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This is a comprehensive review of the principles and applications of adaptive optics (AO) in ophthalmology. It has been combined with flood illumination ophthalmoscopy, scanning laser ophthalmoscopy, as well as optical coherence tomography to image photoreceptors, retinal pigment epithelium (RPE), retinal ganglion cells, lamina cribrosa and the retinal vasculature. In this review, we highlight the clinical studies that have utilised AO to understand disease mechanisms. However, there are some limitations to using AO in a clinical setting including the cost of running an AO imaging service, the time needed to scan patients, the lack of normative databases and the very small size of area imaged. However, it is undoubtedly an exceptional research tool that enables visualisation of the retina at a cellular level.

Bevacizumab has been suggested to have similar effectiveness to ranibizumab for treatment of neovascular age-related macular degeneration. The Inhibition of VEGF in Age-related choroidal Neovascularisation (IVAN) trial was designed to compare these drugs and different regimens. Here, we report the findings at the prespecified 2-year timepoint. In a multicentre, 2×2 factorial, non-inferiority randomised trial, we enrolled adults aged at least 50 years with active, previously untreated neovascular age-related macular degeneration and a best corrected distance visual acuity (BCVA) of at least 25 letters from 23 hospitals in the UK. Participants were randomly assigned (1:1:1:1) to intravitreal injections of ranibizumab (0·5 mg) or bevacizumab (1·25 mg) in continuous (every month) or discontinuous (as needed) regimens, with monthly review. Study participants and clinical assessors were masked to drug allocation. Allocation to continuous or discontinuous treatment was masked up to 3 months, at which point investigators and participants were unmasked. The primary outcome was BCVA at 2 years, with a prespecified non-inferiority limit of 3·5 letters. The primary safety outcome was arterial thrombotic event or hospital admission for heart failure. Analyses were by modified intention to treat. This trial is registered, number ISRCTN92166560. Between March 27, 2008, and Oct 15, 2010, 628 patients underwent randomisation. 18 were withdrawn; 610 received study drugs (314 ranibizumab; 296 bevacizumab) and were included in analyses. 525 participants reached the visit at 2 years: 134 ranibizumab in continuous regimen, 137 ranibizumab in discontinuous regimen, 127 bevacizumab in continuous regimen, and 127 bevacizumab in discontinuous regimen. For BCVA, bevacizumab was neither non-inferior nor inferior to ranibizumab (mean difference −1·37 letters, 95% CI −3·75 to 1·01; p=0·26). Discontinuous treatment was neither non-inferior nor inferior to continuous treatment (−1·63 letters, −4·01 to 0·75; p=0·18). Frequency of arterial thrombotic events or hospital admission for heart failure did not differ between groups given ranibizumab (20 [6%] of 314 participants) and bevacizumab (12 [4%] of 296; odds ratio [OR] 1·69, 95% CI 0·80–3·57; p=0·16), or those given continuous (12 [4%] of 308) and discontinuous treatment (20 [7%] of 302; 0·56, 0·27–1·19; p=0·13). Mortality was lower with continuous than discontinuous treatment (OR 0·47, 95% CI 0·22–1·03; p=0·05), but did not differ by drug group (0·96, 0·46–2·02; p=0·91). Ranibizumab and bevacizumab have similar efficacy. Reduction in the frequency of retreatment resulted in a small loss of efficacy irrespective of drug. Safety was worse when treatment was administered discontinuously. These findings highlight that the choice of anti-VEGF treatment strategy is less straightforward than previously thought. UK National Institute for Health Research Health Technology Assessment programme.

In this study, the subfoveal injection of a gene-therapy vector carrying nonmutated CHM, the gene that, when mutated, causes a form of blindness called choroideremia, was followed by an improvement in visual acuity in two of six patients at 3.5 years after injection. To the Editor: Two recent clinical reports of retinal gene therapy with adeno-associated virus (AAV) vectors in patients with Leber’s congenital amaurosis showed initial gains in visual function that subsequently declined. 1 , 2 We previously reported early improvement in visual acuity in two of six patients who received retinal gene therapy in one eye (the study eye) to treat choroideremia, 3 a disease that is characterized by atrophy of the choriocapillaris and retinal pigment epithelium and involves vision loss that leads to blindness. Choroideremia is caused by loss-of-function mutations in the gene CHM . We delivered nonmutated CHM in an AAV vector . . .

ObjectiveTo estimate the incidence of acute cerebral ischaemia detected by magnetic resonance imaging (MRI) in acute central retinal artery occlusion (CRAO), branch retinal artery occlusion (BRAO) and transient monocular vision loss (TMVL).MethodsStudies reporting the incidence of acute cerebral ischaemia, detected by MRI, within 7 days from diagnosis of acute CRAO, BRAO and TMVL up to January 2019 were systematically searched for on Pubmed, Medline and Cochrane Library. Meta-analysis was performed using random effects model. The primary outcome was the pooled estimate of incidence of acute cerebral ischaemia in CRAO, BRAO and TMVL cohorts including both neurologically symptomatic and asymptomatic patients, expressed as a proportion along with 95% confidence intervals (CIs). The pooled estimate of incidence of asymptomatic acute cerebral ischaemia represented a secondary outcome measure.ResultsFor the primary outcome, the pooled proportion of acute cerebral ischaemia was 0.30 (CI 0.24–0.36) in the CRAO cohort, and 0.25 (CI 0.16–0.37) in the BRAO cohort, without statistical heterogeneity. The rate of acute cerebral ischaemia was 11.8% in the TMVL cohort. For the secondary outcome, the pooled proportion of asymptomatic acute cerebral ischaemia was 0.22 (CI 0.16–0.28) in the CRAO cohort, 0.29 (CI 0.20–0.41) in the BRAO cohort and 0.08 (CI 0.05–0.15) in the TMVL cohort, with no statistical heterogeneity.Conclusions30% of patients with acute CRAO and 25% of patients with acute BRAO presented an acute cerebral ischaemia on MRI. Such high rates support a care pathway of prompt referral of such patients for neurological evaluation and brain imaging.

Choroideremia is an X-linked recessive disease that leads to blindness due to mutations in the CHM gene, which encodes the Rab escort protein 1 (REP1). We assessed the effects of retinal gene therapy with an adeno-associated viral (AAV) vector encoding REP1 (AAV.REP1) in patients with this disease. In a multicentre clinical trial, six male patients (aged 35–63 years) with choroideremia were administered AAV.REP1 (0·6–1·0×1010 genome particles, subfoveal injection). Visual function tests included best corrected visual acuity, microperimetry, and retinal sensitivity tests for comparison of baseline values with 6 months after surgery. This study is registered with ClinicalTrials.gov, number NCT01461213. Despite undergoing retinal detachment, which normally reduces vision, two patients with advanced choroideremia who had low baseline best corrected visual acuity gained 21 letters and 11 letters (more than two and four lines of vision). Four other patients with near normal best corrected visual acuity at baseline recovered to within one to three letters. Mean gain in visual acuity overall was 3·8 letters (SE 4·1). Maximal sensitivity measured with dark-adapted microperimetry increased in the treated eyes from 23·0 dB (SE 1·1) at baseline to 25·3 dB (1·3) after treatment (increase 2·3 dB [95% CI 0·8–3·8]). In all patients, over the 6 months, the increase in retinal sensitivity in the treated eyes (mean 1·7 [SE 1·0]) was correlated with the vector dose administered per mm2 of surviving retina (r=0·82, p=0·04). By contrast, small non-significant reductions (p>0·05) were noted in the control eyes in both maximal sensitivity (–0·8 dB [1·5]) and mean sensitivity (–1·6 dB [0·9]). One patient in whom the vector was not administered to the fovea re-established variable eccentric fixation that included the ectopic island of surviving retinal pigment epithelium that had been exposed to vector. The initial results of this retinal gene therapy trial are consistent with improved rod and cone function that overcome any negative effects of retinal detachment. These findings lend support to further assessment of gene therapy in the treatment of choroideremia and other diseases, such as age-related macular degeneration, for which intervention should ideally be applied before the onset of retinal thinning. UK Department of Health and Wellcome Trust.

Retinal gene therapy has shown great promise in treating retinitis pigmentosa (RP), a primary photoreceptor degeneration that leads to severe sight loss in young people. In the present study, we report the first-in-human phase 1/2, dose-escalation clinical trial for X-linked RP caused by mutations in the RP GTPase regulator ( RPGR ) gene in 18 patients over up to 6 months of follow-up ( https://clinicaltrials.gov/ : NCT03116113). The primary outcome of the study was safety, and secondary outcomes included visual acuity, microperimetry and central retinal thickness. Apart from steroid-responsive subretinal inflammation in patients at the higher doses, there were no notable safety concerns after subretinal delivery of an adeno-associated viral vector encoding codon-optimized human RPGR (AAV8 -coRPGR ), meeting the pre-specified primary endpoint. Visual field improvements beginning at 1 month and maintained to the last point of follow-up were observed in six patients. Early results from a first-in-human retinal gene therapy trial for X-linked retinitis pigmentosa indicate that, at an intermediate dose, AAV8- RPGR is safe and in a subset of patients can lead to gains in visual function.

Retinal gene therapy is increasingly recognized as a novel molecular intervention that has huge potential in treating common causes of blindness, the majority of which have a genetic aetiology 1 – 5 . Choroideremia is a chronic X-linked retinal degeneration that was first described in 1872 6 . It leads to progressive blindness due to deficiency of Rab-escort protein 1 (REP1). We designed an adeno-associated viral vector to express REP1 and assessed it in a gene therapy clinical trial by subretinal injection in 14 patients with choroideremia. The primary endpoint was vision change in treated eyes 2 years after surgery compared to unoperated fellow eyes. Despite complications in two patients, visual acuity improved in the 14 treated eyes over controls (median 4.5 letter gain, versus 1.5 letter loss, P  = 0.04), with 6 treated eyes gaining more than one line of vision (>5 letters). The results suggest that retinal gene therapy can sustain and improve visual acuity in a cohort of predominantly late-stage choroideremia patients in whom rapid visual acuity loss would ordinarily be predicted. The long-term follow-up results of a phase 1/2 retinal gene therapy clinical trial for choroideremia ( NCT01461213 ) support the safety and efficacy of the treatment.

To evaluate the influence AMD risk genomic variants have on macular thickness in the normal population. UK Biobank participants with no significant ocular history were included using the UK Biobank Resource (project 2112). Spectral-domain optical coherence tomography (SD-OCT) images were taken and segmented to define retinal layers. The influence of AMD risk single-nucleotide polymorphisms (SNP) on retinal layer thickness was analysed. AMD risk associated SNPs were strongly associated with outer-retinal layer thickness. The inner-segment outer segment (ISOS)-retinal pigment epithelium (RPE) thickness measurement, representing photoreceptor outer segments was most significantly associated with the cumulative polygenic risk score, composed of 33 AMD-associated variants, resulting in a decreased thickness (p = 1.37 × 10 –67 ). Gene–gene interactions involving the NPLOC4-TSPAN10 SNP rs6565597 were associated with significant changes in outer retinal thickness. Thickness of outer retinal layers is highly associated with the presence of risk AMD SNPs. Specifically, the ISOS-RPE measurement. Changes to ISOS-RPE thickness are seen in clinically normal individuals with AMD risk SNPs suggesting structural changes occur at the macula prior to the onset of disease symptoms or overt clinical signs.

Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world. It is a multifactorial disease, and current therapy predominantly limits damage only when it has already occurred. The macula is a source of high metabolic activity, and is therefore exposed to correspondingly high levels of reactive oxygen species (ROS). With age, the balance between production of ROS and local antioxidant levels is shifted, and damage ensues. Systemic ROS and antioxidant levels in AMD reflect these local processes. Genetic studies investigating mutations in antioxidant genes in AMD are inconclusive and further studies are indicated, especially to determine the role of mitochondria. Oral antioxidant supplements could be beneficial, and diet modification may help. Future treatments might either increase antioxidant capacity or reduce the production of ROS, using methods such as genetic manipulation. This article reviews the role of oxidative stress in AMD and the potential therapies that might have a role in preventing the blindness resulting from this disease.