Late-onset central areolar choroidal dystrophy (CACD) may easily be confused with geographic atrophy (GA) in AMD. To detect discerning features, the morphologic changes in CACD patients and in AMD ...patients were assessed with confocal scanning laser ophthalmoscopy (cSLO), fundus autofluorescence (FAF), and spectral-domain optical coherence tomography (SD-OCT).
A total of 30 CACD patients with identified PRPH2 gene mutations were analyzed and compared to 19 patients with early AMD and 13 patients with AMD-associated GA. The presence of drusen and pigment clumping was determined with color fundus photography. High-resolution in vivo imaging was performed with cSLO and SD-OCT. FAF images and SD-OCT volume scans were analyzed in each study eye.
On FAF, a speckled FAF pattern occurred significantly more often in CACD (85%) than in early AMD (5.6%; P < 0.0001). There was a significantly higher frequency of sub-RPE deposits in eyes with AMD than in eyes with CACD (36.8% versus 2.1% of scans, P = 0.0019). Reticular drusen could be visualized by SD-OCT and FAF imaging in 52.6% of the eyes with early AMD and in 100% of the eyes with GA, whereas this drusen phenotype did not manifest in eyes with CACD.
Although outer retinal atrophy is the clinically common feature in advanced CACD as well as GA, there are microstructural alterations on high-resolution SD-OCT and FAF imaging that allow for the differentiation between CACD and AMD. The findings may help to identify patients in whom a diagnostic PRPH2 screening is warranted. (ClinicalTrials.gov number, NCT00393692.).
To develop consensus terminology and criteria for defining atrophy based on OCT findings in the setting of age-related macular degeneration (AMD).
Consensus meeting.
Panel of retina specialists, ...image reading center experts, retinal histologists, and optics engineers.
As part of the Classification of Atrophy Meetings (CAM) program, an international group of experts surveyed the existing literature, performed a masked analysis of longitudinal multimodal imaging for a series of eyes with AMD, and reviewed the results of this analysis to define areas of agreement and disagreement. Through consensus discussions at 3 meetings over 12 months, a classification system based on OCT was proposed for atrophy secondary to AMD. Specific criteria were defined to establish the presence of atrophy.
A consensus classification system for atrophy and OCT-based criteria to identify atrophy.
OCT was proposed as the reference standard or base imaging method to diagnose and stage atrophy. Other methods, including fundus autofluorescence, near-infrared reflectance, and color imaging, provided complementary and confirmatory information. Recognizing that photoreceptor atrophy can occur without retinal pigment epithelium (RPE) atrophy and that atrophy can undergo an evolution of different stages, 4 terms and histologic candidates were proposed: complete RPE and outer retinal atrophy (cRORA), incomplete RPE and outer retinal atrophy, complete outer retinal atrophy, and incomplete outer retinal atrophy. Specific OCT criteria to diagnose cRORA were proposed: (1) a region of hypertransmission of at least 250 μm in diameter, (2) a zone of attenuation or disruption of the RPE of at least 250 μm in diameter, (3) evidence of overlying photoreceptor degeneration, and (4) absence of scrolled RPE or other signs of an RPE tear.
A classification system and criteria for OCT-defined atrophy in the setting of AMD has been proposed based on an international consensus. This classification is a more complete representation of changes that occur in AMD than can be detected using color fundus photography alone. Longitudinal information is required to validate the implied risk of vision loss associated with these terms. This system will enable such future studies to be undertaken using consistent definitions.
To establish a process to evaluate and standardize a state-of-the-art nomenclature for reporting neovascular age-related macular degeneration (AMD) data.
Consensus meeting.
An international panel of ...retina specialists, imaging and image reading center experts, and ocular pathologists.
During several meetings organized under the auspices of the Macula Society, an international study group discussed and codified a set nomenclature framework for classifying the subtypes of neovascular AMD and associated lesion components.
A consensus classification of neovascular AMD.
The study group created a standardized working definition of AMD. The components of neovascular AMD were defined and subclassified. Disease consequences of macular neovascularization were delineated.
The framework of a consensus nomenclature system, a definition of AMD, and a delineation of the subtypes of neovascular AMD were developed. Establishing a uniform set of definitions will facilitate comparison of diverse patient groups and different studies. The framework presented is modified and updated readily, processes that are anticipated to occur on a periodic basis. The study group suggests that the consensus standards outlined in this article be used in future reported studies of neovascular AMD and clinical practice.
This trial was conducted to investigate the clinical equivalence of the proposed biosimilar FYB201 and reference ranibizumab in patients with treatment-naive, subfoveal choroidal neovascularization ...caused by neovascular age-related macular degeneration (nAMD).
This was a prospective, multicenter, evaluation-masked, parallel-group, 48-week, phase III randomized study.
A total of 477 patients were randomly assigned to receive FYB201 (n = 238) or reference ranibizumab (n = 239).
Patients received FYB201 or reference ranibizumab 0.5 mg by intravitreal (IVT) injection in the study eye every 4 weeks.
The primary end point was change from baseline in best-corrected visual acuity (BCVA) by Early Treatment Diabetic Retinopathy Study (ETDRS) letters at 8 weeks before the third monthly IVT injection. Biosimilarity of FYB201 to its originator was assessed via a 2-sided equivalence test, with an equivalence margin in BCVA of 3 ETDRS letters.
The BCVA improved in both groups, with a mean improvement of +5.1 (FYB201) and +5.6 (reference ranibizumab) ETDRS letters at week 8. The analysis of covariance (ANCOVA) least squares mean difference for the change from baseline between FYB201 and reference ranibizumab was –0.4 ETDRS letters with a 90% confidence interval (CI) of –1.6 to 0.9. Primary end point was met as the 90% CI was within the predefined equivalence margin. Adverse events were comparable between treatment groups.
FYB201 is biosimilar to reference ranibizumab in terms of clinical efficacy and ocular and systemic safety in the treatment of patients with nAMD.
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 (NCT02194803) 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 (≤4, rarely OCT examined; 5–8, moderately OCT examined; ≥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.
Fundus autofluorescence imaging Schmitz-Valckenberg, Steffen; Pfau, Maximilian; Fleckenstein, Monika ...
Progress in retinal and eye research,
March 2021, 2021-Mar, 2021-03-00, 20210301, Volume:
81
Journal Article
Peer reviewed
Fundus autofluorescence (FAF) imaging is an in vivo imaging method that allows for topographic mapping of naturally or pathologically occurring intrinsic fluorophores of the ocular fundus. The ...dominant sources are fluorophores accumulating as lipofuscin in lysosomal storage bodies in postmitotic retinal pigment epithelium cells as well as other fluorophores that may occur with disease in the outer retina and subretinal space. Photopigments of the photoreceptor outer segments as well as macular pigment and melanin at the fovea and parafovea may act as filters of the excitation light. FAF imaging has been shown to be useful with regard to understanding of pathophysiological mechanisms, diagnostics, phenotype-genotype correlation, identification of prognostic markers for disease progression, and novel outcome parameters to assess efficacy of interventional strategies in chorio-retinal diseases. More recently, the spectrum of FAF imaging has been expanded with increasing use of green in addition to blue FAF, introduction of spectrally-resolved FAF, near-infrared FAF, quantitative FAF imaging and fluorescence life time imaging (FLIO). This article gives an overview of basic principles, FAF findings in various retinal diseases and an update on recent developments.
•Fundus autofluorescence (FAF) imaging allows for metabolic mapping of the photoreceptor layer and retinal pigment epithelium in-vivo•Several sources and confounders of the detected signal should be taken into consideration for the interpretation of FAF image data•The application has been expanded with innovations and further developments of imaging systems•The clinical application includes macular and retinal degenerations, dystrophies, toxic retinopathies, inflammatory diseases and retinal tumours
To describe the rationale and design of the VOYAGER (NCT05476926) study, which aims to investigate the safety and effectiveness of faricimab and the Port Delivery System with ranibizumab (PDS) for ...neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME) in clinical practice. VOYAGER also aims to understand drivers of clinical practice treatment outcomes by gaining novel insight into the intersection of treatment regimens, decisions, anatomic outcomes, and vision.
Primary data collection, noninterventional, prospective, multinational, multicenter clinical practice study.
At least 5000 patients initiating/continuing faricimab or PDS for nAMD/DME (500 sites, 31 countries).
Management will be per usual care, with no mandated scheduled visits/imaging protocol requirements. Using robust methodologies, relevant clinical and ophthalmic data, including visual acuity (VA), and data on treatment clinical setting/regimens/philosophies, presence of anatomic features, and safety events will be collected. Routinely collected fundus images will be uploaded to the proprietary Imaging Platform for analysis. An innovative investigator interface will graphically display the patient treatment journey with the aim of optimizing treatment decisions.
Primary end point: VA change from baseline at 12 months per study cohort (faricimab in nAMD and in DME, PDS in nAMD). Secondary end points: VA change over time and per treatment regimens (fixed, treat-and-extend, pro re nata, and other) and number. Exploratory end points: VA change in relation to presence/location of anatomic features that impact vision (fluid, central subfield thickness, fibrosis, atrophy, subretinal hyperreflective material, diabetic retinopathy severity, and disorganization of retinal inner layers) and per treatment regimen/philosophies. The impact of regional and practice differences on outcomes will be assessed as will safety.
Recruitment commenced in November 2022 and will continue until late 2027, allowing for up to 5 years follow-up. Exploratory interim analyses are planned annually.
VOYAGER is an innovative study of retinal diseases that will assess the effectiveness and safety of faricimab and PDS in nAMD and DME and identify clinician- and disease-related factors driving treatment outcomes in clinical practices globally to help optimize vision outcomes.
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Fundus-controlled perimetry (FCP, also called ‘microperimetry’) allows for spatially-resolved mapping of visual sensitivity and measurement of fixation stability, both in clinical practice as well as ...research. The accurate spatial characterization of visual function enabled by FCP can provide insightful information about disease severity and progression not reflected by best-corrected visual acuity in a large range of disorders. This is especially important for monitoring of retinal diseases that initially spare the central retina in earlier disease stages. Improved intra- and inter-session retest-variability through fundus-tracking and precise point-wise follow-up examinations even in patients with unstable fixation represent key advantages of these technique. The design of disease-specific test patterns and protocols reduces the burden of extensive and time-consuming FCP testing, permitting a more meaningful and focused application. Recent developments also allow for photoreceptor-specific testing through implementation of dark-adapted chromatic and photopic testing. A detailed understanding of the variety of available devices and test settings is a key prerequisite for the design and optimization of FCP protocols in future natural history studies and clinical trials. Accordingly, this review describes the theoretical and technical background of FCP, its prior application in clinical and research settings, data that qualify the application of FCP as an outcome measure in clinical trials as well as ongoing and future developments.
•Fundus-controlled perimetry enables spatially-resolved testing of visual sensitivity.•Through fundus-tracking, even patients with unstable fixation may be examined.•Recent developments allow for partially photoreceptor-specific testing of function.•Reliability and ability to detect change is evident for multiple retinal diseases.•Applications include macular and retinal degenerations, dystrophies, toxic retinopathies and inflammatory diseases.
To determine the interreader agreement for reticular pseudodrusen (RPD) assessment on combined infrared reflectance (IR) and OCT imaging in the early stages of age-related macular degeneration across ...a range of different criteria to define their presence.
Interreader agreement study.
Twelve readers from 6 reading centers.
All readers evaluated 100 eyes from individuals with bilateral large drusen for the following: (1) the presence of RPD across a range of different criteria and (2) the number of Stage 2 or 3 RPD lesions (from 0 to ≥ 5 lesions) on an entire OCT volume scan and on a selected OCT B-scan. Supportive information was available from the corresponding IR image.
Interreader agreement, as assessed by Gwet’s first-order agreement coefficient (AC1).
When evaluating an entire OCT volume scan, there was substantial interreader agreement for the presence of any RPD, any or ≥ 5 Stage 2 or 3 lesions, and ≥ 5 definite lesions on en face IR images corresponding to Stage 2 or 3 lesions (AC1 = 0.60–0.72). On selected OCT B-scans, there was also moderate-to-substantial agreement for the presence of any RPD, any or ≥ 5 Stage 2 or 3 lesions (AC1 = 0.58–0.65) and increasing levels of agreement with increasing RPD stage (AC1 = 0.08, 0.56, 0.78, and 0.99 for the presence of any Stage 1, 2, 3, and 4 lesions, respectively). There was substantial agreement regarding the number of Stage 2 or 3 lesions on an entire OCT volume scan (AC1 = 0.68), but only fair agreement for this evaluation on selected B-scans (AC1 = 0.30).
There was generally substantial or near-substantial—but not near-perfect—agreement for assessing the presence of RPD on entire OCT volume scans or selected B-scans across a range of differing RPD criteria. These findings underscore how interreader variability would likely contribute to the variability of findings related to the clinical associations of RPD. The low levels of agreement for assessing RPD number on OCT B-scans underscore the likely challenges of quantifying RPD extent with manual grading.
Proprietary or commercial disclosure may be found after the references.
IMPORTANCE: Sensitive outcome measures for disease progression are needed for treatment trials in geographic atrophy (GA) secondary to age-related macular degeneration (AMD). OBJECTIVE: To quantify ...photoreceptor degeneration outside regions of GA in eyes with nonexudative AMD, to evaluate its association with future GA progression, and to characterize its spatio-temporal progression. DESIGN, SETTING, AND PARTICIPANTS: Monocenter cohort study (Directional Spread in Geographic Atrophy NCT02051998) and analysis of data from a normative data study at a tertiary referral center. One hundred fifty-eight eyes of 89 patients with a mean (SD) age of 77.7 (7.1) years, median area of GA of 8.87 mm2 (IQR, 4.09-15.60), and median follow-up of 1.1 years (IQR, 0.52-1.7 years), as well as 93 normal eyes from 93 participants. EXPOSURES: Longitudinal spectral-domain optical coherence tomography (SD-OCT) volume scans (121 B-scans across 30° × 25°) were segmented with a deep-learning pipeline and standardized in a pointwise manner with age-adjusted normal data (z scores). Outer nuclear layer (ONL), photoreceptor inner segment (IS), and outer segment (OS) thickness were quantified along evenly spaced contour lines surrounding GA lesions. Linear mixed models were applied to assess the association between photoreceptor-related imaging features and GA progression rates and characterize the pattern of photoreceptor degeneration over time. MAIN OUTCOMES AND MEASURES: Association of ONL thinning with follow-up time (after adjusting for age, retinal topography z score, and distance to the GA boundary). RESULTS: The study included 158 eyes of 89 patients (51 women and 38 men) with a mean (SD) age of 77.7 (7.1) years. The fully automated B-scan segmentation was accurate (dice coefficient, 0.82; 95% CI, 0.80-0.85; compared with manual markings) and revealed a marked interpatient variability in photoreceptor degeneration. The ellipsoid zone (EZ) loss-to-GA boundary distance and OS thickness were prognostic for future progression rates. Outer nuclear layer and IS thinning over time was significant even when adjusting for age and proximity to the GA boundary (estimates of −0.16 μm/y; 95% CI, −0.30 to −0.02; and −0.17 μm/y; 95% CI, −0.26 to −0.09). CONCLUSIONS AND RELEVANCE: Distinct and progressive alterations of photoreceptor laminae (exceeding GA spatially) were detectable and quantifiable. The degree of photoreceptor degeneration outside of regions of retinal pigment epithelium atrophy varied markedly between eyes and was associated with future GA progression. Macula-wide photoreceptor laminae thinning represents a potential candidate end point to monitor treatment effects beyond mere GA lesion size progression.
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