Peripapillary retinal nerve fibre layer thinning in patients with X-linked retinoschisis.

AIMS: To assess peripapillary retinal nerve fibre layer (pRNFL) thickness in patients with X-linked retinoschisis (XLRS), as pRNFL thinning may limit functional improvements in gene therapy trials. METHODS: This retrospective multicentre study included 49 eyes from 25 patients diagnosed with XLRS. Data collected with multimodal imaging at baseline and last follow-up (when available) included age, best-recorded visual acuity (BRVA), central retinal thickness, macular volume (MV), presence and location of peripheral retinoschisis and pRNFL thickness in the global (G), superotemporal (TS), superonasal (NS), inferotemporal (TI), inferonasal (NI), nasal (N) and temporal (T) sectors. Retinal sensitivity, assessed by microperimetry, was also recorded for seven patients at baseline. RESULTS: pRNFL was thinner (below the fifth percentile) in at least one sector in 72% of right eyes and 79% of left eyes, with thinning across three or more sectors in 20% of right and 17% of left eyes. In 44% of cases, thinning occurred in the temporal sectors of both eyes, with no nasal sectoral thinning. Number of peripheral retinoschisis quadrants matched thinned pRNFL sectors. A strong positive correlation was found between MV and temporal pRNFL thickness (r=0.71, p<0.01), while weak negative correlation trends were noted with age (p=0.05) and BRVA (logMAR; p=0.12) related to temporal thickness of pRNFL sectors. CONCLUSION: pRNFL thinning, predominantly sectoral and linked to macular or peripheral retinoschisis, occurs in about three-quarters of patients with XLRS, while diffuse thinning occurs in one-fifth. Temporal pRNFL thinning might occur only after the collapse of intraretinal cystoid cavities in the macula.

Assessment of Blood Flow Velocity in Retinal Vasculitis Using the Retinal Function Imager-A Pilot Study.

Background: This pilot study aimed to evaluate the Retinal Function Imager (RFI) for visualizing retinal vasculature and assessment of blood flow characteristics in patients with retinal vasculitis. The RFI is a non-invasive imaging device measuring the blood flow velocity (BFV) in secondary and tertiary retinal vessels using hemoglobin as an intrinsic motion-contrast agent. Methods: To test the feasibility of the RFI for patients with retinal vasculitis, capillary perfusion maps (nCPMs) were generated from 15 eyes of eight patients (five females; mean age: 49 ± 12 years) with a mean uveitis duration of 74 ± 85 months. Five of these patients had birdshot chorioretinopathy, and three had primarily non-occlusive venous retinal vasculitis of unknown origin. To reflect that the BFV may be more reduced in patients with prolonged disease, patients were classified into a short-term (uveitis duration: 8-15 months) and a long-term uveitis group (uveitis duration: 60-264 months). Data were compared with healthy controls (16 eyes of 11 patients; mean age 45 ± 12 years; 8 females). Results: The mean BFV in the controls was 3.79 ± 0.50 mm/s in the retinal arteries and 2.35 ± 0.44 mm/s in the retinal veins, which was significantly higher compared to the retinal vasculitis group. Patients revealed an arterial BFV of 2.75 ± 0.74 mm/s (p < 0.001) and a venous BFV of 1.75 ± 0.51 mm/s (p = 0.016). In the short-term group, a trend towards a decreased venular and arteriolar BFV was seen, while a significant reduction was observed in the long-term group. The patients' microvasculature anatomy revealed by the nCPMs appeared unevenly distributed and a lower number of blood vessels were seen, along with a lower degree of complexity of their branching patterns, when compared with controls. Conclusions: This study demonstrated a reduction in venular and arteriolar BFVs in patients with retinal vasculitis. BFV alterations were already observed in early disease stages and became more pronounced in progressed disease. Additionally, we showed that retinal microvasculature changes may be observed by nCPMs. Retinal imaging with the RFI may serve as a diagnostic and quantifying tool in retinal vasculitis.

Greener intravitreal injections: a narrative review.

Healthcare services are significant contributors to climate change. Ophthalmology, by virtue of the volume of appointments and procedures it generates, is thought to play a major role in this regard. Intravitreal injections (IVI) are a commonly performed ophthalmological procedure to treat patients with conditions such as macular neovascularisation secondary to neovascular age-related macular disease or myopia, diabetic macular oedema, and retinal vein occlusions. As IVIs become more ubiquitous, addressing their environmental impact and sustainability will become increasingly important. Strategies to tackle carbon emissions from IVIs may target the following areas which align with the Greenhouse Gas Protocol scopes: building energy; water consumption; travel to appointments; manufacture and procurement of the drug and other necessary materials; and waste disposal. We propose a path towards a more sustainable approach for IVIs, and discuss its potential safety as well as the patient experience.

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.

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.

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.

X-Linked Retinoschisis Masquerading Uveitis.

X-linked retinoschisis (XLRS) shows features also seen in patients with uveitis and is recognized as an uveitis masquerade syndrome. This retrospective study aimed to describe characteristics of XLRS patients with an initial uveitis diagnosis and to contrast these to patients with an initial XLRS diagnosis. Patients referred to a uveitis clinic, which turned out to have XLRS (n = 4), and patients referred to a clinic for inherited retinal diseases (n = 18) were included. All patients underwent comprehensive ophthalmic examinations, including retinal imaging with fundus photography, ultra-widefield fundus imaging, and optical coherence tomography (OCT). In patients with an initial diagnosis of uveitis, a macular cystoid schisis was always interpreted as an inflammatory macular edema; vitreous hemorrhages were commonly interpreted as intraocular inflammation. Patients with an initial diagnosis of XLRS rarely (2/18; p = 0.02) showed vitreous hemorrhages. No additional demographic, anamnestic, and anatomical differences were found. An increased awareness of XLRS as a uveitis masquerade syndrome may facilitate early diagnosis and may prevent unnecessary therapies.

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.

PHOTORECEPTOR DAMAGE IN TERSON SYNDROME.

PURPOSE: To describe photoreceptor damage in patients with Terson syndrome as a potential cause for inconsistent clinical outcomes. METHODS: Clinical evaluation and retinal imaging in six patients. RESULTS: Four patients were women and two men, with an average age of 46.8 years (SD 8.9). Four patients suffered aneurysmal subarachnoid hemorrhage, one vertebral artery dissection, and one superior sagittal sinus thrombosis. In 11 eyes, a consistent pattern of outer retinal changes within the central retina affecting the ellipsoid zone and the outer nuclear layer was observed, indicating photoreceptor damage. Areas of photoreceptor damage showed poor spatial correlation with intraocular hemorrhage, particularly subinternal limiting membrane hemorrhage. The observed retinal abnormalities demonstrated incomplete recovery over long-term follow-up 3.5 to 8 years posthemorrhage, irrespective of surgical or conservative treatment strategy, and had variable impact on the patients' visual function. CONCLUSION: The observations suggest that photoreceptor damage in Terson syndrome likely represents a distinct manifestation of this condition, which could be caused by transient ischemia of the outer retina secondary to acute rise in intracranial pressure.

Topographic patterns of retinal lesions in multiple evanescent white dot syndrome.

PURPOSE: To demonstrate different topographic distributions of multiple-evanescent white dot syndrome (MEWDS) and secondary MEWDS disease and to describe possible associations. METHODS: Clinical evaluation and multimodal retinal imaging in 27 subjects with MEWDS (29 discrete episodes of MEWDS). Ophthalmic assessment included best-corrected visual acuity testing and multimodal retinal imaging with OCT, blue-light autofluorescence, fluorescein and indocyanine green angiography, fundus photography, and widefield pseudocolor and autofluorescence fundus imaging. RESULTS: The topographic distribution of MEWDS lesions was centered on or around the optic disc (n = 17, 59%), centered on the macula (n = 7, 24%), sectoral (n = 2, 7%), or was indeterminate (n = 3, 10%). The MEWDS episodes either occurred in the absence ('primary MEWDS'; n = 14, 48%) or presence of concurrent chorioretinal pathology ('secondary MEWDS'; n = 15, 52%). In patients with the latter, MEWDS lesions were often centered around a coexisting chorioretinal lesion. The majority of patients in both groups experienced resolution of their symptoms and retinal changes on multimodal imaging by 3 months. CONCLUSIONS: Distinct distributions of MEWDS lesions were identified. MEWDS may occur in tandem with other chorioretinal pathology, which may impact the topography of MEWDS lesions.

The retinal phenotype in primary hyperoxaluria type 2 and 3.

BACKGROUND: The primary hyperoxalurias (PH1-3) are rare inherited disorders of the glyoxylate metabolism characterized by endogenous overproduction of oxalate. As oxalate cannot be metabolized by humans, oxalate deposits may affect various organs, primarily the kidneys, bones, heart, and eyes. Vision loss induced by severe retinal deposits is commonly seen in infantile PH1; less frequently and milder retinal alterations are found in non-infantile PH1. Retinal disease has not systematically been investigated in patients with PH2 and PH3. METHODS: A comprehensive ophthalmic examination was performed in 19 genetically confirmed PH2 (n = 7) and PH3 (n = 12) patients (median age 11 years, range 3-59). RESULTS: Median best corrected visual acuity was 20/20. In 18 patients, no retinal oxalate deposits were found. A 30-year-old male with PH2 on maintenance hemodialysis with plasma oxalate (Pox) elevation (> 100 µmol/l; normal < 7.4) demonstrated bilateral drusen-like, hyperreflective deposits which were interpreted as crystallized oxalate. Two siblings of consanguineous parents with PH2 presented with retinal degeneration and vision loss; exome-wide analysis identified a second monogenic disease, NR2E3-associated retinal dystrophy. CONCLUSIONS: Retinal disease manifestation in PH2 and PH3 is rare but mild changes can occur at least in PH2-associated kidney failure. Decline in kidney function associated with elevated plasma oxalate levels could increase the risk of systemic oxalosis. Deep phenotyping combined with genomic profiling is vital to differentiate extrarenal disease in multisystem disorders such as PH from independent inherited (retinal) disease. A higher resolution version of the Graphical abstract is available as Supplementary information.

Morphological and functional parameters in X-linked retinoschisis patients-A multicentre retrospective cohort study.

Introduction: X-linked retinoschisis (XLRS) is a potential target for gene supplementation approaches. To establish potential structural and functional endpoints for clinical trials, a comprehensive understanding of the inter-eye symmetry, relationship between structural and functional parameters, and disease progression is vital. Methods: In this retrospective multicentre study, 118 eyes of 59 XLRS patients with RS1 mutations were assessed. Information from center databases included: RS1 variant; age at presentation; best-corrected visual acuity (BCVA), central retinal thickness (CRT), macular volume (MV) at presentation and at the last follow up; full-field electroretinogram (ERG) findings; presence of peripheral retinoschisis and complications (vitreous hemorrhage, retinal detachment); treatment with systemic or topical carbonic anhydrase inhibitors (CAI). Results: Inter-eye symmetry revealed strong correlation in CRT (r = 0.77; p < 0.0001) and moderate correlations in MV (r = 0.51, p < 0.0001) and BCVA (r = 0.49; p < 0.0001). Weak or no correlations were observed between BCVA and structural parameters (CRT, MV). Peripheral retinoschisis was observed in 40 (68%), retinal detachment in 9 (15%), and vitreous hemorrhage in 5 (8%) patients, respectively. Longitudinal examinations (mean, 4.3 years) showed no BCVA changes; however, a reduction of the CRT (p = 0.02), and MV (p = 0.01) was observed. Oral and/or topical CAI treatment did not significantly alter the CRT (p = 0.34). Discussion: The XLRS phenotype demonstrates a strong CRT symmetry between the eyes within individual patients and stable BCVA over several years. BCVA exhibits a weak correlation with the morphological parameters of retinal thickness (CRT MV). In our cohort, longitudinal functional changes were not significant, likely attributed to the short average follow-up period. Furthermore, CAI treatment didn't influence both morphological and functional outcomes.

Impaired glutamylation of RPGRORF15 underlies the cone-dominated phenotype associated with truncating distal ORF15 variants.

Pathogenic variants in the Retinitis pigmentosa GTPase regulator (RPGR) gene lead to a clinically severe form of X-linked retinal dystrophy. However, it remains unclear why some variants cause a predominant rod, while others result in a cone-dominated phenotype. Post-translational glutamylation of the photoreceptor-specific RPGRORF15 isoform by the TTLL5 enzyme is essential for its optimal function in photoreceptors, and loss of TTLL5 leads to retinal dystrophy with a cone phenotype. Here we show that RPGR retinal disease, studied in a single cohort of 116 male patients, leads to a clear progressive shift from rod- to cone-dominating phenotype as the RPGRORF15 variant location approaches the distal part of the Open Reading Frame 15 (ORF15) region. The rod photoreceptor involvement on the contrary diminishes along the RGPR sequence, and the variants associated with the cone only phenotype are located predominantly in the very distal part, including the C-terminal basic domain. Moreover, these distal truncating RPGRORF15 variants disrupt the interaction with TTLL5 and lead to a significant impairment of RPGR glutamylation. Thus, consistent with the phenotype of TTLL5 pathogenic variants, our study shows that RPGRORF15 variants, which disrupt its basic domain and the interaction with TTLL5, also impair RPGR glutamylation and lead to the cone phenotype. This has implications for ongoing gene therapy clinical trials where the application of RPGR with impaired glutamylation may be less effective in treating RGPR dystrophies and may even convert a rod-cone dystrophy into a cone dystrophy phenotype.

[Sustainability in ophthalmology : Adaptation to the climate crisis and mitigation]. / Nachhaltigkeit in der Augenheilkunde : Adaptation an die Klimakrise und Mitigation.

The climate crisis is threatening the health of current and future generations and represents a particular challenge for healthcare systems. To address man-made climate change, comprehensive adaptation and mitigation strategies are crucial. Medicine and ophthalmology offer various opportunities to reduce the CO2 (carbon dioxide) footprint - these should be implemented and politically encouraged. Data-driven sustainability tools may provide options to evaluate the environmental footprint and to initiate optimization strategies. Life cycle assessments are an approach to systemically measure the environmental footprint and may facilitate sustainable decisions processes. The German health system needs to develop quantifiable and holistic strategies to reduce CO2; sustainability might become a future performance indicator. This article discusses examples of adaptation to the climate crisis and mitigation in ophthalmology and beyond.

GUCY2D-Related Retinal Dystrophy with Autosomal Dominant Inheritance-A Multicenter Case Series and Review of Reported Data.

To report the clinical phenotype and associated genotype of a European patient cohort with GUCY2D-related autosomal-dominant (AD) cone-/cone-rod dystrophy (COD/CORD), we retrospectively analyzed 25 patients (17 female, range 12-68) with GUCY2D-related AD-COD/CORD from three major academic centers in Europe and reviewed the previously published data of 148 patients (visual acuity (VA), foveal thickness, age of first symptoms, and genetic variant). Considering all the patients, the onset of first symptoms was reported at a median age of 7 years (interquartile range 5-19 years, n = 78), and mainly consisted of reduced VA, photophobia and color vision abnormality. The disease showed a high degree of inter-eye symmetry in terms of VA (n = 165, Spearman's ρ = 0.85, p < 0.0001) and foveal thickness (Spearman's ρ = 0.96, n = 38, p < 0.0001). Disease progression was assessed by plotting VA as a function of age (n = 170). A linear best-fit analysis suggested a loss of 0.17 logMAR per decade (p < 0.0001). We analyzed the largest cohort described so far (n = 173), and found that the most common mutations were p.(Arg838Cys) and p.(Arg838His). Furthermore, the majority of patients suffered severe vision loss in adulthood, highlighting a window of opportunity for potential intervention. The emerging patterns revealed by this study may aid in designing prospective natural history studies to further define endpoints for future interventional trials.