[Severe Conjunctival and Corneal Epithelial Dysplasia: A Case Series]. / Schwere konjunktivale und korneale epitheliale Dysplasie: eine Fallserie.

BACKGROUND/OBJECTIVES: Ocular surface squamous neoplasia (OSSN) are among the most frequent non-pigmented malignancies of the ocular surface. They have a wide range of histological characteristics - ranging from mild epithelial dysplasia to invasive carcinoma of the squamous cells of the cornea. They may be restricted to the conjunctiva or also involve the cornea. As there are no leading symptoms in the early stages, diagnosis may be very delayed in patients who do not receive regular ophthalmological treatment. The present case series describes clinical and histological data on OSSN and includes clinical and histological data on OSSN, including possible clinical presentations, important risk factors, special histological and cytological features and therapeutic options. METHODS: Retrospective case series of patients with histologically confirmed severe epithelial dysplasia of the conjunctiva and cornea consistent with OSSN who presented to the Department of Ophthalmology in Basel University Hospital. The analysis covered demographic data, symptoms, diagnostic testing (photo documentation, brush biopsy), treatment and cytological and/or histological material and findings. RESULTS: We report on five patients aged between 41 and 92 years at the time of diagnosis. The histological findings in all patients included severe epithelial dysplasia, but with a heterogenous clinical presentation. In all cases, the lesion started in the conjunctiva, but traversed the limbus and extended to the cornea. The primary treatment was always surgical removal. In one patient, this had to be repeated several times due to recurrent metaplasia and was complemented by subsequent mitomycin C therapy. The clinical outcome ranged between total restitution of the original state to inevitable enucleation. CONCLUSION: The clinical presentation of OSSN is highly heterogenous, so that the initial diagnosis is difficult. There are no official guidelines for treatment, so that the treatment of choice varied between clinics. Regular ophthalmological follow-ups are recommended, even after complete surgical excision. Possible relevant concomitant diseases and risk factors must be identified before therapy.

Anti-VEGF Treatment for Secondary Neovascularization in Pseudoxanthoma Elasticum - Age of Onset, Treatment Frequency, and Visual Outcome.

PURPOSE: To assess the onset, treatment frequency, and visual outcome of anti-vascular endothelial growth factor (anti-VEGF) treatment due to secondary choroidal neovascularization (CNV) in patients with pseudoxanthoma elasticum (PXE). DESIGN: Retrospective cohort study METHODS: One-hundred six eyes of 53 patients with PXE were analyzed. The assessment of CNV activity relied on hemorrhage visible on funduscopy and intra- / subretinal fluid on optical coherence tomography (OCT), individually defining a shortening or extension of treatment interval. Best-corrected visual acuity (BCVA) at baseline, age at anti-VEGF therapy initiation, and BCVA-drop events at exudation onset (worsening of BCVA of 2 or more lines) were documented. Further, we assessed the number of injections during the first year and the total number of injections, the time to treatment initiation of the fellow eye, and BCVA over time. RESULTS: During a median observation period of 77 months (IQR 49; 126) patients received a median number of 28.0 anti-VEGF-injections (IQR 9.8; 43.5). Eight patients received no injection (median age at baseline 38.1 years), 11 patients underwent anti-VEGF treatment in one eye (median age 47.2 years) and 34 patients in both eyes (median age 51.8 years). The median age at the first anti-VEGF treatment was 52.80 years (IQR 47.2-57.6). Applying Cox regression models, the median "survival" time of fellow eye until treatment initiation was 16.8 months. In the group of bilateral treated patients, the median time difference was 9.6 months (IQR 2.1- 32.4, range 0-122) The median number of injections was 5.5 per eye in the first year of treatment (IQR 3-7) and was associated with the total number of injections in the observation period (2.33, CI 1.22-3.44, P < .001). A better BCVA at the last follow-up visit was associated with a better baseline BCVA (P < .001, R2 = 0.318) and with the absence of a BCVA drop at the onset of exudation (P = 0.035, R2 = 0.339). CONCLUSIONS: The results of this study indicate that anti-VEGF treatment is required for most PXE patients at a relatively young age. Once treatment in one eye is initiated, the time to fellow eye treatment is relatively short. A BCVA drop before treatment initiation is a risk factor for worse visual outcomes, suggesting that treatment is prudent before exudation affects the central retina. Given the young age of onset and intensive treatment needs, patients with PXE might particularly benefit from longer-acting anti-VEGF therapeutics.

Ellipsoid Zone recovery in Macular Telangiectasia Type 2 (MacTel).

PURPOSE: To describe imaging features of Macular Telangiectasia Type 2 (MacTel) eyes experiencing ellipsoid zone (EZ) recovery. METHODS: MacTel patients with EZ-recovery were identified from the Natural History and Observational Registry Study and underwent retinal imaging including optical coherence tomography (OCT) and fundus photography. Eyes were graded according to the classification system by Gass and Blodi, the EZ-loss area was measured and OCT parameters were assessed by two independent readers. Parameters were analysed for their presence prior to EZ-recovery. RESULTS: Twenty-four eyes of 21 patients (12 female, 57.12%; mean age 68 ± 8.54 years) were included in this study and followed for 21.25 ± 12.79 months. At baseline, mean EZ-loss area was 0.036 ± 0.028 mm2 and 0.01 ± 0.013 mm2 at follow-up (p<0.001). A persisting external limiting membrane overlaying the EZ-loss was detected in 16 cases (66%) and hyperreflective changes in the outer retina were present in 18 cases (75%). Best corrected visual acuity was 0.23 (20/32) ± 0.33 logMar at baseline and 0.34 (20/40) ± 0.34 logMar at follow up (p=0.3). CONCLUSION: Distinct OCT features precede ellipsoid zone recovery in MacTel and warrant further studies investigating implications for patient care and clinical trial interpretation.

Ranibizumab Biosimilars in Treating Retinal Disorders: A Cost-Effective Revolution?

Ranibizumab, is a humanized, monoclonal antibody fragment that binds and inactivates vascular endothelial growth factor-A (VEGF-A) and VEGF-B. One of the main indications for an intravitreal treatment with ranibizumab is age-related macular degeneration (AMD), which is a retinal disease with a high worldwide socioeconomic impact. Biosimilars constitute biological products that demonstrate similar pharmacodynamic and pharmacokinetic characteristics with a reference product, as well as comparable clinical efficacy, safety and immunogenicity. Since the approval of the first biosimilar Razumab, there has been a variety of new biosimilars available on the market. They offer the advantage of the same good clinical and safety results at a better price. All Ranibizumab biosimilars that have gained approval were tested in double masked Phase 3 clinical studies. The use of Ranibizumab biosimilars in neovascular AMD is well reported in the bibliography. Nevertheless, over the last few years, there is a tendency of using biosimilars in other retinal diseases like retinopathy of prematurity (ROP), diabetic macular edema (DME) or polypoidal choroidal vasculopathy (PCV). In conclusion, ranibizumab biosimilars offer a promising avenue for the management of retinal diseases, especially in countries with lower socioeconomic status, where there is lack of availability of innovator ranibizumab. However, further research is required to fully explore their efficacy, safety, and long-term outcomes in a plethora of retinal diseases.

Local and Global Associations of Reticular Pseudodrusen in Age-Related Macular Degeneration.

PURPOSE: To investigate the spatial distribution of reticular pseudodrusen (RPD) in eyes with age-related macular degeneration (AMD) and their correlation with functional measures, retinal thickness, and changes over time. DESIGN: Longitudinal, cohort study. PARTICIPANTS: Thirty-five participants with RPD and spectrum of AMD severity (including no AMD). METHODS: Multimodal imaging was graded by a reading center, including evaluation of color fundus imaging to assess AMD severity scores. Reticular pseudodrusen presence on OCT volumes was confirmed on en face imaging and the RPD extent was contoured on infrared images. One study eye per participant underwent rod-mediated dark adaptation, measuring rod intercept time (RIT) at 5° and/or 12° superior to the fovea. MAIN OUTCOME MEASURES: The primary outcome was RIT and OCT thickness measures which were correlated with RPD area. RESULTS: A total of 51 eyes had ≥ 1 visit with RPD detected (mean follow-up, 2.19 ± 2.04 years; range, 0-5 years), totaling 169 eye-based visits with RPD. Of the 51 eyes with RPD, 5 (9.8%) developed geographic atrophy and 17 (33.3%) progressed to neovascular AMD. Larger RPD areas were detected more frequently in AMD severity scores 6-7. Reticular pseudodrusen area within an eye generally increased over time. The lesion distribution showed a predilection for the superior retina, especially the outer superior subfield of the ETDRS grid, with the central subfield having least involvement. Reticular pseudodrusen area was inversely correlated with central subfield thickness and positively correlated with RIT at 5° (P = 0.001; r2 = 0.01) and 12° (P = 0.004; r2 = 0.01). Rod-mediated dark adaptation at 5° reached the test ceiling in > 85% of visits, irrespective of RPD lesion presence/absence at the test location. Retinal thickness decreased monotonically, with the central subfield demonstrating the greatest percentage change over 5 years (Δ = -5.47%). CONCLUSIONS: In AMD, RPD involve predominantly the superior retina but can involve all ETDRS subfields and evolve over time. Eyes with RPD exhibit structural and functional impairments that can be measured beyond the boundaries of the RPD lesions, suggesting changes associated with RPD are associated with both local changes and a more widespread process. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Establishing Fully-Automated Fundus-Controlled Dark Adaptometry: A Validation and Retest-Reliability Study.

Purpose: The purpose of this study was to establish and validate a novel fundus-controlled dark-adaptometry method. Methods: We developed a custom dark-adaptometry software for the S-MAIA device using the open-perimetry-interface. In the validation-substudy, participants underwent dark-adaptometry testing with a comparator device (MonCvONE, 59% rhodopsin bleach, cyan and red stimuli centered at 2 degrees, 4 degrees, and 6 degrees eccentricity). Following a brief break (approximately 5 minutes), the participants were bleached again and underwent dark-adaptometry testing with the S-MAIA device (same loci). In the retest reliability-substudy, participants were tested twice with the S-MAIA device (same loci as above). Nonlinear curve fitting was applied to extract dark-adaptation curve parameters. Validity and repeatability were summarized in terms of the mean bias and 95% limits of agreement (LoAs). Results: In the validation-substudy (N = 20 participants, median age interquartile range [IQR] 31.5 years [IQR = 25.8, 62.0]), measures of rod-mediated dark-adaptation showed little to no between method differences for the cone-rod-break-time (bias 95% confidence interval [95% CI] of +0.1 minutes [95% CI = -0.6 to 0.8]), rod-intercept-time (-0.23 minutes [95% CI = -1.38 to 0.93]), and S2 slope (-0.01 LogUnits/minutes [95% CI = -0.02 to -0.01]). In the retest reliability-substudy (N = 10 participants, 32.0 years [95% CI = 27.0, 57.5]), the corresponding LoAs were (cone-rod-break-time) -3.94 to 2.78 minutes, (rod-intercept-time) -4.55 to 3.11 minutes, and (S2 slope [rate-limited component of rod recovery]) -0.03 to 0.03 LogUnits/minutes. The LoAs for the steady-state cone and rod thresholds were -0.28 to 0.33 LogUnits and -0.34 to 0.28 LogUnits. Conclusions: The devised fundus-controlled dark-adaptometry method yields valid and reliable results. Translational Relevance: Fundus-controlled dark-adaptometry solves the critical need for localized testing of the visual cycle and retinoid transfer in eyes with unstable fixation.

Multimodal imaging and deep learning in geographic atrophy secondary to age-related macular degeneration.

Geographic atrophy (GA) secondary to age-related macular degeneration is among the most common causes of irreversible vision loss in industrialized countries. Recently, two therapies have been approved by the US FDA. However, given the nature of their treatment effect, which primarily involves a relative decrease in disease progression, discerning the individual treatment response at the individual level may not be readily apparent. Thus, clinical decision-making may have to rely on the quantification of the slope of GA progression before and during treatment. A panel of imaging modalities and artificial intelligence (AI)-based algorithms are available for such quantifications. This article aims to provide a comprehensive overview of the fundamentals of GA imaging, the procedures for diagnosis and classification using these images, and the cutting-edge role of AI algorithms in automatically deriving diagnostic and prognostic insights from imaging data.

The Optical Coherence Tomography and Microperimetry Biomarker Evaluation in Patients with Geographic Atrophy (OMEGA) Study: Design and Baseline Characteristics - OMEGA Report 1.

INTRODUCTION: The aim of this study was to describe the design and the participants' baseline characteristics of a prospective natural history study of geographic atrophy (GA) secondary to age-related macular degeneration. METHODS: The optical coherence tomography (OCT) and microperimetry biomarker evaluation in patients with GA (OMEGA) study was conducted at a tertiary referral center (ClinicalTrials.gov identifier: NCT05963646). Participants were followed for 12 months during 4 visits (baseline and follow-up exams at weeks 12, 24, and 48) with best-corrected Early Treatment of Diabetic Retinopathy Study visual acuity, low-luminance visual acuity (LLVA), and quick contrast sensitivity function testing. Further, participants underwent spectral-domain OCT, OCT angiography, fundus autofluorescence imaging, and mesopic microperimetry testing. RESULTS: Thirty participants (median [IQR] age of 79 [77, 84] years) and 37 study eyes were included with a (median [IQR]) GA area of 1.40 mm2 (0.49, 5.24) at baseline. Out of 37 study eyes, six developed macular neovascularizations (16%). The study-eye best-corrected visual acuity was (median [IQR]) 0.18 logarithm of the minimum angle of resolution (logMAR) (0.06, 0.26), LLVA 0.66 logMAR (0.36, 0.88), and the microperimetry mean sensitivity 18.4 dB (9.21, 20.9). The highest correlation between square root GA area and a visual function test was evident for LLVA (R2 of 0.578), followed by area under the log contrast sensitivity function curve (0.519) and microperimetral retinal sensitivity (0.487). CONCLUSION: This report lays out the design and baseline characteristics of the OMEGA study, which aims to contribute to the understanding of the natural history of GA. The OMEGA study will provide estimates of the ability to detect change and retest reliability for a panel of structure and functional assessments.

LOW-DOSE SUPPLEMENTATION WITH RETINOL IMPROVES RETINAL FUNCTION IN EYES WITH AGE-RELATED MACULAR DEGENERATION BUT WITHOUT RETICULAR PSEUDODRUSEN.

PURPOSE: The aim of this study was to determine the functional impact of oral vitamin A supplementation in patients with intermediate age-related macular degeneration with and without reticular pseudodrusen (RPD) demonstrating dysfunction in dark adaptation. METHODS: Five patients with intermediate age-related macular degeneration and without RPD (AMD group; mean ± SD age 78.0 ± 4.7 years) and seven with RPD (RPD group; age 74.1 ± 11.2 years) were supplemented with 16,000 IU of vitamin A palmitate for 8 weeks. Assessment at baseline, 4, 8, and 12 weeks included scotopic thresholds, dark adaptation, best-corrected and low luminance visual acuities, and the low-luminance quality of life questionnaire. RESULTS: In the linear mixed model, rod intercept time improved significantly in the AMD group (mean [95% CI] change -1.1 minutes [-1.8; -0.5] after 4 weeks ( P < 0.001) and -2.2 min [-2.9 to -1.6] after 8 weeks of vitamin A supplementation ( P < 0.001). The dark adaptation cone plateau also significantly improved (i.e., more sensitive cone threshold) at 4 and 8 weeks ( P = 0.026 and P = 0.001). No other parameters improved in the AMD group, and there was no significant improvement in any parameter in the RPD group despite significantly elevated serum vitamin A levels measurable in both groups after supplementation ( P = 0.024 and P = 0.013). CONCLUSION: Supplementation with 16,000 IU vitamin A, a lower dose than used in previous studies, partially overcomes the pathophysiologic functional changes in AMD eyes. The lack of improvement in the RPD group may indicate structural impediments to increasing vitamin A availability in these patients and/or may reflect the higher variability observed in the functional parameters for this group.

Choriocapillaris Flow Signal Impairment in Patients With Pseudoxanthoma Elasticum.

Purpose: To quantify choriocapillaris flow alterations in patients with pseudoxanthoma elasticum (PXE) in pre-atrophic stages and its association with structural changes of the choroid and outer retina. Methods: Thirty-two eyes of 21 patients with PXE and 35 healthy eyes of 35 controls were included. The density of choriocapillaris flow signal deficits (FDs) was quantified on 6 × 6-mm optical coherence tomography angiography (OCTA) images. Spectral-domain optical coherence tomography (SD-OCT) images were analyzed for thicknesses of the choroid and outer retinal microstructure and correlated with choriocapillaris FDs in the respective Early Treatment Diabetic Retinopathy Study subfield. Results: The multivariable mixed model analysis for choriocapillaris FDs revealed significantly higher FDs associated with the group (PXE patients vs. controls +13.6; 95% confidence interval [CI] 9.87-17.3; P < 0.001), with increasing age (+0.22% per year; 95% CI 0.12-0.33; P < 0.001), and with retinal location (significantly higher FDs in nasal compared to temporal subfields). Choroidal thickness (CT) did not differ significantly between both groups (P = 0.078). The CT and choriocapillaris FDs were inversely correlated (-1.92 µm per %FDs; interquartile range -2.81 to -1.03; P < 0.001). Larger values of the choriocapillaris FDs were associated with significant thinning of the overlying photoreceptor layers (outer segments: -0.21 µm per %FDs, P < 0.001; inner segments: -0.12 µm per %FDs, P = 0.001; outer nuclear layer: -0.72 µm per %FDs; P < 0.001). Conclusions: Patients with PXE display significant alterations of the choriocapillaris on OCTA even in pre-atrophic stages and in the absence of significant choroidal thinning. The analysis favors choriocapillaris FDs over choroidal thickness as a potential early outcome measure for future interventional trials in PXE. Further, increased FDs in nasal compared to temporal locations mirror the centrifugal spread of Bruch's membrane calcification in PXE.

Diagnostic Accuracy of the Amsler Grid Test for Detecting Neovascular Age-Related Macular Degeneration: A Systematic Review and Meta-analysis.

Importance: Patients with nonneovascular age-related macular degeneration (AMD) are encouraged to use the Amsler grid test for self-assessment to facilitate early diagnosis. The test is widely recommended, suggesting a belief that it signals worsening AMD, warranting its use in home monitoring. Objective: To systematically review studies of the diagnostic test accuracy of the Amsler grid in the diagnosis of neovascular AMD and to perform diagnostic test accuracy meta-analyses. Data Sources: A systematic literature search was conducted in 12 databases for relevant titles from database inception until May 7, 2022. Study Selection: Studies included those with groups defined as having (1) neovascular AMD and (2) either healthy eyes or eyes with nonneovascular AMD. The index test was the Amsler grid. The reference standard was ophthalmic examination. After removal of obviously irrelevant reports, 2 authors (J.B. and M.S.) independently screened the remaining references in full text for potential eligibility. Disagreements were resolved by a third author (Y.S.). Data Extraction and Synthesis: Two authors (J.B. and I.P.) independently extracted all data and evaluated quality and applicability of eligible studies using the Quality Assessment of Diagnostic Accuracy Studies 2. Disagreements were resolved by a third author (Y.S.). Main Outcomes and Measures: Sensitivity and specificity of the Amsler grid for detecting neovascular AMD with comparators being either healthy control participants or patients with nonneovascular AMD. Results: Of 523 records screened, 10 studies were included with a total of 1890 eyes (mean participant age ranging from 62 to 83 years). Sensitivity and specificity to diagnose neovascular AMD were 67% (95% CI, 51%-79%) and 99% (95% CI, 85%-100%), respectively, when comparators were healthy control participants and 71% (95% CI, 60%-80%) and 63% (95% CI, 49%-51%), respectively, when control participants were patients with nonneovascular AMD. Overall, potential sources of bias were low across studies. Conclusions and Relevance: Although the Amsler grid is easy and inexpensive to use for detection of metamorphopsia, its sensitivity may be at levels typically not recommended for monitoring. Coupling this lower sensitivity with only moderate specificity to identify neovascular AMD in a population at risk, these findings suggest that such patients typically should be encouraged to undergo ophthalmic examination regularly, regardless of any results of Amsler grid self-assessment.

[Ocular alterations in patients with Alport syndrome-An update]. / Okuläre Veränderungen bei Patienten mit Alport-Syndrom ­ ein Update.

BACKGROUND AND OBJECTIVE: Alport syndrome (AS) is a rare hereditary systemic disease that results in alterations of the kidneys, inner ear, and various structures of the eye. It is caused by mutations in one of the genes encoding collagen type IV. In recent years, new and innovative imaging techniques have added characteristics of ocular alterations in AS and provided new insights, including into the pathogenesis of the disease. The aim of this paper is to provide an overview of the current knowledge of ocular changes in AS, as well as to present the Alport ocular pass. METHOD: Narrative review article. RESULTS: Ocular manifestations of AS include changes in the cornea, lens, and retina. Specifically, posterior polymorphic corneal dystrophy, anterior lenticonus (pathognomonic for AS), and various retinal changes have been described, which have been further characterized in recent years by newer imaging techniques. In particular, foveal changes in AS may present as both a thickened central retina in the context of foveal hypoplasia or a staircase-like thinning of the fovea. Both lesions could provide further insights into the role of type IV collagen in ocular structures. CONCLUSION: The AS can manifest in various structures of the eye. The staircase-like changes of the central retina in AS patients indicate the important role of collagen type IV in the homeostasis and regular function of the inner retinal layers. The often mild foveal hypoplasia may provide clues to the role of collagen type IV in retinal embryogenesis. While anterior lenticonus is pathognomonic for AS and can be treated easily by refractive lens exchange, the only option currently available for retinal alterations is close follow-up and, if necessary, treatment of systemic complications of AS.

Hyperreflective Foci in Age-Related Macular Degeneration are Associated with Disease Severity and Functional Impairment.

PURPOSE: To analyze presence of hyperreflective foci (HRF) across different age-related macular degeneration (AMD) severities and examine its correlation with other structural and functional AMD features. DESIGN: Longitudinal, single-center, case-control study. PARTICIPANTS: One hundred and fifty-eight participants aged > 50 years old with varying AMD severities (including no AMD). METHODS: Color fundus imaging was used to assess AMD severity and hyperpigmentation (PGM) presence. Subretinal drusenoid deposits (SDD) and HRF were detected on OCT volumes. The correlations of HRF with additional AMD features were evaluated using linear and logistic mixed-effects models. One study eye per participant underwent dark adaptation (DA) testing to measure rod intercept time (RIT) for structure function associations. Eyes were followed longitudinally and changes in AMD severity and RIT were measured relative to HRF presence. MAIN OUTCOME MEASURES: The primary outcome was presence of HRF, which was compared with presence of other AMD features and DA impairment. RESULTS: One hundred and fifty-eight participants (median baseline age of 73.1 [interquartile range (IQR) = 66-79] years) contributing 1277 eye visits were included. Hyperreflective foci (HRF) were detected more frequently in higher AMD severities. Hyperreflective-foci presence was significantly associated with PGM presence (odds ratio 832.9, P < 0.001) and SDD presence (odds ratio 9.42, P = 0.017). Eyes with HRF demonstrated significantly longer DA (median 27.1 [IQR = 16-40] minutes) than those without HRF (13.5 [10-22] minutes) but less than eyes with SDD only (40 [28-40] minutes). Highest RIT values were found in eyes with both HRF and SDD (40.0 [40-40] minutes). Age and HRF explained a similar proportion of RIT variability as age and SDD. Eyes that developed HRF demonstrated baseline RITs closer to eyes with HRF at baseline, compared with eyes that never developed HRF (29.1 [16-40], 38.5 [22-40] versus 13.1 [10-22] minutes; Kruskal-Wallis P < 0.001). CONCLUSIONS: The progressively increased presence of HRF in higher AMD severities, and its correlation with previously associated AMD biomarkers, suggests HRF is an important OCT feature adding to the understanding of disease progression. Hyperreflective foci presence was associated with delays in DA, indicating HRF is a marker for visual cycle impairment. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.