Frank G. Holz

Introduction: There is an unmet medical need for therapies in intermediate age-related macular degeneration (iAMD). The prospective European multi-center cohort study MACUSTAR validates structural, functional and patient-reported iAMD endpoints for use in future trials. The multiplicity of assessments allows characterizing iAMD in more dimensions than previously available. We describe the heterogeneity of assessments in the iAMD baseline cohort of the MACUSTAR study. Methods: A wide range of assessments were administered across 20 European study sites in accordance with established guidelines. These assessments encompassed multiple structural evaluations, such as color fundus photography, fundus autofluorescence, and optical coherence tomography. Additionally, functional tests were conducted, including assessments of best-corrected and low-luminance visual acuity (VA), Moorfields acuity, contrast sensitivity, reading speed, mesopic and scotopic microperimetry, and dark adaptometry. Moreover, patient-reported outcome assessments, specifically the Vision Impairment in Low Luminance questionnaire, were also incorporated into the evaluation process. Associations between variables were investigated using Phi coefficients, Pearson correlation coefficients and age-corrected regression models. Results: Five-hundred eighty-five individuals with iAMD (66% women; mean (standard deviation) age: 72±7 years) were included in the MACUSTAR study. Forty-nine percent had pigmentary abnormalities, 27% had reticular pseudodrusen; 10% and 9% had incomplete and complete retinal pigment epithelium and outer retinal atrophy at baseline, respectively. Mean best-corrected VA, low-luminance VA and mesopic average threshold on microperimetry at baseline were 0.03±0.11 logMAR, 0.24±0.16 logMAR and 23.3±3.7 dB. Mean VILL subscale scores at baseline were 2±2 to 2±3 logits. Phi coefficients between structural assessments ranged between 0.17 and 0.22 (median 0.21); correlation coefficients between function tests ranged between 0.07 and 0.69 (median 0.34) and between VILL scores ranged between 0.21 and 0.68 (median 0.23). Conclusion: The findings from this broad and comprehensive spectrum of assessments of structure, function, and patient-reported outcomes in iAMD suggest that the disease spectrum is diverse and heterogeneous and that further efforts are necessary to fully understand and characterize iAMD in all its complexities. A further in-depth characterization will enable novel enrichment strategies for clinical trials in iAMD. Trial registration: ClinicalTrials.gov, NCT03349801. Registered on November 22, 2017

Zusammenfassung Fragestellung Die Zulassung neuer Therapien in der Augenheilkunde macht klinische Studien essenziell notwendig. Regelmäßig stellt die Rekrutierung geeigneter Studienpatienten eine große Herausforderung für die teilnehmenden Kliniken dar. Viele Patienten haben grundsätzliche Vorbehalte und Ängste gegenüber Studien, die sie von einer Teilnahme abhalten. Da diese Bedenken an allen Standorten im Land ähnlich sind, soll ihnen mit einem breit anwendbaren Video begegnet werden. Erstmalig werden darin die Aspekte einer Studienteilnahme rein aus der Patientenperspektive vermittelt. Methodik Das Konzept für das Video wurde von der AG DOG (Deutsche Ophthalmologische Gesellschaft) Klinische Studienzentren erarbeitet. An mehreren Standorten wurden Patienten für die Mitwirkung gesucht und 2 geeignete Protagonisten ausgewählt. Die Mitwirkung war freiwillig und ehrenamtlich. Die Dreharbeiten fanden in Q (Quartal) 3 und Q4 2021 in Baden-Württemberg statt. Die Produktion lag in den Händen der Agentur grasshopper kreativ, Tübingen. Ergebnis Die beiden Patienten schildern ihre eigenen Bedenken vor der Studie und wie sie die Studienteilnahme selbst erlebt haben. Dabei kommen Aspekte wie die Freiwilligkeit, das Rücktrittsrecht, Angst vor unangenehmen Untersuchungen, die zeitliche Belastung u. a. m. zur Sprache. Die Patienten gehen auch auf ihre persönliche Motivation zur Teilnahme ein. Das Video ist authentisch in seiner Wirkung, in deutscher Sprache gehalten und mit Untertiteln für Bereiche versehen, wo es ohne Ton präsentiert werden muss. Diese Untertitel sind auch in englischer Sprache verfügbar, um den Interessentenkreis auszuweiten. Schlussfolgerung Mit dem Video steht ein wichtiges Instrument zur Aufklärung von Patienten und für die Rekrutierung klinischer Studien an Augenkliniken kostenfrei zur Verfügung.

Traditional endpoints assessing visual function are limited by their responsiveness to interventions restoring or maintaining vision. An alternative concept is assessing instrumental activities of daily living (IADL). Herein, we review all available vision-specific IADL instruments relevant for vision restoration trials and report data for the most promising instrument. Six relevant instruments exist: The Low Vision Functional Status Evaluation (LVFSE), Timed IADL (TIADL), Melbourne Low-Vision Activities of Daily Living Index (MLVAI), Assessment of Disability Related to Vision (ADREV), Functional Low-Vision Observer Rated Assessment (FLORA), and Very Low Vision IADL (IADL-VLV). Both internal consistency and test-retest data were available for the LVFSE, MLVAI, and IADL-VLV. In a sample from a low-vision clinic (n = 51; age 57 ± 16 years), we report additional validation data on the IVI-VLV including test–retest reliability (intraclass correlation coefficient 0.981 [0.961; 0.991]). The LVSFE was noticeably less reliable than the MLVAI and the IADL-VLV. Content and construct validity data were available for the LVFSE, TIADL, MLVAI, ADREV, and IADL-VLV, but only the MLVAI and IADL-VLV were developed for an ultra-low vision context. Ceiling effects were present across instruments. Thus, of all appropriate IADL instruments related to vision, the IADL-VLV and MLVAI best meet existing requirements for use in vision restoration trials, e.g., in gene therapies or visual prostheses in inherited retinal diseases, but require further validation.

Background/Purpose: Treating neovascular age-related macular degeneration with intravitreal aflibercept treat-and-extend (T&E) can reduce treatment burden. ARIES assessed whether intravitreal aflibercept early-start T&E was noninferior to late-start T&E. Methods: A randomized, open-label, Phase 3b/4 study that included treatment-naïve patients aged ≥50 years with the best-corrected visual acuity 73–25 Early Treatment Diabetic Retinopathy Study letters and active choroidal neovascularization secondary to AMD. Patients received 2 mg intravitreal aflibercept at Week (W) 0, W4, W8, and W16. At W16, patients were randomized 1:1 to early-start (2W interval adjustments) or late-start T&E (8W intervals until W48 then 2W interval adjustments). Primary endpoint: the best-corrected visual acuity change from randomization to W104. Results: Two-hundred seventy-one patients were randomized. The mean (SD) best-corrected visual acuity at baseline was 60.2 (12.1; early-T&E) and 61.3 (10.8; late-T&E) letters. The mean (SD) best-corrected visual acuity change (W16–104) was −2.1 (11.4) versus −0.4 (8.4) letters (early-T&E vs. late-T&E; least-squares mean difference: −2.0; 95% confidence interval: −4.75 to 0.71; P = 0.0162 for noninferior); +4.3 (13.4) versus +7.9 (11.9) letters (W0–104). The mean (SD) number of injections was 12.0 (2.3) versus 13.0 (1.8). From baseline to W104, 93.4% and 96.2% maintained best-corrected visual acuity; the mean (SD) central retinal thickness change was −161.6 (135.6) µm and −158.6 (125.1) µm. The last injection interval (W104) was ≥12W for 47.2% and 51.9% of patients. Conclusion: Outcomes were similar between patients with neovascular age-related macular degeneration treated with an intravitreal aflibercept early-T&E or late-T&E regimen after initial dosing, with one injection difference over 2 years. Trial Registration: ClinicalTrials.gov Identifier: NCT02581891 https://clinicaltrials.gov/ct2/show/NCT02581891. Supplemental Digital Contents (files 1 http://links.lww.com/IAE/B419).

In recent years, the relationship between vitamin D and health has received growing attention from the scientific and medical communities. Vitamin D deficiencies have been repeatedly associated with various acute and chronic diseases, including age-related macular degeneration (AMD). Its active metabolite, 1α,25-dihydoxy vitamin D, acts as a modulator of cell proliferation, differentiation and apoptosis, and cumulative data from experimental and observational studies suggest that relatively a lower vitamin D status could be a potential risk factor for the development of early and/or late AMD. Herein, we made a narrative review of the mechanisms linking a potential role of vitamin D with the current concepts of AMD pathophysiology.

Die Therapie der neovaskulären altersabhängigen Makuladegeneration (nvAMD) mit Inhibitoren des vaskulären endothelialen Wachstumsfaktors hat sich seit Einführung in Deutschland deutlich verbessert. In verschiedenen Anwendungsbeobachtungen zum Einsatz von Ranibizumab und Aflibercept in Deutschland hat sich in den letzten Jahren – parallel zur steigenden Behandlungsfrequenz – ein verbesserter Funktionsgewinn am Ende des 1. Behandlungsjahrs gezeigt. Dies spiegelt sich z. T. auch in retrospektiven Fallserien wider. Mit längeren Verlaufszeiträumen, z. B. für eine Nachbeobachtung von mehr als 3 Jahren, stellt sich trotz des initialen Visusgewinns ein zunehmender Funktionsverlust ein, sodass langfristig nur der Ausgangsvisus gehalten werden konnte. Eine Therapieverzögerung ist vor allem im ländlichen Bereich und bei einer Betreuung an verschiedenen Einrichtungen (z. B. mehreren Praxen oder Praxis und Klinik) ein Problem. Erfreulicherweise weisen hier aktuellere Auswertungen auf eine positive Entwicklung hin. Therapieverzögerung wurde reduziert, Therapie- bzw. Injektionsfrequenz erhöht und Therapieergebnisse verbessert. Dieser Trend muss sich fortsetzen, damit optimale, unter Routinebedingungen zu erreichende Therapieergebnisse in Deutschland erzielt werden. Treatment of neovascular age-related macular degeneration (AMD) with anti-vascular endothelial growth factor agents has been improved since its introduction in Germany. Several observational studies have demonstrated an increased frequency of injections in parallel with improved visual outcomes during the first year of treatment over the last 7 years. These results are reflected in several case series. However, studies with a longer follow-up reported that visual function regressed to baseline vision following an initial improvement, e.g. during the first three years of treatment. A delay in treatment initiation has been reported mainly for rural areas and management models involving more than one ophthalmologist or institution. Encouragingly, recent data confirm a positive trend towards reducing treatment delay, increasing injection frequency and improving treatment outcomes. Still, further improvements are needed to attain optimal treatment outcomes achievable under routine clinical conditions in Germany.

Purpose: To investigate structural correlates corresponding to the appearance of increased fundus autofluorescence (FAF) in the perilesional area of geographic atrophy (GA) secondary to age-related macular degeneration. Methods: Serial FAF images of 181 eyes with GA of 134 patients participating in the Directional Spread in Geographic Atrophy study (NCT02051998) were screened for increased FAF spots that had developed during the review period. Thickness and reflectivity of the retinal pigment epithelium (RPE)–basal lamina complex, as well as the integrity of the external limiting membrane (ELM) and the ellipsoid zone (EZ), respectively, in corresponding optical coherence tomography (OCT) scans were compared between the time points before and after the appearance of increased FAF. Adjacent areas without development of abnormal FAF were assessed as internal control. Results: A total of 36 areas (15 eyes) with de novo developed increased FAF spots and 54 control areas were included. Analysis of the corresponding OCT images revealed an increase in RPE–basal lamina complex thickness (31.8 ± 7.3 to 42.1 ± 11.9 μm [P < 0.001]) and reflectivity (reflectivity ratio: 1.42 ± 0.11 to 1.54 ± 0.27 [P = 0.009]) corresponding to an increased FAF signal while there was no significant change in control areas. Development of increased FAF spots was associated with disruption of the ELM and the EZ. Conclusions: Increase of RPE–basal lamina complex thickness and reflectivity was spatially and temporally associated with the development of increased FAF spots in eyes with GA. In addition, outer retinal disruption may contribute to the corresponding increased FAF signal.