Habilitation

Titel und Inhaltsverzeichnis Einleitung Zielsetzung und Fragestellung Material und Methoden Ergebnisse Diskussion Zusammenfassung und Schlussfolgerung Literaturbverzeichnis Abkürzungen und Visuseinteilung Lebenslauf Danksagung6 Zusammenfassung und Schlussfolgerung Die Choroidale Neovaskularisation (CNV) ist die häufigste Ursache einer exsudativen Makulopathie und geht mit starken subjektiven und objektiven Funktionseinschränkungen einher. Es handelt sich hierbei um eine pathologische Angiogenese im Bereich der Makula. Die häufigste Ursache einer CNV ist die altersbedingte Makuladegenration (AMD), gefolgt von der hohen Myopie, post-entzündlichen, idiopathischen und weiteren selteneren Ursachen. Für die meisten CNV liegen keine effektiven und gleichzeitig etablierten Behandlungsmethoden vor. Die Photodynamische Therapie (PDT) ist ein neues kombiniertes Therapiekonzept, wobei durch einen Photosensibilisator eine Photothrombose der CNV und ein Sistieren der Exsudation unter Schonung der neurosensorischen Netzhaut erreicht wird. In dieser Arbeit wurde die Effektivität und Sicherheit der PDT im klinischen Alltag untersucht. Neben der bereits etablierten Indikation der PDT bei subfovealen überwiegend klassischen CNV bei AMD und bestimmten CNV bei Myopie, wurden weitere Anwendungsbereiche analysiert. Hierbei wurden seltene Untergruppen wie juxta- und extrafoveal gelegene CNV, CNV bei kombinierten Pathologien wie Myopie und AMD, CNV auf Grund post-entzündlicher oder idiopathischer Genese behandelt und evaluiert. Neben den Basisdaten wurden vor allem die Verläufe nach PDT an Hand verschiedener funktioneller Parameter und der Auswertung der morphologischen Kriterien an Hand der Fluoreszenz-Angiographien analysiert. Weiterhin sind die Nebenwirkungen und Komplikationen beurteilt und eine Analyse möglicher Einflussfaktoren auf den funktionellen Verlauf durchgeführt worden. Die Ergebnisse wurden anschließend im Kontext mit der aktuellen Literatur diskutiert. Bei den AMD-bedingten CNV kann mittels PDT die Exsudation und Leckage bei allen Läsionsformen, unabhängig davon, ob okkult, minimal klassisch oder überwiegend klassisch reduziert bzw. gestoppt werden. Eine moderate Sehverschlechterung von 3 oder mehr Linien, kann in der Mehrzahl der Fälle vermieden werden. Als wichtigste signifikante Einflussfaktoren für bessere funktionelle Ergebnisse wurden die Lokalisation der CNV und das Patientenalter identifiziert. Bei nicht subfovealer CNV-Lage kann der Visus tatsächlich ohne Verlust über einen Zeitraum von 3 Jahren stabilisiert werden. Weitere, weniger ausgeprägte Einflussfaktoren sind eine kleine Läsionsgröße und ein zunehmender klassischer Anteil der CNV. Bei CNV auf Grund einer hohen Myopie zeigt sich eine gute Wirksamkeit der PDT. Es wurde im Einzelnen festgestellt, dass auch bei einem schlechteren Ausgangsvisus oder dem gleichzeitigen Vorhandensein von AMD-Veränderungen vergleichbare Ergebnisse erzielt werden können. Die wichtigsten Einflussfaktoren sind die CNV-Lage und das Patientenalter. Je weiter die CNV initial vom fovealen Zentrum entfernt ist, desto besser ist der Visusverlauf. Die Ergebnisse sind besser als bei der Behandlung von CNV bei AMD. Bei der Gruppe der post-entzündlichen und idiopathischen CNV zeigt sich jeweils im Mittel ein Visusanstieg, der über 3 Jahre bestehen bleibt. Trotz der verschiedenen Diagnosen im Einzelnen, besteht ein gleichermaßen gutes Ansprechen auf die Therapie. Wie bei den anderen Diagnosen ist die CNV-Lage auch hier der wichtigste Einflussfaktor, gefolgt vom Patientenalter. Bei juxta/extrafovealer CNV resultiert auch nach 3 Jahren ein signifkanter Visusanstieg. Die PDT stellt sich als ein nebenwirkungs- und komplikationsarmes Verfahren dar. Es treten Rezidive in einer mit den anderen Therapieoptionen vergleichbaren Häufigkeit auf, die gut therapierbar sind. Es konnten häufig bisher nicht systematisch analysierte Veränderungen im RPE beobachtet werden, die aber funktionell von untergeordneter Bedeutung sind. Die PDT bietet unabhängig von der zu Grunde liegenden Pathologie die Möglichkeit, eine CNV zu verschließen und in eine fibrovaskuläre, klinisch und angiographisch inaktive Narbe umzuwandeln. Die funktionell besten Ergebnisse werden bei nicht subfovealer Lage erzielt. Krankheitsbilder die bei jüngeren Patienten auftreten haben eine bessere Prognose. Die besten Ergebnisse werden bei den post-entzündlichen bzw. idiopathischen CNV, gefolgt von den myopen CNV erzielt. Weitere Anstrengungen, die PDT gegebenenfalls durch Kombination mit anderen Verfahren zu optimieren, sind jedoch zu fordern, da durch die Reperfusion der CNV und die damit vebundene langen Behandlungsdauer bis zum Erreichen eines stabilen Befundes viel Zeit benötigt wird, in der viel an potenzieller Funktion verloren geht

KESTREL and KITE Phase 3 studies: 100-week results with brolucizumab in patients with diabetic macular edema.

PURPOSE To report the 100-week outcomes from KESTREL and KITE. DESIGN Two phase 3, double-masked, active-controlled, randomized trials. METHODS Patients with diabetic macular edema (DME) were randomized 1:1:1 to brolucizumab 3 mg/6 mg (BRO3/BRO6) or aflibercept 2 mg (AFL) in KESTREL (N=566) or 1:1 to BRO6 or AFL in KITE (N=360). BRO3/BRO6 arms received 5 loading doses every 6 weeks (q6w) followed by q12w dosing, with an option to adjust to q8w at predefined disease activity assessment visits. In KITE, at Week 72, based on the disease stability assessment, treatment intervals could be extended by 4 weeks in the BRO6 arm. AFL arms received 5 monthly loading doses followed by fixed q8w dosing. RESULTS At Week 100, change from baseline in BCVA (letters) was +8.8 for BRO6 and +10.6 for AFL in KESTREL; +10.9 for BRO6 and +8.4 for AFL in KITE. In both studies, fewer BRO6 subjects had intraretinal fluid and/or subretinal fluid versus (vs) AFL. Results were achieved with 32.9% (KESTREL) and 47.5% (KITE) of BRO6 subjects maintained on q12w and q12w/q16w dosing, respectively. Intraocular inflammation rates for BRO6 vs AFL were 4.2% vs 1.1% (KESTREL) and 2.2% vs 1.7% (KITE) of which retinal vasculitis rates were 0.5% vs 0% in KESTREL, with no cases in KITE. Retinal vascular occlusion rates were 1.6% vs 0.5% (KESTREL) and 0.6% in both treatment arms in KITE. CONCLUSION Results show the long-term efficacy and durability of brolucizumab in improving visual and anatomical outcomes in DME; the overall safety profile of brolucizumab remained unchanged through Year 2

Retinal Vascular Occlusion after COVID-19 Vaccination : More Coincidence than Causal Relationship? Data from a Retrospective Multicentre Study

Background: To investigate whether vaccination against SARS-CoV-2 is associated with the onset of retinal vascular occlusive disease (RVOD). Methods: In this multicentre study, data from patients with central and branch retinal vein occlusion (CRVO and BRVO), central and branch retinal artery occlusion (CRAO and BRAO), and anterior ischaemic optic neuropathy (AION) were retrospectively collected during a 2-month index period (1 June–31 July 2021) according to a defined protocol. The relation to any previous vaccination was documented for the consecutive case series. Numbers of RVOD and COVID-19 vaccination were investigated in a case-by-case analysis. A case– control study using age- and sex-matched controls from the general population (study participants from the Gutenberg Health Study) and an adjusted conditional logistic regression analysis was conducted. Results: Four hundred and twenty-one subjects presenting during the index period (61 days) were enrolled: one hundred and twenty-one patients with CRVO, seventy-five with BRVO, fifty-six with CRAO, sixty-five with BRAO, and one hundred and four with AION. Three hundred and thirty-two (78.9%) patients had been vaccinated before the onset of RVOD. The vaccines given were BNT162b2/BioNTech/Pfizer (n = 221), followed by ChadOx1/AstraZeneca (n = 57), mRNA1273/Moderna (n = 21), and Ad26.COV2.S/Johnson & Johnson (n = 11; unknown n = 22). Our case–control analysis integrating population-based data from the GHS yielded no evidence of an increased risk after COVID-19 vaccination (OR = 0.93; 95% CI: 0.60–1.45, p = 0.75) in connection with a vaccination within a 4-week window. Conclusions: To date, there has been no evidence of any association between SARS-CoV-2 vaccination and a higher RVOD risk

Rationale and design of the randomised clinical trial comparing early medication change (EMC) strategy with treatment as usual (TAU) in patients with Major Depressive Disorder - the EMC trial

<p>Abstract</p> <p>Background</p> <p>In Major Depressive Disorder (MDD), the traditional belief of a delayed onset of antidepressants' effects has lead to the concept of current guidelines that treatment durations should be between 3-8 weeks before medication change in case of insufficient outcome. Post hoc analyses of clinical trials, however, have shown that improvement usually occurs within the first 10-14 days of treatment and that such early improvement (Hamilton Depression Rating Scale [HAMD] decrease ≥20%) has a substantial predictive value for final treatment outcome. Even more important, non-improvement (HAMD decrease <20%) after 14 days of treatment was found to be highly predictive for a poor final treatment outcome.</p> <p>Methods/Design</p> <p>The EMC trial is a phase IV, multi-centre, multi-step, randomized, observer-blinded, actively controlled parallel-group clinical trial to investigate for the first time prospectively, whether non-improvers after 14 days of antidepressant treatment with an early medication change (EMC) are more likely to attain remission (HAMD-17 ≤7) on treatment day 56 compared to patients treated according to current guideline recommendation (treatment as usual; TAU). In level 1 of the EMC trial, non-improvers after 14 days of antidepressant treatment will be randomised to an EMC strategy or TAU. The EMC strategy for this study schedules a first medication change on day 15; in case of non-improvement between days 15-28, a second medication change will be performed. TAU schedules the first medication change after 28 days in case of non-response (HAMD-17 decrease <50%). Both interventions will last 42 days. In levels 2 and 3, EMC strategies will be compared with TAU strategies in improvers on day 14, who experience a stagnation of improvement during the course of treatment. The trial is supported by the German Federal Ministry of Education and Research (BMBF) and will be conducted in cooperation with the BMBF funded Interdisciplinary Centre Clinical Trials (IZKS) at the University Medical Centre Mainz and at six clinical trial sites in Germany.</p> <p>Discussion</p> <p>If the EMC strategies lead to significantly more remitters, changes of clinical practice, guidelines for the treatment of MDD as well as research settings can be expected.</p> <p>Trial Registration</p> <p><b>Clincaltrials.gov Identifier</b>: NCT00974155; <b>EudraCT</b>: 2008-008280-96.</p

Grundlagen der Vitrektomie unter Verwendung intraokularer Tamponaden – ein chirurgischer Basiskurs

This article is intended to clearly present the basic principles for the use of intraocular tamponades in vitreous/retinal surgery in the event of retinal detachment and other pathologies using additional video footage. It examines the various gases, silicone oils and perfluorocarbon liquids with their indications, administration and in particular intraoperative handling including pitfalls and complications. Characteristic animations show the principles of use in surgery in a comprehensible way. The two lead authors dedicate this article to their teacher Prof. Dr. V.-P. Gabel, who in the early 1990s successfully established the first vitrectomy courses for ophthalmologists at Regensburg University Eye Clinic each year. Many colleagues who still work in retinal surgery today first started learning about this segment on these courses. The other coauthors participated under his supervision in annual vitrectomy wet labs run by the German Academy of Ophthalmology

Use of Imaging Modalities in Real Life: Impact on Visual Acuity Outcomes of Ranibizumab Treatment for Neovascular Age-Related Macular Degeneration in Germany

Background. To date, there are limited prospective real-world data on the impact of optical coherence tomography (OCT) diagnostics on treatment outcomes in neovascular age-related macular degeneration (nAMD). Therefore, the prospective, noninterventional OCEAN study () evaluated the use of OCT imaging and its impact on functional outcomes in Germany.Methods. The use of OCT imaging for treatment decisions was documented in nAMD patients receiving intravitreal ranibizumab injections at 347 study centres. Best-corrected visual acuity (BCVA) testing and treatment were performed according to routine clinical practice and documented over 24 months.Results. The majority of the 3,631 nAMD patients (59.6%) received a combination of OCT and fluorescein angiography imaging within the first 6 months. Over the remaining study course, this combination was used infrequently (range: 7.6% to 13.4%) and continually decreased over time; most patients received only OCT examinations (range: 48.9% to 52.5%; median: 3 within 12 months and 4 within 24 months). Subgroups according to the number of OCT examinations (= 8, well monitored) were associated with different treatment frequencies and outcomes: Rarely OCT-examined patients had received a median of 4 injections (range: 1-19) at 24 months; well-monitored patients had received a median of 8 injections (range: 1-21) at 24 months. Rarely OCT-examined patients had a mean change of BCVA of -0.3 letters (+/- 26.1) at 24 months (n = 165); well-monitored patients showed a change of +2.0 letters (+/- 20.8) at 24 months (n = 249). Time-to-response was greater for rarely examined than well-monitored patients, while duration-of-response was similar.Conclusion. Low number of visits as well as high number of treatment decisions without the use of OCT may contribute to undertreatment and poorer functional outcomes in patients undergoing ranibizumab treatment for nAMD in Germany. One potential reason for this could be that OCT was not covered by insurance for all patients during the study

Reporting of Safety Events during Anti-VEGF Treatment: Pharmacovigilance in a Noninterventional Trial

Aim. The prospective, noninterventional OCEAN study assessed the safety of intravitreal ranibizumab injections for treatment of neovascular age-related macular degeneration, diabetic macular edema, and retinal vein occlusion under real-world conditions in Germany. Methods. Adults receiving ≥1 ranibizumab (0.5 mg) injections were recruited by 369 ophthalmologists and followed for 24 months. Information on adverse events (AEs) was reported by the treating physician or detected by the data management team. Collected information included observed AE, AE start and end date, intensity, causal relationship, outcome, severity, suspected drug, and actions taken. Results. 2,687 AEs were reported for 1,176 of the 5,781 patients who had received a total of 32,621 injections: 27.4% nonserious AEs, 30.3% serious AEs, 27.3% nonserious adverse drug reactions (ADRs), and 15.0% serious ADRs. Most patients reported no AEs (79.7%) or only 1 AE (10.3%). AEs were most commonly reported in the Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC) Eye disorders (9.4% of patients) and General disorders and administration site conditions (5.8%). The most frequent AEs by MedDRA preferred term (PT) were visual acuity reduced (3.5% of patients), intraocular pressure increased (2.5%), and drug ineffective (2.1%). AEs occurred most frequently after 3 or 4 injections (1,129 of 2,687 AEs). The proportion of AEs in the SOC Eye disorders decreased slightly with increasing number of injections, from 39.8% of events after 1 or 2 injections to 29.1% after 5 or more injections. Rates of the most frequently reported PTs did not show any consistent increase with increasing number of injections. A decrease in overall AE rates was observed over the study course. Conclusions. The results did not raise any new safety concerns for ranibizumab. The findings allow conclusions to be drawn on how pharmacovigilance data can be collected even more effectively in real-world studies to facilitate discussion on benefit-risk ratio

Intravitreal Ranibizumab Therapy for Diabetic Macular Edema in Routine Practice: Two-Year Real-Life Data from a Non-interventional, Multicenter Study in Germany

IntroductionThe prospective, non-interventional OCEAN study examined the use of intravitreal ranibizumab injections for the treatment of diabetic macular oedema (DME) in a real-world setting in Germany.MethodsAdults with DME receiving 1ranibizumab (0.5mg) injections were recruited by 250ophthalmologists. Best-corrected visual acuity (VA) testing, imaging and treatments were performed according to the investigators' routine practice and documented over 24months.ResultsThe full analysis set included 1226 participants. Mean baseline VA was 60.6 [95% CI: 59.7; 61.5] Early Treatment Diabetic Retinopathy Study letters. VA improved by 15letters in 21.5% and 23.5% of the participants at 12months and 24months, respectively. They received a mean number of 4.42 [95% CI: 4.30; 4.54] injections in the first year and 5.52 [95% CI: 5.32; 5.73] injections over 24months, which was markedly lower than in clinical trials. Only 33.4% of the participants received an upload with four initial monthly injections as recommended by the German ophthalmologic societies. Time-to-event analyses that account for missing data inherent to a non-interventional study design demonstrated that participants receiving 7injections in the first year had a faster response, but the duration of the response was shorter compared to the subgroups receiving 1-3 and 4-6injections. Serious adverse events were reported for 143/1250 (11.4%) participants in the safety population.ConclusionUnder-treatment is a major problem of DME anti- vascular endothelial growth factor therapy under real life conditions. Despite fewer injections given compared to randomised controlled trials with a consequently reduced overall mean visual gain, a profound functional improvement (15letters) was achieved over 2years in 23.5% of eyes with DME.Trial Registration NumberNCT02194803, ClinicalTrials.gov.FundingNovartis Pharma GmbH, Nuremberg, Germany