Reliability of Spectral-Domain OCT Ellipsoid Zone Area and Shape Measurements in Retinitis Pigmentosa.

PURPOSE: We investigate the ellipsoid zone (EZ) area and EZ boundary shape measurement reliability and the operability characteristics of two methods of EZ boundary delineation in spectral-domain optical coherence tomography (SD-OCT). METHODS: EZ boundaries in SD-OCT scans of 122 eyes from 64 subjects with autosomal dominant retinitis pigmentosa were delineated by three raters using two methods, termed the profile and en face methods. For each method, we determined the measurement reliabilities for boundary area (EZ area) and boundary shape, percentage of eyes with measurable EZ (measurability), time required, and effect of rater experience. RESULTS: With expert raters, inter- and intrarater area intraclass correlation coefficients (ICCs) were 0.986 and 0.980 (profile) and 0.959 and 0.976 (en face), respectively. In comparison, the corresponding shape ICCs were 0.906 and 0.891 (profile) and 0.845 and 0.885 (en face), indicating lower reliability for the raw measurements (P ≤ 0.01). Only profile method interrater reliability depended on experience. Average measurement times per eye were 8.2 (profile) and 4.1 (en face) minutes. Measurability percentages were 99.2% (profile) and 73.0% (en face). CONCLUSIONS: The slower profile method had better measurability, and with expert raters yielded the best area and shape reliabilities. The faster, but less sensitive, en face method still showed excellent reliability, and was less dependent on experience. Shape analysis reveals the boundary measurements underpinning EZ area have lower reliability than suggested by area analysis. TRANSLATIONAL RELEVANCE: This study provides new reliability perspectives and logistical considerations for the manual measurement procedures that generate EZ area outcome measures.

Agreement and reliability statistics for shapes.

We describe a methodology for assessing agreement and reliability among a set of shapes. Motivated by recent studies of the reliability of manually segmented medical images, we focus on shapes composed of rasterized, binary-valued data representing closed geometric regions of interest. The methodology naturally generalizes to N dimensions and other data types, though. We formulate the shape variance, shape correlation and shape intraclass correlation coefficient (ICC) in terms of a simple distance metric, the Manhattan norm, which quantifies the absolute difference between any two shapes. We demonstrate applications of this methodology by working through example shape variance calculations in 1-D, for the analysis of overlapping line segments, and 2-D, for the analysis of overlapping regions. We also report the results of a simulated reliability analysis of manually delineated shape boundaries, and we compare the shape ICC with the more conventional and commonly used area ICC. The proposed shape-sensitive methodology captures all of the variation in the shape measurements, and it provides a more accurate estimate of the measurement reliability than an analysis of only the measured areas.

Multi-parametric T2 * magnetic resonance fingerprinting using variable echo times.

The use of quantitative imaging biomarkers in the imaging of various disease states, including cancer and neurodegenerative disease, has increased in recent years. T1 , T2 , and T2 * relaxation time constants have been shown to be affected by tissue structure or contrast infusion. Acquiring these biomarkers simultaneously in a multi-parametric acquisition could provide more robust detection of tissue changes in various disease states including neurodegeneration and cancer. Traditional magnetic resonance fingerprinting (MRF) has been shown to provide quick, quantitative mapping of T1 and T2 relaxation time constants. In this study, T2 * relaxation is added to the MRF framework using variable echo times (TE). To demonstrate the feasibility of the method and compare incremental and golden angle spiral rotations, simulated phantom data was fit using the proposed method. Additionally, T1 /T2 /T2 */δf MRF as well as conventional T1 , T2 , and T2 * acquisitions were acquired in agar phantoms and the brains of three healthy volunteers. Golden angle spiral rotation was found to reduce inaccuracy resulting from off resonance effects. Strong correlations were found between conventional and MRF values in the T1 , T2 , and T2 * relaxation time constants of the agar phantoms and healthy volunteers. In this study, T2 * relaxation has been incorporated into the MRF framework by using variable echo times, while still fitting for T1 and T2 relaxation time constants. In addition to fitting these relaxation time constants, a novel method for fitting and correcting off resonance effects has been developed.

Longitudinal characterisation of function and structure of Bietti crystalline dystrophy: report on a novel homozygous mutation in CYP4V2.

BACKGROUND: Bietti crystalline dystrophy (BCD) is a rare inherited disorder characterised by fine crystalline deposits in the corneal limbus and retinal posterior pole. In 2004, mutations in the CYP4V2 gene were identified as the cause of BCD. Here, we describe the report of a homozygous point mutation in a patient with BCD and provide detailed characterisation of functional and structural changes over 20 years. METHODS: At regular intervals, the patient underwent repeat ophthalmic evaluations. DNA was extracted from buccal swabs, amplified by standard PCR and analysed for homology to the CYP4V2 sequence. Homology modelling was conducted using Iterative Threading ASSEmbly Refinement and molecular dynamics simulations using GROningen MAchine for Chemical Simulations. RESULTS: The proband, a 47-year-old woman of German ancestry was diagnosed with crystalline retinopathy at age 25. Over the next 20 years, visual acuity and function gradually declined with progression of retinal pigment epithelium and choroidal atrophy. When first tested at 39 years of age, the multifocal electroretinogram (ERG) was markedly abnormal, more so for the right eye, whereas the full-field ERG was more symmetrical and lagged other measures of visual function. Gene sequencing showed a single C>T point mutation in exon 9 encoding a R400C amino acid change. Computational modelling suggests the mutation impairs function due to loss of a hydrogen bonding interaction with the propionate side chains of the haeme prosthetic group. CONCLUSION: This is the first report of a homozygous R400C mutation in CYP4V2 with protein modelling showing high likelihood of enzyme dysfunction. The comprehensive long-term clinical follow-up provides insight into disease progression and highlights possible anti-inflammatory modulation of disease severity.

Comparison of nonparametric methods for static visual field interpolation.

Visual field testing with standard automated perimetry produces a sparse representation of a sensitivity map, sometimes called the hill of vision (HOV), for the retina. Interpolation or resampling of these data is important for visual display, clinical interpretation, and quantitative analysis. Our objective was to compare several popular interpolation methods in terms of their utility to visual field testing. We evaluated nine nonparametric scattered data interpolation algorithms and compared their performances in normal subjects and patients with retinal degeneration. Interpolator performance was assessed by leave-one-out cross-validation accuracy and high-density interpolated HOV surface smoothness. Radial basis function (RBF) interpolation with a linear kernel yielded the best accuracy, with an overall mean absolute error (MAE) of 2.01 dB and root-mean-square error (RMSE) of 3.20 dB that were significantly better than all other methods (p ≤ 0.003). Thin-plate spline RBF interpolation yielded the best smoothness results (p < 0.001) and scored well for accuracy with overall MAE and RMSE values of 2.08 and 3.28 dB, respectively. Natural neighbor interpolation, which may be a more readily accessible method to some practitioners, also performed well. While no interpolator will be universally optimal, these interpolators are good choices among nonparametric methods.

Structure-Function Modeling of Optical Coherence Tomography and Standard Automated Perimetry in the Retina of Patients with Autosomal Dominant Retinitis Pigmentosa.

PURPOSE: To assess relationships between structural and functional biomarkers, including new topographic measures of visual field sensitivity, in patients with autosomal dominant retinitis pigmentosa. METHODS: Spectral domain optical coherence tomography line scans and hill of vision (HOV) sensitivity surfaces from full-field standard automated perimetry were semi-automatically aligned for 60 eyes of 35 patients. Structural biomarkers were extracted from outer retina b-scans along horizontal and vertical midlines. Functional biomarkers were extracted from local sensitivity profiles along the b-scans and from the full visual field. These included topographic measures of functional transition such as the contour of most rapid sensitivity decline around the HOV, herein called HOV slope for convenience. Biomarker relationships were assessed pairwise by coefficients of determination (R2) from mixed-effects analysis with automatic model selection. RESULTS: Structure-function relationships were accurately modeled (conditional R(2)>0.8 in most cases). The best-fit relationship models and correlation patterns for horizontally oriented biomarkers were different than vertically oriented ones. The structural biomarker with the largest number of significant functional correlates was the ellipsoid zone (EZ) width, followed by the total photoreceptor layer thickness. The strongest correlation observed was between EZ width and HOV slope distance (marginal R(2) = 0.85, p<10(-10)). The mean sensitivity defect at the EZ edge was 7.6 dB. Among all functional biomarkers, the HOV slope mean value, HOV slope mean distance, and maximum sensitivity along the b-scan had the largest number of significant structural correlates. CONCLUSIONS: Topographic slope metrics show promise as functional biomarkers relevant to the transition zone. EZ width is strongly associated with the location of most rapid HOV decline.

Interpretation of Flood-Illuminated Adaptive Optics Images in Subjects with Retinitis Pigmentosa.

The purpose of this study was to correlate features on flood-illuminated adaptive optics (AO) images with color fundus, fundus autofluorescence (FAF) and spectral domain optical coherence tomography (SD-OCT) images in patients with retinitis pigmentosa (RP). We imaged 39 subjects diagnosed with RP using the rtx1™ flood-illuminated AO camera from Imagine Eyes (Orsay, France). We observed a correlation between hyper-autofluoresence changes on FAF, disruption of the interdigitation zone (IZ) on SD-OCT and loss of reflective cone profiles on AO. Four main patterns of cone-reflectivity were seen on AO: presumed healthy cone mosaics, hypo-reflective blurred cone-like structures, higher frequency disorganized hyper-reflective spots, and lower frequency hypo-reflective spots. These regions were correlated to progressive phases of cone photoreceptor degeneration observed using SD-OCT and FAF. These results help provide interpretation of en face images obtained by flood-illuminated AO in subjects with RP. However, significant ambiguity remains as to what truly constitutes a cone, especially in areas of degeneration. With further refinements in technology, flood illuminated AO imaging has the potential to provide rapid, standardized, longitudinal and lower cost imaging in patients with retinal degeneration.

Parafoveal cone abnormalities and recovery on adaptive optics in posterior uveitis.

PURPOSE: To determine if adaptive optics (AO) flood illumination imaging can detect subclinical changes in 4 cases of posterior uveitis affecting the outer retina. OBSERVATIONS: In all 4 cases, the affected eye showed altered areas in the photoreceptor mosaic on AO that corresponded to changes on other imaging modalities. Abnormalities not apparent on other imaging modalities were also noted. In one case of multifocal choroiditis with acute outer retinal atrophy, AO revealed decreased visualization of photoreceptors in the unaffected eye that was not noted on spectral domain-optical coherence tomography. In the patient with multiple evanescent white dot syndrome, focal photoreceptor abnormalities were more apparent on AO compared to other imaging modalities, and these areas normalized on AO during follow-up. Five weeks after initiation of high dose prednisone and azathioprine in a patient with serpiginous choroidopathy, AO images showed recovery in apparent parafoveal cone density. CONCLUSIONS AND IMPORTANCE: AO detects subclinical changes in the photoreceptor layer in posterior uveitis that can recover over time. AO may be useful in following outer retinal inflammatory conditions.

Assessment of Different Sampling Methods for Measuring and Representing Macular Cone Density Using Flood-Illuminated Adaptive Optics.

PURPOSE: To describe a standardized flood-illuminated adaptive optics (AO) imaging protocol suitable for the clinical setting and to assess sampling methods for measuring cone density. METHODS: Cone density was calculated following three measurement protocols: 50 × 50-µm sampling window values every 0.5° along the horizontal and vertical meridians (fixed-interval method), the mean density of expanding 0.5°-wide arcuate areas in the nasal, temporal, superior, and inferior quadrants (arcuate mean method), and the peak cone density of a 50 × 50-µm sampling window within expanding arcuate areas near the meridian (peak density method). Repeated imaging was performed in nine subjects to determine intersession repeatability of cone density. RESULTS: Cone density montages could be created for 67 of the 74 subjects. Image quality was determined to be adequate for automated cone counting for 35 (52%) of the 67 subjects. We found that cone density varied with different sampling methods and regions tested. In the nasal and temporal quadrants, peak density most closely resembled histological data, whereas the arcuate mean and fixed-interval methods tended to underestimate the density compared with histological data. However, in the inferior and superior quadrants, arcuate mean and fixed-interval methods most closely matched histological data, whereas the peak density method overestimated cone density compared with histological data. Intersession repeatability testing showed that repeatability was greatest when sampling by arcuate mean and lowest when sampling by fixed interval. CONCLUSIONS: We show that different methods of sampling can significantly affect cone density measurements. Therefore, care must be taken when interpreting cone density results, even in a normal population.

VFMA: Topographic Analysis of Sensitivity Data From Full-Field Static Perimetry.

PURPOSE: To analyze static visual field sensitivity with topographic models of the hill of vision (HOV), and to characterize several visual function indices derived from the HOV volume. METHODS: A software application, Visual Field Modeling and Analysis (VFMA), was developed for static perimetry data visualization and analysis. Three-dimensional HOV models were generated for 16 healthy subjects and 82 retinitis pigmentosa patients. Volumetric visual function indices, which are measures of quantity and comparable regardless of perimeter test pattern, were investigated. Cross-validation, reliability, and cross-sectional analyses were performed to assess this methodology and compare the volumetric indices to conventional mean sensitivity and mean deviation. Floor effects were evaluated by computer simulation. RESULTS: Cross-validation yielded an overall R2 of 0.68 and index of agreement of 0.89, which were consistent among subject groups, indicating good accuracy. Volumetric and conventional indices were comparable in terms of test-retest variability and discriminability among subject groups. Simulated floor effects did not negatively impact the repeatability of any index, but large floor changes altered the discriminability for regional volumetric indices. CONCLUSIONS: VFMA is an effective tool for clinical and research analyses of static perimetry data. Topographic models of the HOV aid the visualization of field defects, and topographically derived indices quantify the magnitude and extent of visual field sensitivity. TRANSLATIONAL RELEVANCE: VFMA assists with the interpretation of visual field data from any perimetric device and any test location pattern. Topographic models and volumetric indices are suitable for diagnosis, monitoring of field loss, patient counseling, and endpoints in therapeutic trials.

Measuring cone density in a Japanese macaque (Macaca fuscata) model of age-related macular degeneration with commercially available adaptive optics.

The aim of this study was to assess the feasibility of using a commercially available high-resolution adaptive optics (AO) camera to image the cone mosaic in Japanese macaques (Macaca fuscata) with dominantly inherited drusen. The macaques examined develop drusen closely resembling those seen in humans with age-related macular degeneration (AMD). For each animal, we acquired and processed images from the AO camera, montaged the results into a composite image, applied custom cone-counting software to detect individual cone photoreceptors, and created a cone density map of the macular region. We conclude that flood-illuminated AO provides a promising method of visualizing the cone mosaic in nonhuman primates. Future studies will quantify the longitudinal change in the cone mosaic and its relationship to the severity of drusen in these animals.

Automatic off-resonance correction in spiral imaging with piecewise linear autofocus.

Off-resonance generates blurring artifacts in spiral images. Applications that often utilize spiral trajectories, such as fine-resolution imaging and rapid scanning, typically preclude the measurement of accurate field maps needed for effective off-resonance correction. Automatic deblurring, or autofocus, algorithms have been developed to estimate the field map directly from the corrupted data prior to off-resonance correction, eliminating the need for field map measurements. These algorithms rely in whole or in part on optimizing an objective function, and suffer from problems related to the accurate minimization and utility of the function. Here, a new method is presented to correct off-resonance blurring automatically without an objective function using a piecewise linear framework. Local linear field maps are estimated with a combination of k-space spectral analysis and mapdrift, an image feature-based correlation technique, for subsequent piecewise linear deblurring. This approach enables field map estimation without optimization, provides accurate off-resonance correction, is suitable for low signal-to-noise ratio and fine-resolution applications, and does not require access to the raw data. Deblurred images from fine-resolution spiral scans of a phantom and healthy volunteers at 3T show that the proposed method can be superior to conventional autofocus and comparable to field map-based correction.

Reduced field of view MRI with rapid, B1-robust outer volume suppression.

MRI scans are inefficient when the size of the anatomy under investigation is small relative to the subject's full extent. The field of view must be expanded, and acquisition times accordingly prolonged. Shorter scans are feasible with reduced field of view imaging (rFOV) using outer volume suppression (OVS), a magnetization preparation sequence that attenuates signal outside a region of interest (ROI). This work presents a new OVS sequence with a cylindrical ROI, short duration, and improved tolerance for B(1)+ inhomogeneity. The sequence consists of a nonselective adiabatic tipdown pulse, which provides B(1)+-robust signal suppression, and a fast 2D spiral cylindrical tipback pulse. Analysis of the Bloch equations with transverse initial magnetization reveals a conjugate symmetric constraint for tipback pulses with small flip angles. This property is exploited to achieve two-shot performance from the single-shot tipback pulse. The OVS sequence is validated in phantoms and in vivo with multislice spiral imaging at 3 T. The relative signal-to-noise ratio efficiency of the proposed sequence was 98% in a phantom and 75-90% in vivo. The effectiveness is demonstrated with cardiovascular rFOV imaging, which exhibits improved resolution and reduced artifacts compared to conventional, full field of view imaging.