Degeneration: A Systematic Review.

BACKGROUND: Neovascular age-related macular degeneration (nAMD) is a leading cause of blind registrations in the developed world. Standard therapy includes the use of anti-vascular endothelial growth factor (anti-VEGF) drugs, and whilst the clinical efficacy is well established, there is variability in the clinical effect of visual outcome. The purpose of this systematic review is to identify whether there is evidence for the influence of demographic and clinical factors on the effectiveness of anti-VEGF therapy in patients with nAMD, in settings comparable to the National Health Service (NHS). METHODS: This systematic review followed the PRISMA guidelines for systematic reviews. Electronic databases Medline, EMBASE, Web of Science, CINAHL and the Cochrane Library were searched for studies dated from 2005 onwards. Studies were appraised using the Newcastle-Ottawa Score, and a narrative synthesis was used. ELIGIBILITY CRITERIA: Population: Patients with nAMD being treated with anti-VEGF therapy. Comparator: Presence or absence of potential predictive demographic and clinical factors. SETTINGS: Comparable settings to NHS hospitals. OUTCOMES: Predicting demographic and clinical factors. STUDY DESIGNS: Randomised controlled trials, prospective cohort studies, retrospective cohort studies and case series dated from 2005. RESULTS: Thirty papers were identified in this review. The evidence suggests that the number of anti-VEGF injections that patients receive, age and lesion size at baseline are factors that influence how effective anti-VEGF therapy is in the short and long term. There was also evidence that suggested that baseline visual acuity influenced the effectiveness of anti-VEGF therapy at longer time points of more than 2 years. Due to a lack of standardised statistical reporting among the included studies, it was not possible to undertake a meaningful statistical synthesis or meta-analysis. CONCLUSIONS: This review has demonstrated that there is some evidence of clinical and demographic factors that affect the effectiveness of anti-VEGF therapy and hence variation in visual acuity (VA) outcome. However, this review was unable to identify as wide a range of factors as was hoped. The findings of this review are important because some of the factors, such as VA and lesion size at diagnosis and the number of injections, are potentially modifiable through improvements in early diagnosis and service provision. Future work also needs to focus on the importance of this variation, such as the effect on patients' quality of life, and how variation can be minimised. SYSTEMATIC REVIEW REGISTRATION: This review has been registered with PROSPERO (Registration number CRD42018094191).

Providing a Safe and Effective Intravitreal Treatment Service: Strategies for Service Delivery.

An aging population leads to increasing demand for medical retina services with chronic diseases being managed in long-term care pathways. Many hospital services struggle to deliver efficient and effective MR care due, at least in part, to infrastructure that does not expand responsively enough to meet the increased demand. A steering committee of retinal specialists from a variety of UK NHS hospital ophthalmology departments with experience of leading and managing NHS retinal services in the intravitreal era came together for the generation of this document to review and compile key aspects that should be considered when optimising intravitreal treatment capacity within MR services. This article aims to provide a useful collation and signposting of key published evidence, consensus and insights on aspects of delivering an intravitreal service, including treatment regimens, virtual clinics, staff training and governance, telemedicine and information technology, and data collection and key performance indicators. The objective is to equip ophthalmologic healthcare professionals with the necessary tools to develop and adapt their local service in the face of current and projected increased demand.

Recommendations by a UK expert panel on an aflibercept treat-and-extend pathway for the treatment of neovascular age-related macular degeneration.

OBJECTIVES: This report aims to provide clear recommendations and practical guidance from a panel of UK retinal experts on an aflibercept treat-and-extend (T&E) pathway that can be implemented in clinical practice. These recommendations may help service providers across the NHS intending to implement a T&E approach, with the aim of effectively addressing the capacity and resource issues putting strain on UK neovascular age-related macular degeneration (nAMD) services while promoting patients' best interests throughout. METHODS: Two structured roundtable meetings of retinal specialists were held in London, UK on 7 December 2018 and 1 March 2019. These meetings were organised and funded by Bayer. RESULTS: The panel provided recommendations for an aflibercept T&E pathway and developed specific criteria based on visual acuity, retinal morphology and optical coherence tomography imaging to guide reduction, maintenance and extension of injection intervals. They also discussed the extension of treatment intervals by 2- or 4-week adjustments to a maximum treatment interval of 16 weeks, the management of retinal fluid and the stopping of treatment. CONCLUSIONS: The long-term benefits of implementing a T&E pathway may include superior visual outcomes compared with a pro re nata (PRN; as needed) protocol, and a lower treatment burden compared with a fixed protocol, which is likely to improve service capacity. Furthermore, the predictable nature of a T&E approach compared with a PRN service may aid capacity planning for the future nAMD treatment demand.

Anatomical and functional outcomes following switching from aflibercept to ranibizumab in neovascular age-related macular degeneration in Europe: SAFARI study.

BACKGROUND/AIMS: Prospective data on switching anti-vascular endothelial growth factors in patients with neovascular age-related macular degeneration (nAMD) who have previously shown no/partial response are limited. This prospective study assessed the effect of switching from aflibercept to ranibizumab on anatomical and functional outcomes in patients with persistent/recurrent disease activity. METHODS: SAFARI (NCT02161575) was a 6-month, prospective, single-arm study conducted in the UK and Germany. Patients, meeting strict eligibility criteria for one of two subgroups (primary treatment failure or suboptimal treatment response), received 3 monthly intravitreal ranibizumab injections (0.5 mg). Thereafter, ranibizumab was administered pro re nata at monthly visits. The primary endpoint was change from baseline (CfB) to day 90 in central subfield retinal thickness (CSRT). Best-corrected visual acuity (BCVA) and retinal morphology parameters were assessed. RESULTS: One hundred patients were enrolled (primary treatment failure, 1; suboptimal treatment response, 99). In the overall population, there was a significant CfB in median CSRT of -30.75 µm (95% CI -59.50,-20.50; p<0.0001) to day 90. Improvements were also observed in other quantitative and qualitative optical coherence tomography parameters. In Early Treatment Diabetic Retinopathy Study letters assessed by category, 55% and 59% of patients gained 0-≥15 letters versus baseline at day 90 and day 180, respectively. However, mean improvements in BCVA (CfB) to each time point were small (≤2 letters). No new safety signals were identified. CONCLUSION: Switching from aflibercept to ranibizumab led to a significant improvement in CSRT, with ~60% experiencing stabilised/improved BCVA. Therefore, patients with nAMD who have shown a suboptimal response to aflibercept may benefit from switching to ranibizumab.

Electrodiagnostic assessment in optic nerve disease.

PURPOSE OF REVIEW: Complementary electrophysiological techniques can be useful in detecting and localizing dysfunction within the visual pathway. Recent developments are outlined in the context of neuro-ophthalmology. RECENT FINDINGS: The relationship between nerve fibre layer anatomy and the pattern visual evoked potential has been addressed, correlating axonal loss with visual pathway dysfunction. Longitudinal assessment of multiple sclerosis patients has defined parameters affecting the utility of the pattern visual evoked potential as an outcome measure in potential treatment trials. In optic nerve tumours, the pattern visual evoked potential may help identify and monitor the disorder. The pattern electroretinogram assesses retinal ganglion cell function and can identify macular dysfunction, possibly mimicking optic nerve disease clinically. The spatial extent of macular dysfunction can be assessed using the multifocal electroretinogram. Objective visual evoked potential assessment of visual acuity can be important in the management of nonorganic visual loss. The multifocal visual evoked potential is a relatively new technique that is attracting increasing research interest, particularly as a measure of visual field loss, but has yet to be established as a reliable diagnostic tool. SUMMARY: Electrophysiology, combined with clinical and imaging investigations, is a powerful diagnostic and monitoring tool. Macular dysfunction can mimic optic nerve disease in the absence of fundus abnormality.

Phenotypical characteristics of idiopathic infantile nystagmus with and without mutations in FRMD7.

Idiopathic infantile nystagmus (IIN) consists of involuntary oscillations of the eyes. The familial form is most commonly X-linked. We recently found mutations in a novel gene FRMD7 (Xq26.2), which provided an opportunity to investigate a genetically defined and homogeneous group of patients with nystagmus. We compared clinical features and eye movement recordings of 90 subjects with mutation in the gene (FRMD7 group) to 48 subjects without mutations but with clinical IIN (non-FRMD7 group). Fifty-eight female obligate carriers of the mutation were also investigated. The median visual acuity (VA) was 0.2 logMAR (Snellen equivalent 6/9) in both groups and most patients had good stereopsis. The prevalence of strabismus was also similar (FRMD7: 7.8%, non-FRMD7: 10%). The presence of anomalous head posture (AHP) was significantly higher in the non-FRMD7 group (P < 0.0001). The amplitude of nystagmus was more strongly dependent on the direction of gaze in the FRMD7 group being lower at primary position (P < 0.0001), compared to non-FRMD7 group (P = 0.83). Pendular nystagmus waveforms were also more frequent in the FRMD7 group (P = 0.003). Fifty-three percent of the obligate female carriers of an FRMD7 mutation were clinically affected. The VA's in affected females were slightly better compared to affected males (P = 0.014). Subnormal optokinetic responses were found in a subgroup of obligate unaffected carriers, which may be interpreted as a sub-clinical manifestation. FRMD7 is a major cause of X-linked IIN. Most clinical and eye movement characteristics were similar in the FRMD7 group and non-FRMD7 group with most patients having good VA and stereopsis and low incidence of strabismus. Fewer patients in the FRMD7 group had AHPs, their amplitude of nystagmus being lower in primary position. Our findings are helpful in the clinical identification of IIN and genetic counselling of nystagmus patients.