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To report efficacy of intravitreal pegcetacoplan treatment over 36 months in eyes with subfoveal geographic atrophy (GA). The GALE (NCT04770545) open-label extension trial adds 12 months of results to the 24-month Phase 3 OAKS (NCT03525613) and DERBY (NCT03525600) trials, representing up to 36 months of continuous pegcetacoplan treatment. They included a heterogeneous population of eyes with subfoveal GA (63%). Pegcetacoplan-treated eyes enrolling in GALE continued at the same interval of pegcetacoplan monthly (PM) or every other month (PEOM). Patients' eyes in sham monthly or every-other-month arms crossed over to receive pegcetacoplan in GALE at the same interval (sham crossover). Consequently, projected sham, calculated from prior 24-month GA growth rate of sham-observed eyes in OAKS and DERBY averaged across four 6-month segments, was the comparator for the first 12 months of GALE (months 24-36). This analysis reports results of eyes with subfoveal GA at baseline. In eyes with subfoveal GA, 84% had best corrected visual acuity (BCVA) ≥20/200 and 38% had BCVA ≥20/63 at OAKS and DERBY baseline. Pegcetacoplan reduced subfoveal GA growth rate by 21% (p<0.0001) with PM and 19% (p=0.0001) with PEOM over 36 months. Increasing efficacy over time was noted between months 24 and 36; 31% reduction in subfoveal GA growth rate with PM and 25% reduction with PEOM (both p<0.0001) compared with projected sham. Microperimetry demonstrated significant reduction in formation of absolute scotomas with PM at 24 months (-2.5 number of scotomas formed; 95% confidence interval [CI]: -4.5, -0.4; p=0.0205) and 36 months (-4.0 number of scotomas formed; 95% CI: -6.8, -1.2; p=0.0050), compared to sham crossover in subfoveal GA. Safety profile in GALE was consistent with OAKS and DERBY. Long-term efficacy of pegcetacoplan in slowing GA progression was demonstrated over 36 months in eyes with subfoveal GA.

PurposeRecent research has found variable evidence on the role of mesopic and dark-adapted scotopic microperimetry assessment in age-related macular degeneration. This scoping review summarises how mesopic and scotopic microperimetry can be used to assess disease progression in age-related macular degeneration and identifies gaps in the literature.MethodsA population, concept, and context approach was used to develop the search strategy. Ovid MEDLINE, EMBASE, Cochrane Library, PubMed, CINAHL Plus, Web of Science, and SCOPUS databases were used to conduct the literature search. The key search terms used in the databases were age-related macular degeneration and microperimetry.ResultsTwelve studies were eligible and included in the review. All the studies (n = 12) were conducted in European countries [Germany (9), Italy (2), and the United Kingdom (1)]. The mesopic and scotopic sensitivities were measured using the Nidek scotopic microperimeter (MP1-S) (n = 6), scotopic Macular Integrity Assessment device (S-MAIA) (n = 5), and both MP1-s and S MAIA (n = 1). 83.3% (n = 10) studied (cross-sectional design) on mesopic, scotopic microperimetry and found reduced rod (scotopic) photoreceptors sensitivities compared to cone (mesopic) photoreceptors sensitivities in patients with small and reticular pseudodrusen despite having good visual acuity. Only 16.7% (n = 2) of studies followed participants with reticular drusen/large drusen for three years (longitudinal design) and found reduced scotopic over mesopic sensitivity at baseline and localized mesopic with profound scotopic sensitivity loss during follow-ups.ConclusionScotopic sensitivity is a better functional indicator than mesopic sensitivity to understand early and intermediate age-related macular degeneration progression. The evidence from longitudinal studies is debatable due to the limited stimuli range of existing microperimeters, smaller sample size, and lost follow-ups.

Aims/hypothesis To determine the extent to which diabetic retinopathy severity stage may be classified using machine learning (ML) and commonly used clinical measures of visual function together with age and sex. Methods We measured the visual function of 1901 eyes from 1032 participants in the Northern Ireland Sensory Ageing Study, deriving 12 variables from nine visual function tests. Missing values were imputed using chained equations. Participants were divided into four groups using clinical measures and grading of ophthalmic images: no diabetes mellitus (no DM), diabetes but no diabetic retinopathy (DM no DR), diabetic retinopathy without diabetic macular oedema (DR no DMO) and diabetic retinopathy with DMO (DR with DMO). Ensemble ML models were fitted to classify group membership for three tasks, distinguishing (A) the DM no DR group from the no DM group; (B) the DR no DMO group from the DM no DR group; and (C) the DR with DMO group from the DR no DMO group. More conventional multiple logistic regression models were also fitted for comparison. An interpretable ML technique was used to rank the contribution of visual function variables to predictions and to disentangle associations between diabetic eye disease and visual function from artefacts of the data collection process. Results The performance of the ensemble ML models was good across all three classification tasks, with accuracies of 0.92, 1.00 and 0.84, respectively, for tasks A–C, substantially exceeding the accuracies for logistic regression (0.84, 0.61 and 0.80, respectively). Reading index was highly ranked for tasks A and B, whereas near visual acuity and Moorfields chart acuity were important for task C. Microperimetry variables ranked highly for all three tasks, but this was partly due to a data artefact (a large proportion of missing values). Conclusions/interpretation Ensemble ML models predicted status of diabetic eye disease with high accuracy using just age, sex and measures of visual function. Interpretable ML methods enabled us to identify profiles of visual function associated with different stages of diabetic eye disease, and to disentangle associations from artefacts of the data collection process. Together, these two techniques have great potential for developing prediction models using untidy real-world clinical data. Graphical Abstract

Background Treatment options for patients with inherited retinal disease are limited, although research into novel therapies is underway. To ensure the success of future clinical trials, appropriate visual function outcome measures that can assess changes resulting from therapeutic interventions are urgently required. Rod-cone degenerations are the most common type of inherited retinal disease. Visual acuity is a standard measure but is typically preserved until late disease stages, frequently making it an unsuitable visual function marker. Alternative measures are required. This study investigates the clinical utility of a range of carefully selected visual function tests and patient reported outcome measures. The aim is to identify suitable outcome measures for future clinical trials that could be considered for regulatory approval. Methods This cross-sectional study involves two participant groups, patients with inherited retinal disease (n = 40) and healthy controls (n = 40). The study has been designed to be flexible and run alongside NHS clinics. The study is split into two parts. Part one includes examining standard visual acuity, low luminance visual acuity, the Moorfields acuity chart visual acuity, mesopic microperimetry and three separate patient reported outcome measures. Part two involves 20 min of dark adaptation followed by two-colour scotopic microperimetry. Repeat testing will be undertaken where possible to enable repeatability analyses. A subset of patients with inherited retinal disease will be invited to participate in a semi-structured interview to gain awareness of participants’ thoughts and feelings around the study and different study tests. Discussion The study highlights a need for reliable and sensitive validated visual function measures that can be used in future clinical trials. This work will build on work from other studies and be used to inform an outcome measure framework for rod-cone degenerations. The study is in keeping with the United Kingdom Department of Health and Social Care research initiatives and strategies for increasing research opportunities for NHS patients as part of their NHS care. Trial registration ISRCTN registry, ISRCTN24016133, Visual Function in Retinal Degeneration, registered on 18th August 2022.

In order to determine the effect of nystagmus on objective visual acuity (VA) estimates, we compared subjective (VA psych ) and objective (VEP, VA VEP ) VA estimates in participants with nystagmus. For this purpose, 20 participants with nystagmus (NY) caused by idiopathic infantile nystagmus, albinism, achiasma or acquired nystagmus were recruited in this study. Estimates of BCVA (best corrected visual acuity) were determined psychophysically (VA psych ; FrACT, Freiburg visual acuity test) and electrophysiologically (VA VEP ; EP2000) according to ISCEV (International Society of Clinical Electrophysiology of Vision) guidelines. For each participant the eye with the stronger fixation instability [Nidek microperimeter (MP-1), Nidek Instruments] was included for further analysis. VA psych vs VA VEP were compared via paired t-tests and the correlation of the difference between VA psych and VA VEP (∆VA) vs the degree of fixation instability was tested with Pearson correlation (r). We found VA VEP to be better than VA psych [by 0.12 Logarithm of the Minimum Angle of Resolution (logMAR); mean ± standard error (SE) of VA VEP vs VA psych : 0.176 ± 0.06 vs. 0.299 ± 0.06, P = 0.017] and ∆VA to be correlated linearly with the degree of fixation instability (r 2 = 0.21,p = 0.048). In conclusion, on average we report a small VA overestimation, around 1 line, for VA VEP compared to VA psych in NY. This overestimation depended on the magnitude of the fixation instability. As a rule of thumb, a reduction of the fixation probability in the central 4° from 100 to 50% leads on average to a VA VEP overestimation of around 0.25 logMAR, i.e. 2.5 lines.

Vogt-Koyanagi-Harada (VKH) disease recovery patterns remain inadequately characterized over extended periods. This study evaluated retinal changes in VKH patients across 5 years using adaptive optics imaging and microperimetry. Twenty-five eyes from 13 patients were monitored longitudinally. Macular cone density gradually increased throughout the observation period but remained below healthy control levels. Eyes with pretreatment cystoid spaces initially showed lower cone density values, but this disparity disappeared after 3 years. Average threshold values improved consistently from baseline, while macular integrity values significantly decreased after 2 years. Cone density correlated significantly with retinal sensitivity. These findings indicate that with appropriate treatment, VKH disease demonstrates progressive improvement in both retinal structure and function over time, though complete structural recovery may not occur. Pretreatment cystoid spaces influence early outcomes but do not significantly affect long-term recovery.

The objective of this study is to define structure–function relationships of pathological lesions related to age-related macular degeneration (AMD) using microperimetry and multimodal retinal imaging. We conducted a cross-sectional study of 87 patients with AMD (30 eyes with early and intermediate AMD and 110 eyes with advanced AMD), compared to 33 normal controls (66 eyes) recruited from a single tertiary center. All participants had enface and cross-sectional optical coherence tomography (Heidelberg HRA-2), OCT angiography, color and infra-red (IR) fundus and microperimetry (MP) (Nidek MP-3) performed. Multimodal images were graded for specific AMD pathological lesions. A custom marking tool was used to demarcate lesion boundaries on corresponding enface IR images, and subsequently superimposed onto MP color fundus photographs with retinal sensitivity points (RSP). The resulting overlay was used to correlate pathological structural changes to zonal functional changes. Mean age of patients with early/intermediate AMD, advanced AMD and controls were 73(SD = 8.2), 70.8(SD = 8), and 65.4(SD = 7.7) years respectively. Mean retinal sensitivity (MRS) of both early/intermediate (23.1 dB; SD = 5.5) and advanced AMD (18.1 dB; SD = 7.8) eyes were significantly worse than controls (27.8 dB, SD = 4.3) (p < 0.01). Advanced AMD eyes had significantly more unstable fixation (70%; SD = 63.6), larger mean fixation area (3.9 mm 2 ; SD = 3.0), and focal fixation point further away from the fovea (0.7 mm; SD = 0.8), than controls (29%; SD = 43.9; 2.6 mm 2 ; SD = 1.9; 0.4 mm; SD = 0.3) (p ≤ 0.01). Notably, 22 fellow eyes of AMD eyes (25.7 dB; SD = 3.0), with no AMD lesions, still had lower MRS than controls (p = 0.04). For specific AMD-related lesions, end-stage changes such as fibrosis (5.5 dB, SD = 5.4 dB) and atrophy (6.2 dB, SD = 7.0 dB) had the lowest MRS; while drusen and pigment epithelial detachment (17.7 dB, SD = 8.0 dB) had the highest MRS. Peri-lesional areas (20.2 dB, SD = 7.6 dB) and surrounding structurally normal areas (22.2 dB, SD = 6.9 dB) of the retina with no AMD lesions still had lower MRS compared to controls (27.8 dB, SD = 4.3 dB) (p < 0.01). Our detailed topographic structure–function correlation identified specific AMD pathological changes associated with a poorer visual function. This can provide an added value to the assessment of visual function to optimize treatment outcomes to existing and potentially future novel therapies.

This retrospective study aimed to assess the impact of subretinal drusenoid deposit (SDD), also known as reticular pseudodrusen, on retinal sensitivity (RS) in patients with intermediate age-related macular degeneration (iAMD) using microperimetry. Eyes meeting the modified criteria of iAMD, including SDD, and total drusen area greater than 0.50 mm 2 were included. The presence of SDD, as well as soft drusen (SD), and specific type of SDD (dot or ribbon) were determined through multimodal imaging modalities including fundus photography, fundus autofluorescence, infrared reflectance image and optical coherence tomography. RS was measured using MAIA microperimetry. A total of 302 eyes from 302 patients were analyzed. Patients with SDD were older and predominantly female. Average RS was significantly lower in eyes with SDD than without SDD. (19.75 (5.06) vs. 21.21 (4.53) (average (SD)), P  = 0.003). The presence of SD alone did not significantly affect RS. Among eyes with SDD, those with ribbon-type SDD exhibited significantly lower RS (18.02 ± 6.49) than those with dot-type SDD (20.67 ± 4.13; P  < 0.001). In multivariable linear regression analysis, older age and the presence of ribbon-type SDD were significantly associated with reduced RS. In conclusion, eyes with iAMD and SDD demonstrate reduced RS, with ribbon-type SDD exerting a greater negative impact on retinal function than dot-type SDD.

The aim of this cross-sectional case-control study is to investigate the possible presence of vascular/neurodegenerative alterations in the retina of type 1 diabetes mellitus (T1DM) patients without diabetic retinopathy (DR). Thirty-four eyes of 34 consecutive T1DM without DR (mean age 21 ± 2 years) were included. Another cohort of 27 eyes (27 healthy control subjects matched with age and sex) was also recruited. All patients underwent multimodal imaging evaluation using structural optical coherence tomography (OCT), OCT-angiography (OCT-A), dynamic vessel analyzer (DVA) and microperimetry. No significant differences were disclosed comparing diabetics and controls for visual acuity, central macular thickness, and subfoveal choroidal thickness. On retinal nerve fiber layer and ganglion cell complex thickness, no significant differences were disclosed comparing each 3-mm-diameter macular and peripapillary subfield between two groups. Using OCT-A, deep capillary plexus perfusion density (PD) of diabetics was significantly lower compared to control group, whereas PD of other retinal/choriocapillaris plexuses and foveal avascular zone area did not show any significant difference. Using DVA, diabetic eyes revealed a significantly decreased vessel response to flicker light in comparison to controls. No differences were disclosed using microperimetry analysis. Taken together, these results suggest that vascular alterations could be the first detectable retinal change in the development of DR.

PurposeTo characterize the fixation and macular integrity of subjects with multiple sclerosis (MS) with and without previous optic neuritis (ON) using microperimetry (MP).MethodsFifty-five eyes of MS patients, subdivided into three groups (28 eyes without ON, 16 with previous ON, and 11 eyes with previous ON in the contralateral eye), and 43 healthy eyes were enrolled (January–November 2018). All cases were evaluated using the MAIA microperimeter (Centervue), analyzing the following parameters: average macular threshold (AT), fixation indexes (P1 and P2), bivariate contour ellipse area (BCEA) for 95% and 63% of points, and horizontal (H) and vertical (V) axes of the ellipse of fixation.ResultsAll MS groups showed a significant reduced AT compared with the control group (p < 0.001). This reduction was more representative (p < 0.001) in eyes with previous ON. No statistically significant differences were found between MS patients with and without previous ON (p > 0.05). Mean AT was correlated with the examination time in all three groups (between ρ = − 0.798 p < 0.001 and ρ = − 0.49 p < 0.001). Significant differences in fixation parameters were only found between control and MS with ON groups (p < 0.02). The ratio of the disease showed a significant correlation with fixation parameters in MS groups (p < 0.02), but not with AT.ConclusionsIn MS patients, macular sensitivity is altered, especially in eyes with previous ON. Likewise, a fixational instability is present in MS patients with ON, with more increase of the V axis of the fixation area than of the H. The ratio of the disease also affects the patient fixation pattern.