Maximilian Pfau

Swept-source OCT angiography imaging of the foveal avascular zone and macular capillary network density in diabetic retinopathy

PURPOSE We compared the area of the foveal avascular zone (FAZ) and macular capillary network density at different retinal layers using swept-source optical coherence tomography angiography (OCT-A) in normal individuals and patients with diabetic retinopathy (DR). METHODS Images (a 3 × 3 mm cube centered on the fovea) were acquired in 40 eyes of 22 normal individuals and 28 eyes of 18 patients with varying levels of DR using a swept-source OCT-A device (central wavelength 1050 nm; A-scan-rate of 100,000 scans per second). En face images of the retinal vasculature were generated from the superficial and deep retinal layers (SRL/DRL). Quantitative analysis of the vessel density (VD) and FAZ area was performed. Vessel density was assessed as the ratio of the retinal area occupied by vessels. RESULTS Among the DR subjects (mean age, 72 years; 61% male), 35.7% of the eyes had mild, 35.7% moderate, and 7.1% severe nonproliferative DR (NPDR), and 21.4% and proliferative DR (PDR). The mean FAZ area in patients with DR and in normal individuals was 0.518 and 0.339 mm2, respectively, for the SRL (P = 0.003), and 0.615 and 0.358 mm2, respectively, for the DRL (P < 0.001). The mean VD (ratio) at the SRL and DRL was statistically significantly lower in patients with DR (SRL, P < 0.001; DRL, P = 0.028). CONCLUSIONS Swept-source OCT-A of the microcirculation in eyes of patients with DR can be used to quantitatively demonstrate alterations in the FAZ and VD in the SRL/DRL of the macula compared to normal eyes. Future longitudinal studies may use these metrics to evaluate changes over time or in response to treatment.

Test-Retest Reliability of Scotopic and Mesopic Fundus-Controlled Perimetry Using a Modified MAIA (Macular Integrity Assessment) in Normal Eyes

Purpose: To assess the intrasession test-retest reliability of scotopic cyan and scotopic red fundus-controlled perimetry (FCP) in normal subjects using a modified MAIA “microperimeter” (macular integrity assessment) device. Methods: Forty-seven normal eyes of 30 subjects (aged 33.8 years) underwent duplicate mesopic (achromatic stimuli, 400-800 nm), scotopic cyan (505 nm), and scotopic red (627 nm) FCP, using a grid of 49 stimuli over 14° of the central retina. Test-retest reliability for pointwise sensitivity (PWS), stability of fixation, reaction time and test duration were analyzed using mixed-effects models. Results: PWS test-retest reliability was good among all 3 types of retinal sensitivity assessments (coefficient of repeatability of 4.75 dB for mesopic, 5.26 dB for scotopic cyan, and 4.06 dB for scotopic red testing). While the mean sensitivity decreased with eccentricity for both mesopic and scotopic red testing, it was highest at 7° eccentricity for the scotopic cyan assessment (p < 0.001). Conclusions: The modified MAIA device allows for reliable scotopic FCP in normal subjects. Our findings suggest that testing of scotopic cyan sensitivity largely reflects rod function.

Green-Light Autofluorescence Versus Combined Blue-Light Autofluorescence and Near-Infrared Reflectance Imaging in Geographic Atrophy Secondary to Age-Related Macular Degeneration.

Purpose To compare the intermodality and interreader agreement for geographic atrophy (GA) lesion size quantification in green-light fundus autofluorescence (GAF; excitation = 518 nm) versus combined blue-light fundus autofluorescence (BAF; excitation = 488 nm) and near-infrared reflectance (NIR; 820 nm) -based grading. Methods Confocal scanning laser ophthalmoscopy (cSLO) GAF, BAF, and NIR images of 40 eyes from 29 patients (mean age 79.7 years) with GA secondary to AMD were recorded according to a standardized protocol. GA areas were analyzed in GAF, BAF combined with NIR (BAF+NIR), or BAF alone, by four independent readers using semiautomated software (RegionFinder; Heidelberg Engineering, Heidelberg, Germany). A mixed-effects model was used to assess the effect of image modality on the measured square-root lesion area. The coefficient of repeatability (CR) and intraclass correlation coefficient (ICC) were assessed for the square-root lesion area, lesion perimeter, and circularity. Results GAF-based measurements were on average 0.062 mm (95% confidence interval [CI] 0.04-0.08 mm) larger than BAF+NIR-based measurements and 0.077 mm (95% CI 0.06 - 0.10 mm) larger than BAF-based measurements. Interreader agreement was highest for GAF-based analysis ([CR, ICC] 0.196 mm, 0.995) followed by BAF+NIR (0.232 mm, 0.992) and BAF alone (0.263 mm, 0.991). The same was noted for the lesion perimeter and circularity. Post hoc review revealed that interreader differences were associated with media opacification interfering with lesion boundary demarcation to a larger extent in BAF than in GAF. Conclusions cSLO-based GAF and combined BAF+NIR imaging with semiautomated lesion delineation allow for an accurate and reproducible quantification of GA. The slightly better interreader agreement using cSLO GAF suggests that its use may be preferable in clinical trials examining the change in lesion size as a clinical endpoint.

Evaluation of Two Systems for Fundus-Controlled Scotopic and Mesopic Perimetry in Eye with Age-Related Macular Degeneration

Purpose The purpose of this study was to evaluate and compare the MP-1S (Nidek Technologies, Padova, Italy) and the S-MAIA (CenterVue, Padova, Italy) for mesopic and scotopic fundus-controlled perimetry (FCP) in age-related macular degeneration (AMD). Methods Eleven eyes from 11 patients underwent mesopic and, after 30 minutes of dark adaptation, scotopic (MP-1S: Goldmann V, 200 ms, background luminance 0.0032 cd/m2; S-MAIA: Goldman III, 200 ms, background luminance <0.0001 cd/m2) FCP. For the S-MAIA device, cyan (505 nm) and red (627 nm) scotopic FCP were performed. For both devices, a grid of 56 stimulus points covering 16° of the central macula was used. Examination time, fixation stability, and threshold values were analyzed. Results The upper end of the dynamic range (≤4 dB of lowest threshold) was frequently reached by the MP-1S for mesopic testing (median 34 of 56 stimuli), while threshold values within the lower 4 dB of the dynamic range were occasionally found with the S-MAIA for scotopic testing (median 3 for cyan, median 2 for red). After correction of the stimulus intensity for the S-MAIA results, the median difference for all stimuli between both devices for mesopic testing was −2.0 dB (interquartile range [−4;0], range –14 to 6). Conclusions The results indicate that robust testing of mesopic and scotopic function is feasible with both devices in patients with AMD, although both devices are susceptible to floor and ceiling effects. Translational Relevance The interpretation and particularly the comparison of both scotopic and mesopic FCP results between the MP-1S and the S-MAIA in AMD eyes need to consider variable susceptibility of floor and ceiling effects. Further software updates are desirable as FCP captures visual functional loss that is not noted with best-corrected central visual acuity and is important for clinical trials in AMD.

Quantitative Features of the Choriocapillaris in Healthy Individuals Using Swept-Source Optical Coherence Tomography Angiography

BACKGROUND AND OBJECTIVE To quantify vessel density (VD) and grey value (GV) as a measure of flow in the choriocapillaris (CC) in healthy subjects with optical coherence tomography angiography (OCTA). PATIENTS AND METHODS In this prospective, noncomparative case series, 3 mm × 3 mm OCTA images of 36 eyes of 22 healthy individuals were obtained using a swept-source instrument. VD and GV levels were calculated on CC en face slabs in the central 1-mm (subfoveal field) and surrounding 2.5-mm parafoveal ring. VD was calculated as a ratio of vessel area over nonvessel area following image binarization. GV was computed as the mean, un-normalized greyscale intensity value for all pixels in the region of interest. For each eye, the procedure was repeated 1 minute to 2 minutes later and intersession repeatability was analyzed. The choroidal thickness (CT) was automatically measured in the subfoveal and parafoveal regions and compared to VD and GV values. RESULTS The VD ratio and GV was lower in the subfoveal field than in the parafoveal four sectors. The intersession intraclass correlation coefficients were high for both VD and GV measurements. There was no correlation observed between CT and VD or GV. CONCLUSIONS Quantitative metrics can be obtained from CC OCTA en face images. These values show moderate to good intersession repeatability. These normative data may be of value as a reference of comparison in future studies of eyes with disease. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:623-631.].

Visual field indices and patterns of visual field deficits in mesopic and dark-adapted two-colour fundus-controlled perimetry in macular diseases

Background/Aims To analyse the retest reliability of visual field indices and to describe patterns of visual field deficits in mesopic and dark-adapted two-colour fundus-controlled perimetry (FCP) in macular diseases. Methods Seventy-seven eyes (30 eyes with macular diseases and 47 normal eyes) underwent duplicate mesopic and dark-adapted two-colour FCP (Scotopic Macular Integrity Assessment, CenterVue). Non-weighted (mean defect, loss variance), variability-weighted (mean deviation, pattern standard deviation (PSD)) and graphical (cumulative defect (Bebie) curves) indices were computed. Reproducibility (coefficient of repeatability, CoR) of these indices was assessed. Cluster analysis was carried out to identify patterns of visual field deficits. Results The intrasession reproducibility was lower for the mean defect as compared with the mean deviation (CoR (dB) 2.67 vs 2.57 for mesopic, 1.71 vs 1.45 for dark-adapted cyan, 1.94 vs 1.87 for dark-adapted red testing) and lower for the square-root loss variance as compared with the PSD (CoR (dB) 1.48 vs 1.34, 0.77 vs 0.65, 1.23 vs 1.03). Hierarchical cluster analysis of the indices disclosed six patterns of visual field deficits (approximately unbiased P value>0.95) with varying degrees of global versus focal defect and rod versus cone dysfunction. These were also reflected by the cumulative defect curves. Conclusion FCP with mesopic and dark-adapted two-colour testing allows for reproducible assessment of different types of retinal sensitivity, whereby mean deviation and PSD exhibited the better retest reliability of the tested indices. Distinct patterns of retinal dysfunction can be identified using this setup, reflecting variable degrees of rod and cone dysfunction in different macular diseases. Dark-adapted two-colour FCP provides additional diagnostic information and allows for refined structure–function correlation in macular diseases.

Distinct Genetic Risk Profile of the Rapidly Progressing Diffuse-Trickling Subtype of Geographic Atrophy in Age-Related Macular Degeneration (AMD)

PURPOSE To genetically characterize a subphenotype of geographic atrophy (GA) in AMD associated with rapid progression and a diffuse-trickling appearance on fundus autofluorescence imaging. METHODS Patients from the Fundus Autofluorescence in Age-Related Macular Degeneration Study were phenotyped for diffuse-trickling GA (dt-GA; n = 44). DNA was analyzed for 10 known AMD-associated genetic variants. A genetic risk score (GRS) was calculated and compared with patients with nondiffuse-trickling GA (ndt-GA; n = 311) and individuals from the 1000 genomes project (1000G; n = 267). Given the phenotypic overlap between diffuse-trickling and late-onset retinal degeneration (LORD), all C1QTNF5 exons and their exon/intron boundaries were sequenced. RESULTS A statistically significant difference in allele frequencies between dt-GA and ndt-GA were found for CFH:rs1061170 and CFH:rs800292 (Pcorrected = 0.03). The ARMS2 variant rs10490924 was significantly more frequent in dt-GA than in 1000G individuals (Pcorrected < 0.01). The GRS of dt-GA patients was in-between the score of the 1000G individuals and that of patients with ndt-GA, significantly differing from both (Pcorrected <0.01). Sequencing of C1QTNF5 revealed 28 unique variants although none showed a statistically significant association with dt-GA when compared with 1000G individuals. CONCLUSIONS The dt-GA phenotype shows a remarkably different genetic risk profile from other GA phenotypes secondary to AMD. Disease-associated C1QTNF5 mutations were not identified. Together, these results suggest that the dt-GA phenotype is associated with a genetic background substantially different from other GA phenotypes and underlines the necessity to refine the clinical phenotyping, specifically when aiming for individualized therapies in AMD.

Persistent visual loss in dengue fever due to outer retinal damage

An 18-year-old woman presented with persistent vision loss and a central scotoma in both eyes since the beginning of an episode of dengue fever 3 weeks previously. Best corrected visual acuity (BCVA) was 20/50 in the right eye and 1/20 in the left eye. Pupillary reaction and intraocular pressure were unremarkable in both eyes. No intraocular inflammation was present in the anterior chamber or the vitreous. Ophthalmoscopy of both eyes revealed darkish red lesions at the posterior pole, which were more extensive in the left eye (Fig.1a,b). No optic disc swelling, retinal haemorrhages or signs of vasculitis were present on funduscopy or fluorescein angiography. Corresponding to the retinal lesions, a mild hypofluorescence was observed in the late phase of indocyanine green angiography, and a disruption of the outer neurosensory retina involving the outer limiting membrane, the myoid and ellipsoid zone as well as the outer segments of the photoreceptors was present on optical coherence tomography (OCT, Fig. 1c,d). Central and paracentral scotomas were present on mesopic funduscontrolled perimetry (Fig. 2a,f ). The mean deviation was −5.43 decibel (dB) for the right eye and −10.07 dB for the left eye. Serological testing identified high antibody titres for dengue virus and was negative for all other tested viruses including Zika virus and human T-lymphotropic virus. As there is no specific antiviral therapy for dengue fever, oral steroids at a dose of 0.5 mg/kg were started and tapered over the course of 2 months, during which the patient was followed up regularly. Figure 2. Top optical coherence tomography scan and infra-red reflectance image at the initial presentation. Bottom left, restoration of optical coherence tomography layers after 1 week after the onset of his symptoms. Right, development of cystoid macular oedema 2 weeks after presentation.

OCT Angiography–Based Detection and Quantification of the Neovascular Network in Exudative AMD

Purpose To investigate the potential of optical coherence tomography (OCT) angiography to detect and quantify the neovascular network in exudative AMD. Methods Treatment-naïve eyes that were diagnosed with exudative AMD were prospectively examined by OCT angiography (OCT-A). The extent of the neovascular network was measured by three independent readers. Interclass-correlation coefficient and area overlap coefficients (OC) were calculated to assess locally precise agreement between measurements. As a reference for interreader agreement, the extent of the neovascular network was further measured on fluorescein angiography (FA) images. Results A total of 31 eyes (27 patients, mean age 82.5 years, 15 female) were included in the study. Neovascularization subtype was classified as type I in 5, type II in 11, type III in 9, and mixed in 6 eyes, respectively. Interreader agreement for measurements of the neovascular network was 0.884 for OCT-A and 0.636 for FA. Overlap coefficient was 0.705 (interquartile [IQR]: 0.450-0.76) for OCT-A and 0.704 (IQR: 0.673-0.750) for FA, respectively. Area agreement was weaker in type III and mixed lesions. Conclusions Optical coherence tomography angiography-based measurements of the new vessel complex in neovascular AMD are feasible with interreader agreement comparable with the values obtained for FA. The results underscore the potential of OCT-A as a noninvasive diagnostic tool in neovascular AMD. Yet, further studies will be required to reveal the origin of poor agreement observed in single eyes and to advance OCT-A toward dependable use (e.g., in a reading center context).

Comparison of Green Versus Blue Fundus Autofluorescence in ABCA4-Related Retinopathy

Purpose To investigate the interreader and intermodality agreement for grading of retinal pigment epithelium (RPE) atrophy lesion size in ABCA4-related retinopathy using green (GAF) and blue fundus autofluorescence (BAF) imaging. Methods In this cross-sectional case series, 97 eyes of 49 patients with RPE atrophy secondary to ABCA4-related retinopathy underwent GAF- (518 nm excitation light) and BAF- (488 nm excitation light) imaging using confocal scanning laser ophthalmoscopy (Spectralis HRA, Heidelberg Engineering, Heidelberg, Germany). Lesions with definitely decreased autofluorescence (DDAF) and questionably decreased autofluorescence (QDAF) in GAF and BAF imaging were analyzed separately by five independent readers using semiautomated software (RegionFinder, Heidelberg Engineering). Intermodality and interreader agreements were assessed for the square-root lesion size, lesion perimeter, and circularity. Results GAF- and BAF-based measurements of DDAF and QDAF showed high intermodality and interreader agreement concerning square-root lesion size, as well as shape descriptive parameters (perimeter and circularity). Interreader agreement of square-root lesion size was slightly, hence not significantly higher for GAF-based grading ([95% coefficients of repeatability, intraclass correlation coefficient] DDAF: 0.215 mm, 0.997; QDAF: 0.712 mm, 0.981) compared to BAF-based grading (DDAF: 0.232 mm, 0.997; QDAF: 0.764 mm, 0.978). However, DDAF-measurements revealed distinctly more reproducible results than QDAF-measurements. Foveal sparing did not interfere with intermodality agreement. Conclusions Both GAF- and BAF-based quantification of RPE atrophy showed very reliable results with possible superiority of GAF in the context of less energetic excitation light. Translational Relevance The high interreader agreement qualifies the use of DDAF progression in GAF and BAF imaging as potential morphologic outcome measure for interventional clinical trials and disease monitoring.