Intravitreal Injections: Improving Sustainability by Reducing Clinical Waste. / Intravitreale Injektionen: Nachhaltigkeit durch Reduktion von Klinikabfall.

BACKGROUND: Intravitreal injections are one of the most commonly performed ophthalmic procedures. It is estimated that over 1 million intravitreal injections are performed in Germany annually. The aim of this study was to quantify the waste and carbon footprint associated with single-use injection sets, and to establish a waste reduction strategy. MATERIAL AND METHODS: The clinical waste and associated carbon footprint from standard disposable injection sets used by tertiary referral centres in Germany (n = 6) and the United Kingdom (n = 2) were assessed. The safety of performing intravitreal injections with a minimalistic material-sparing approach was evaluated. RESULTS: The average weight of an injection set (and hence the waste generated from each injection) was 165 g. On average, each injection set comprised 145 g (88%) of plastic, 2.1 g (1.3%) of metal, 4.3 g (2.6%) of paper, and 12.9 g (7.8%) of gauze/swabs. The production of such injection sets was extrapolated to a CO2 equivalent of 752.6 tonnes (t), and the incineration of the resulting waste to a CO2 equivalent of 301.7 t. For 1 million injections, this equates to 145.2 t of plastic, 2.1 t of metal, 4.3 t of paper, and 12.9 t of gauze/swabs. A material-sparing approach can reduce injection set-associated waste by 99% without necessarily compromising patient safety. CONCLUSION: A resource-saving approach to intravitreal injections can minimise the generation of clinical waste and its associated carbon footprint, thereby supporting sustainability.

Rescue of cone and rod photoreceptor function in a CDHR1-model of age-related retinal degeneration.

Age-related macular degeneration (AMD) is the most common cause of untreatable blindness in the developed world. Recently, CDHR1 has been identified as the cause of a subset of AMD that has the appearance of the "dry" form, or geographic atrophy. Biallelic variants in CDHR1-a specialized protocadherin highly expressed in cone and rod photoreceptors-result in blindness from shortened photoreceptor outer segments and progressive photoreceptor cell death. Here we demonstrate long-term morphological, ultrastructural, functional, and behavioral rescue following CDHR1 gene therapy in a relevant murine model, sustained to 23-months after injection. This represents the first demonstration of rescue of a monogenic cadherinopathy in vivo. Moreover, the durability of CDHR1 gene therapy seems to be near complete-with morphological findings of the rescued retina not obviously different from wildtype throughout the lifespan of the mouse model. A follow-on clinical trial in patients with CDHR1-associated retinal degeneration is warranted. Hypomorphic CDHR1 variants may mimic advanced dry AMD. Accurate clinical classification is now critical, as their pathogenesis and treatment are distinct.

IMPG2-Related Maculopathy.

PURPOSE: To investigate the phenotype, variability, and penetrance of IMPG2-related maculopathy. DESIGN: Retrospective observational case series. METHODS: Clinical evaluation, multimodal retinal imaging, genetic testing, and molecular modeling. RESULTS: A total of 25 individuals with a mono-allelic IMPG2 variant were included, 5 of whom were relatives of patients with IMPG2-associated retinitis pigmentosa. A distinct maculopathy was present in 17 individuals (median age, 52 years; range, 20-72 years), and included foveal elevation with or without subretinal vitelliform material or focal atrophy of the retinal pigment epithelium. Best-corrected visual acuity (BCVA) was ≥20/50 in the better eye (n = 15), and 5 patients were asymptomatic. Longitudinal observation (n = 8, up to 19 years) demonstrated stable maculopathy (n = 3), partial/complete resorption (n = 4) or increase (n = 1) of the subretinal material, with overall stable vision (n = 6). No manifest maculopathy was observed in 8 individuals (median age, 58 years; range, 43-83 years; BCVA ≥20/25), all were identified through segregation analysis. All 8 individuals were asymptomatic, with minimal foveal changes observed on optical coherence tomography in 3 cases. A total of 18 different variants were detected, 11 of them truncating. Molecular modeling of 5 missense variants [c.727G>C, c.1124C>A, c.2816T>A, c.3047T>C, and c.3193G>A] supported the hypothesis that these have a loss-of-function effect. CONCLUSIONS: Mono-allelic IMPG2 variants may result in haploinsufficiency manifesting as a maculopathy with variable penetrance and expressivity. Family members of patients with IMPG2-related retinitis pigmentosa may present with vitelliform lesions. The maculopathy often remains limited to the fovea and is usually associated with moderate visual impairment.

Developing a Continuous Severity Scale for Macular Telangiectasia Type 2 Using Deep Learning and Implications for Disease Grading.

PURPOSE: Deep learning (DL) models have achieved state-of-the-art medical diagnosis classification accuracy. Current models are limited by discrete diagnosis labels, but could yield more information with diagnosis in a continuous scale. We developed a novel continuous severity scaling system for macular telangiectasia (MacTel) type 2 by combining a DL classification model with uniform manifold approximation and projection (UMAP). DESIGN: We used a DL network to learn a feature representation of MacTel severity from discrete severity labels and applied UMAP to embed this feature representation into 2 dimensions, thereby creating a continuous MacTel severity scale. PARTICIPANTS: A total of 2003 OCT volumes were analyzed from 1089 MacTel Project participants. METHODS: We trained a multiview DL classifier using multiple B-scans from OCT volumes to learn a previously published discrete 7-step MacTel severity scale. The classifiers' last feature layer was extracted as input for UMAP, which embedded these features into a continuous 2-dimensional manifold. The DL classifier was assessed in terms of test accuracy. Rank correlation for the continuous UMAP scale against the previously published scale was calculated. Additionally, the UMAP scale was assessed in the κ agreement against 5 clinical experts on 100 pairs of patient volumes. For each pair of patient volumes, clinical experts were asked to select the volume with more severe MacTel disease and to compare them against the UMAP scale. MAIN OUTCOME MEASURES: Classification accuracy for the DL classifier and κ agreement versus clinical experts for UMAP. RESULTS: The multiview DL classifier achieved top 1 accuracy of 63.3% (186/294) on held-out test OCT volumes. The UMAP metric showed a clear continuous gradation of MacTel severity with a Spearman rank correlation of 0.84 with the previously published scale. Furthermore, the continuous UMAP metric achieved κ agreements of 0.56 to 0.63 with 5 clinical experts, which was comparable with interobserver κ values. CONCLUSIONS: Our UMAP embedding generated a continuous MacTel severity scale, without requiring continuous training labels. This technique can be applied to other diseases and may lead to more accurate diagnosis, improved understanding of disease progression, and key imaging features for pathologic characteristics. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Hypomorphic CDHR1 variants may result in retinitis pigmentosa with relative preservation of cone function.

PURPOSE: Retinitis pigmentosa (RP) associated with biallelic variants in CDHR1 has rarely been reported, and detailed phenotyping data are not available. RP implies relative preservation of foveal cones, when compared to cone-rod dystrophy associated with biallelic null variants in CDHR1. We hypothesize that RP may occur in association with one or more hypomorphic CDHR1 alleles. MATERIALS AND METHODS: Retrospective report of a 48-year-old patient with CDHR1-associated RP with a hypomorphic missense variant c.562 G>A, p. (Gly188Ser) and a novel, unreported variant affecting a canonical splice acceptor site (c.784-1 G>C). Clinical examination, multimodal retinal imaging, electroretinography, visual field testing, and mesopic microperimetry were undertaken 8 years apart. Scotopic microperimetry was also performed. The DNA sequence context of the variants was examined to identify theoretical CRISPR-Cas9 base-editing strategies. RESULTS: The patient presented at 35 years with a 12-year history of nyctalopia. His best corrected visual acuity was 20/20. Clinical presentation, multimodal retinal imaging studies, electroretinography, and mesopic microperimetry were typical of a progressive rod-cone dystrophy (i.e. classic RP). There were no scotomas within the central field as would be expected at this age in CDHR1-associated cone-rod dystrophy. Scotopic microperimetry suggested some preservation of macular cone over rod function, although both were severely impaired. A suitable CRISPR adenine base editor was identified that could theoretically correct the missense variant c.562 G>A, p. (Gly188Ser). CONCLUSIONS: CDHR1-associated RP shows a relative preservation of cone function in the presence of a presumed hypomorphic allele and may be considered a hypomorphic disease phenotype. Further work is required to identify modifying factors that determine disease phenotype since macular dystrophy, with relative sparing of rods, may also occur with hypomorphic CDHR1 alleles.

Genetic Counseling For Predictive Retinal Imaging.

This Viewpoint discusses genetic counseling for predictive retinal imaging.

Progression of PROM1-Associated Retinal Degeneration as Determined by Spectral-Domain Optical Coherence Tomography Over a 24-Month Period.

PURPOSE: To evaluate the progression of atrophy as determined by spectral-domain optical coherence tomography (SD-OCT) in patients with molecularly confirmed PROM1-associated retinal degeneration (RD) over a 24-month period. DESIGN: International, multicenter, prospective case series. METHODS: A total of 13 eyes (13 patients) affected with PROM1-associated RD were enrolled at 5 sites and SD-OCT images were obtained at baseline and after 24 months. Loss of mean thickness (MT) and intact area were estimated after semi-automated segmentation for the following individual retinal layers in the central subfield (CS), inner ring, and outer ring of the ETDRS grid: retinal pigment epithelium (RPE), outer segments (OS), inner segments (IS), outer nuclear layer (ONL), inner retina (IR), and total retina (TR). RESULTS: Statistically significant losses of thickness of RPE and TR were detected in the CS and inner ring and of ONL and IS in the outer ring (all P < .05); a statistically significant decrease in the intact area of RPE and IS was observed in the inner ring, and of ONL in the outer ring (all P < .05); the change in MT and the intact area of the other layers showed a trend of decline over an observational period of 24 months. CONCLUSIONS: Significant thickness losses could be detected in outer retinal layers by SD-OCT over a 24-month period in patients with PROM1-associated retinal degeneration. Loss of thickness and/or intact area of such layers may serve as potential endpoints for clinical trials that aim to slow down the disease progression of PROM1-associated retinal degeneration.

Optical Coherence Tomography Feature of Retinoschisis in CRB1-Associated Maculopathy.

This case report describes 2 individuals with hyperreflective columns in the outer nuclear layer observed on optical coherence tomography and possible implications for CRB1-associated maculopathy.

Correlation Between Fundus Autofluorescence Pattern and Retinal Function on Microperimetry in Choroideremia.

Purpose: In patients with choroideremia, it is not known how smooth and mottled patterns on short-wavelength fundus autofluorescence (AF) imaging relate to retinal function. Methods: A retrospective case-note review was undertaken on 190 patients with choroideremia at two specialist centers for retinal genetics. Twenty patients with both smooth and mottled zones on short-wavelength AF imaging and concurrent mesopic microperimetry assessments were included. Mean retinal sensitivities within the smooth and mottled zones were compared between choroideremia patients, and identical points on mesopic microperimetry collected from 12 age-matched controls. Longitudinal analyses were undertaken at 2 and 5 years in a subset of patients. Results: In patients with choroideremia, mean retinal sensitivities at baseline were significantly greater in the smooth zone (26.1 ± 2.0 dB) versus the mottled zone (20.5 ± 4.2 dB) (P < 0.0001). Mean retinal sensitivities at baseline were similar in the smooth zone between choroideremia patients and controls (P = 0.054) but significantly impaired in the mottled zone in choroideremia compared to controls (P < 0.0001). The rate of decline in total sensitivity over 5 years was not significant in either the smooth or mottled zone in a small subset of choroideremia patients (n = 7; P = 0.344). Conclusions: In choroideremia, retinal sensitivity as determined by microperimetry correlates with patterns on AF imaging: retinal function in the smooth zone, where the retinal pigment epithelium is anatomically preserved, is similar to controls, but retinal sensitivity in the mottled zone is impaired. Translational Relevance: Patterns on AF imaging may represent a novel, objective outcome measure for clinical trials in choroideremia as a surrogate for retinal function.

Subclinical Angioid Streaks with Pseudodrusen: A New Phenotype of Age-Related Macular Degeneration.

INTRODUCTION: To describe subclinical angioid streaks (AS) as a frequent, peculiar age-related macular degeneration (AMD) phenotype, comparing features of eyes with subclinical AS with those of eyes with AMD without AS. METHODS: This was a retrospective, observational study. Among a patient cohort with AMD, we selected patients without known causes for AS whose eyes showed signs of angioid streaks (AS) on structural optical coherence tomography (OCT) but not on fundus examination. Selected OCT features of AS were Bruch's membrane (BM) breaks and large BM dehiscences. RESULTS: Among 543 eyes of 274 patients with AMD (mean ± standard deviation: 82 ± 7 years), 73 eyes of 46 patients (81 ± 7 years; p = 0.432) showed AS features on OCT (OCT AS) that were not visible on fundus examination. Estimated prevalence of subclinical age-related AS was 13.4% (95% confidence interval 10.3-16.3%) in this AMD population. Fifty-three eyes (73%) with AS features were affected by peripapillary atrophy, often with a "petaloid-like" pattern, similar to typical features of AS disease. Almost all cases (97%) presented reticular pseudodrusen (RPD), with (41%) or without (59%) drusen showing a significant difference in RPD prevalence in OCT AS eyes in comparison to AMD eyes without subclinical AS using generalized estimating equations (P < 0.001). Among the 73 subclinical AS cases, 71 were affected by late AMD (57 with macular neovascularization, 14 with geographic atrophy), showing a more advanced AMD stage in comparison with AMD eyes without subclinical AS (P < 0.001). The following OCT features were disclosed: BM breaks in 100% of cases and BM dehiscences in 37%. CONCLUSIONS: Subclinical AS in eyes with AMD is a peculiar phenotype of the disease, with features suggesting a primary involvement of Bruch's membrane and clinical similarities with mild, late-onset pseudoxanthoma elasticum.

Fundus autofluorescence imaging using red excitation light.

Retinal disease accounts significantly for visual impairment and blindness. An important role in the pathophysiology of retinal disease and aging is attributed to lipofuscin, a complex of fluorescent metabolites. Fundus autofluorescence (AF) imaging allows non-invasive mapping of lipofuscin and is a key technology to diagnose and monitor retinal disease. However, currently used short-wavelength (SW) excitation light has several limitations, including glare and discomfort during image acquisition, reduced image quality in case of lens opacities, limited visualization of the central retina, and potential retinal light toxicity. Here, we establish a novel imaging modality which uses red excitation light (R-AF) and overcomes these drawbacks. R-AF images are high-quality, high-contrast fundus images and image interpretation may build on clinical experience due to similar appearance of pathology as on SW-AF images. Additionally, R-AF images may uncover disease features that previously remained undetected. The R-AF signal increases with higher abundance of lipofuscin and does not depend on photopigment bleaching or on the amount of macular pigment. Improved patient comfort, limited effect of cataract on image quality, and lack of safety concerns qualify R-AF for routine clinical monitoring, e.g. for patients with age-related macular degeneration, Stargardt disease, or for quantitative analysis of AF signal intensity.

Unmet needs and future perspectives in hydroxychloroquine retinopathy.

Retinopathy is a well-recognized toxic effect of hydroxychloroquine treatment. As hydroxychloroquine retinopathy is potentially a vision-threatening condition, early detection is imperative to minimize vision loss due to drug toxicity. However, early detection of hydroxychloroquine retinopathy is still challenging even with modern retinal imaging techniques. No treatment has been established for this condition, except for drug cessation to minimize further damage. In this perspective article, we aimed to summarize the knowledge gaps and unmet needs in current clinical practice and research in hydroxychloroquine retinopathy. The information presented in this article may help guide the future directions of screening practices and research in hydroxychloroquine retinopathy.

Hydroxychloroquine-induced Retinal Toxicity.

Long-term use of hydroxychloroquine can cause retinopathy, which may result in severe and progressive visual loss. In the past decade, hydroxychloroquine use has markedly increased and modern retinal imaging techniques have enabled the detection of early, pre-symptomatic disease. As a consequence, the prevalence of retinal toxicity in long-term hydroxychloroquine users is known to be higher than was previously estimated. The pathophysiology of the retinopathy is incompletely characterised, although significant advances have been made in understanding the disease from clinical imaging studies. Hydroxychloroquine retinopathy elicits sufficient public health concern to justify the implementation of retinopathy screening programs for patients at risk. Here, we describe the historical background of hydroxychloroquine retinopathy and summarize its current understanding. We review the utility and limitations of each of the mainstream diagnostic tests used to detect hydroxychloroquine retinopathy. The key considerations towards a consensus on the definition of hydroxychloroquine retinopathy are outlined in the context of what is known of the natural history of the disease. We compare the current screening recommendations for hydroxychloroquine retinopathy, identifying where additional evidence is required, and the management of proven cases of toxicity. Finally, we highlight the areas for further investigation, which may further reduce the risk of visual loss in hydroxychloroquine users.