Correlation of Automated Computed Tomography Volumetric Analysis Metrics With Motility Disturbances in Thyroid Eye Disease.

PURPOSE: The authors sought to examine relationships between CT metrics derived via an automated method and clinical parameters of extraocular muscle changes in thyroid eye disease (TED). METHODS: CT images of 204 orbits in the setting of TED were analyzed with an automated segmentation tool developed at the institution. Labels were applied to orbital structures of interest on the study images, which were then registered against a previously established atlas of manually indexed orbits derived from 35 healthy individuals. Point-wise correspondences between study and atlas images were then compared via a fusion algorithm to highlight metrics of interest where TED orbits differed from healthy orbits. RESULTS: Univariate analysis demonstrated several correlations between CT metrics and clinical data. Metrics pertaining to the extraocular muscles-including average diameter, maximum diameter, and muscle volume-were strongly correlated (p < 0.05) with the presence of ocular motility deficits with regards to the superior, inferior, and lateral recti (with exception of superior rectus motility deficits being mildly correlated with muscle volume [p = 0.09]). Motility defects of the medial rectus were strongly correlated with muscle volume, and only weakly correlated with average and maximum muscle diameter. CONCLUSIONS: The novel method of automated imaging metrics may provide objective, rapid clinical information which may have utility in prevention and recognition of visual impairments in TED before they reach an advanced or irreversible stage and while they are able to be improved with immunomodulatory treatments.

Assessment of Orbital Computed Tomography (CT) Imaging Biomarkers in Patients with Thyroid Eye Disease.

To understand potential orbital biomarkers generated from computed tomography (CT) imaging in patients with thyroid eye disease. This is a retrospective cohort study. From a database of an ongoing thyroid eye disease research study at our institution, we identified 85 subjects who had both clinical examination and laboratory records supporting the diagnosis of thyroid eye disease and concurrent imaging prior to any medical or surgical intervention. Patients were excluded if imaging quality or type was not amenable to segmentation. The images of 170 orbits were analyzed with the developed automated segmentation tool. The main outcome measure was to cross 25 CT structural metrics for each eye with nine clinical markers using a Kendall rank correlation test to identify significant relationships. The Kendall rank correlation test between automatically calculated CT metrics and clinical data demonstrated numerous correlations. Extraocular rectus muscle metrics, such as the average diameter of the superior, medial, and lateral rectus muscles, showed a strong correlation (p < 0.05) with loss of visual acuity and presence of ocular motility defects. Hertel measurements demonstrated a strong correlation (p < 0.05) with volumetric measurements of the optic nerve and other orbital metrics such as the crowding index and proptosis. Optic neuropathy was strongly correlated (p < 0.05) with an increase in the maximum diameter of the superior muscle. This novel method of automated imaging metrics may provide objective, rapid clinical information. This data may be useful for appreciation of severity of thyroid eye disease and recognition of risk factors of visual impairment from dysthyroid optic neuropathy from CT imaging.

Imaging biomarkers in thyroid eye disease and their clinical associations.

The purpose of this study is to understand the phenotypes of thyroid eye disease (TED) through data derived from a multiatlas segmentation of computed tomography (CT) imaging. Images of 170 orbits of 85 retrospectively selected TED patients were analyzed with the developed automated segmentation tool. Twenty-five bilateral orbital structural metrics were used to perform principal component analysis (PCA). PCA of the 25 structural metrics identified the two most dominant structural phenotypes or characteristics, the "big volume phenotype" and the "stretched optic nerve phenotype," that accounted for 60% of the variance. Most of the subjects in the study have either of these characteristics or a combination of both. A Kendall rank correlation between the principal components (phenotypes) and clinical data showed that the big volume phenotype was very strongly correlated ( p - value < 0.05 ) with motility defects, and loss of visual acuity. Whereas, the stretched optic nerve phenotype was strongly correlated ( p - value < 0.05 ) with an increased Hertel measurement, relatively better visual acuity, and smoking. Two clinical subtypes of TED, type 1 with enlarged muscles and type 2 with proptosis, are recognizable in CT imaging. Our automated algorithm identifies the phenotypes and finds associations with clinical markers.

Robust Multicontrast MRI Spleen Segmentation for Splenomegaly Using Multi-Atlas Segmentation.

OBJECTIVE: Magnetic resonance imaging (MRI) is an essential imaging modality in noninvasive splenomegaly diagnosis. However, it is challenging to achieve spleen volume measurement from three-dimensional MRI given the diverse structural variations of human abdomens as well as the wide variety of clinical MRI acquisition schemes. Multi-atlas segmentation (MAS) approaches have been widely used and validated to handle heterogeneous anatomical scenarios. In this paper, we propose to use MAS for clinical MRI spleen segmentation for splenomegaly. METHODS: First, an automated segmentation method using the selective and iterative method for performance level estimation (SIMPLE) atlas selection is used to address the concerns of inhomogeneity for clinical splenomegaly MRI. Then, to further control outliers, semiautomated craniocaudal spleen length-based SIMPLE atlas selection (L-SIMPLE) is proposed to integrate a spatial prior in a Bayesian fashion and guide iterative atlas selection. Last, a graph cuts refinement is employed to achieve the final segmentation from the probability maps from MAS. RESULTS: A clinical cohort of 55 MRI volumes (28 T1 weighted and 27 T2 weighted) was used to evaluate both automated and semiautomated methods. CONCLUSION: The results demonstrated that both methods achieved median Dice , and outliers were alleviated by the L-SIMPLE (≍1 min manual efforts per scan), which achieved 0.97 Pearson correlation of volume measurements with the manual segmentation. SIGNIFICANCE: In this paper, spleen segmentation on MRI splenomegaly using MAS has been performed.

Quantitative characterization of optic nerve atrophy in patients with multiple sclerosis.

BACKGROUND: Optic neuritis (ON) is one of the most common presentations of multiple sclerosis (MS). Magnetic resonance imaging (MRI) of the optic nerves is challenging because of retrobulbar motion, orbital fat and susceptibility artifacts from maxillary sinuses; therefore, axonal loss is investigated with the surrogate measure of a single heuristically defined point along the nerve as opposed to volumetric investigation. OBJECTIVE: The objective of this paper is to derive optic nerve volumetrics along the entire nerve length in patients with MS and healthy controls in vivo using high-resolution, clinically viable MRI. METHODS: An advanced, isotropic T2-weighted turbo spin echo MRI was applied to 29 MS patients with (14 patients ON+) or without (15 patients ON-) history of ON and 42 healthy volunteers. An automated tool was used to estimate and compare whole optic nerve and surrounding cerebrospinal fluid radii along the length of the nerve. RESULTS AND CONCLUSION: Only ON+ MS patients had a significantly reduced optic nerve radius compared to healthy controls in the central segment of the optic nerve. Using clinically available MRI methods, we show and quantify ON volume loss for the first time in MS patients.

Effects of b-Value and Number of Gradient Directions on Diffusion MRI Measures Obtained with Q-ball Imaging.

High-angular-resolution diffusion-weighted imaging (HARDI) MRI acquisitions have become common for use with higher order models of diffusion. Despite successes in resolving complex fiber configurations and probing microstructural properties of brain tissue, there is no common consensus on the optimal b-value and number of diffusion directions to use for these HARDI methods. While this question has been addressed by analysis of the diffusion-weighted signal directly, it is unclear how this translates to the information and metrics derived from the HARDI models themselves. Using a high angular resolution data set acquired at a range of b-values, and repeated 11 times on a single subject, we study how the b-value and number of diffusion directions impacts the reproducibility and precision of metrics derived from Q-ball imaging, a popular HARDI technique. We find that Q-ball metrics associated with tissue microstructure and white matter fiber orientation are sensitive to both the number of diffusion directions and the spherical harmonic representation of the Q-ball, and often are biased when under sampled. These results can advise researchers on appropriate acquisition and processing schemes, particularly when it comes to optimizing the number of diffusion directions needed for metrics derived from Q-ball imaging.

Improved Automatic Optic Nerve Radius Estimation from High Resolution MRI.

The optic nerve (ON) is a vital structure in the human visual system and transports all visual information from the retina to the cortex for higher order processing. Due to the lack of redundancy in the visual pathway, measures of ON damage have been shown to correlate well with visual deficits. These measures are typically taken at an arbitrary anatomically defined point along the nerve and do not characterize changes along the length of the ON. We propose a fully automated, three-dimensionally consistent technique building upon a previous independent slice-wise technique to estimate the radius of the ON and surrounding cerebrospinal fluid (CSF) on high-resolution heavily T2-weighted isotropic MRI. We show that by constraining results to be three-dimensionally consistent this technique produces more anatomically viable results. We compare this technique with the previously published slice-wise technique using a short-term reproducibility data set, 10 subjects, follow-up <1 month, and show that the new method is more reproducible in the center of the ON. The center of the ON contains the most accurate imaging because it lacks confounders such as motion and frontal lobe interference. Long-term reproducibility, 5 subjects, follow-up of approximately 11 months, is also investigated with this new technique and shown to be similar to short-term reproducibility, indicating that the ON does not change substantially within 11 months. The increased accuracy of this new technique provides increased power when searching for anatomical changes in ON size amongst patient populations.

Multi-atlas Segmentation Enables Robust Multi-contrast MRI Spleen Segmentation for Splenomegaly.

Non-invasive spleen volume estimation is essential in detecting splenomegaly. Magnetic resonance imaging (MRI) has been used to facilitate splenomegaly diagnosis in vivo. However, achieving accurate spleen volume estimation from MR images is challenging given the great inter-subject variance of human abdomens and wide variety of clinical images/modalities. Multi-atlas segmentation has been shown to be a promising approach to handle heterogeneous data and difficult anatomical scenarios. In this paper, we propose to use multi-atlas segmentation frameworks for MRI spleen segmentation for splenomegaly. To the best of our knowledge, this is the first work that integrates multi-atlas segmentation for splenomegaly as seen on MRI. To address the particular concerns of spleen MRI, automated and novel semi-automated atlas selection approaches are introduced. The automated approach interactively selects a subset of atlases using selective and iterative method for performance level estimation (SIMPLE) approach. To further control the outliers, semi-automated craniocaudal length based SIMPLE atlas selection (L-SIMPLE) is proposed to introduce a spatial prior in a fashion to guide the iterative atlas selection. A dataset from a clinical trial containing 55 MRI volumes (28 T1 weighted and 27 T2 weighted) was used to evaluate different methods. Both automated and semi-automated methods achieved median DSC > 0.9. The outliers were alleviated by the L-SIMPLE (≈1 min manual efforts per scan), which achieved 0.9713 Pearson correlation compared with the manual segmentation. The results demonstrated that the multi-atlas segmentation is able to achieve accurate spleen segmentation from the multi-contrast splenomegaly MRI scans.

Short Term Reproducibility of a High Contrast 3-D Isotropic Optic Nerve Imaging Sequence in Healthy Controls.

The optic nerve (ON) plays a crucial role in human vision transporting all visual information from the retina to the brain for higher order processing. There are many diseases that affect the ON structure such as optic neuritis, anterior ischemic optic neuropathy and multiple sclerosis. Because the ON is the sole pathway for visual information from the retina to areas of higher level processing, measures of ON damage have been shown to correlate well with visual deficits. Increased intracranial pressure has been shown to correlate with the size of the cerebrospinal fluid (CSF) surrounding the ON. These measures are generally taken at an arbitrary point along the nerve and do not account for changes along the length of the ON. We propose a high contrast and high-resolution 3-D acquired isotropic imaging sequence optimized for ON imaging. We have acquired scan-rescan data using the optimized sequence and a current standard of care protocol for 10 subjects. We show that this sequence has superior contrast-to-noise ratio to the current standard of care while achieving a factor of 11 higher resolution. We apply a previously published automatic pipeline to segment the ON and CSF sheath and measure the size of each individually. We show that these measures of ON size have lower short-term reproducibility than the population variance and the variability along the length of the nerve. We find that the proposed imaging protocol is (1) useful in detecting population differences and local changes and (2) a promising tool for investigating biomarkers related to structural changes of the ON.

On the Fallacy of Quantitative Segmentation for T1-Weighted MRI.

T1-weighted magnetic resonance imaging (MRI) generates contrasts with primary sensitivity to local T1 properties (with lesser T2 and PD contributions). The observed signal intensity is determined by these local properties and the sequence parameters of the acquisition. In common practice, a range of acceptable parameters is used to ensure "similar" contrast across scanners used for any particular study (e.g., the ADNI standard MPRAGE). However, different studies may use different ranges of parameters and report the derived data as simply "T1-weighted". Physics and imaging authors pay strong heed to the specifics of the imaging sequences, but image processing authors have historically been more lax. Herein, we consider three T1-weighted sequences acquired the same underlying protocol (MPRAGE) and vendor (Philips), but "normal study-to-study variation" in parameters. We show that the gray matter/white matter/cerebrospinal fluid contrast is subtly but systemically different between these images and yields systemically different measurements of brain volume. The problem derives from the visually apparent boundary shifts, which would also be seen by a human rater. We present and evaluate two solutions to produce consistent segmentation results across imaging protocols. First, we propose to acquire multiple sequences on a subset of the data and use the multi-modal imaging as atlases to segment target images any of the available sequences. Second (if additional imaging is not available), we propose to synthesize atlases of the target imaging sequence and use the synthesized atlases in place of atlas imaging data. Both approaches significantly improve consistency of target labeling.

Structural Functional Associations of the Orbit in Thyroid Eye Disease: Kalman Filters to Track Extraocular Rectal Muscles.

Pathologies of the optic nerve and orbit impact millions of Americans and quantitative assessment of the orbital structures on 3-D imaging would provide objective markers to enhance diagnostic accuracy, improve timely intervention and eventually preserve visual function. Recent studies have shown that the multi-atlas methodology is suitable for identifying orbital structures, but challenges arise in the identification of the individual extraocular rectus muscles that control eye movement. This is increasingly problematic in diseased eyes, where these muscles often appear to fuse at the back of the orbit (at the resolution of clinical computed tomography imaging) due to inflammation or crowding. We propose the use of Kalman filters to track the muscles in three-dimensions to refine multi-atlas segmentation and resolve ambiguity due to imaging resolution, noise, and artifacts. The purpose of our study is to investigate a method of automatically generating orbital metrics from CT imaging and demonstrate the utility of the approach by correlating structural metrics of the eye orbit with clinical data and visual function measures in subjects with thyroid eye disease. The pilot study demonstrates that automatically calculated orbital metrics are strongly correlated with several clinical characteristics. Moreover, the superior, inferior, medial and lateral rectus muscles obtained using Kalman filters are each correlated with different categories of functional deficit. These findings serve as foundation for further investigation in the use of CT imaging in the study, analysis and diagnosis of ocular diseases, specifically thyroid eye disease.

Disambiguating the optic nerve from the surrounding cerebrospinal fluid: Application to MS-related atrophy.

PURPOSE: Our goal is to develop an accurate, automated tool to characterize the optic nerve (ON) and cerebrospinal fluid (CSF) to better understand ON changes in disease. METHODS: Multi-atlas segmentation is used to localize the ON and sheath on T2-weighted MRI (0.6 mm(3) resolution). A sum of Gaussian distributions is fit to coronal slice-wise intensities to extract six descriptive parameters, and a regression forest is used to map the model space to radii. The model is validated for consistency using tenfold cross-validation and for accuracy using a high resolution (0.4 mm(2) reconstructed to 0.15 mm(2)) in vivo sequence. We evaluated this model on 6 controls and 6 patients with multiple sclerosis (MS) and a history of optic neuritis. RESULTS: In simulation, the model was found to have an explanatory R-squared for both ON and sheath radii greater than 0.95. The accuracy of the method was within the measurement error on the highest possible in vivo resolution. Comparing healthy controls and patients with MS, significant structural differences were found near the ON head and the chiasm, and structural trends agreed with the literature. CONCLUSION: This is a first demonstration that the ON can be exclusively, quantitatively measured and separated from the surrounding CSF using MRI.

Vanderbilt University Institute of Imaging Science Center for Computational Imaging XNAT: A multimodal data archive and processing environment.

The Vanderbilt University Institute for Imaging Science (VUIIS) Center for Computational Imaging (CCI) has developed a database built on XNAT housing over a quarter of a million scans. The database provides framework for (1) rapid prototyping, (2) large scale batch processing of images and (3) scalable project management. The system uses the web-based interfaces of XNAT and REDCap to allow for graphical interaction. A python middleware layer, the Distributed Automation for XNAT (DAX) package, distributes computation across the Vanderbilt Advanced Computing Center for Research and Education high performance computing center. All software are made available in open source for use in combining portable batch scripting (PBS) grids and XNAT servers.

Constructing a statistical atlas of the radii of the optic nerve and cerebrospinal fluid sheath in young healthy adults.

Optic neuritis is a sudden inflammation of the optic nerve (ON) and is marked by pain on eye movement, and visual symptoms such as a decrease in visual acuity, color vision, contrast and visual field defects. The ON is closely linked with multiple sclerosis (MS) and patients have a 50% chance of developing MS within 15 years. Recent advances in multi-atlas segmentation methods have omitted volumetric assessment. In the past, measuring the size of the ON has been done by hand. We utilize a new method of automatically segmenting the ON to measure the radii of both the ON and surrounding cerebrospinal fluid (CSF) sheath to develop a normative distribution of healthy young adults. We examine this distribution for any trends and find that ON and CSF sheath radii do not vary between 20-35 years of age and between sexes. We evaluate how six patients suffering from optic neuropathy compare to this distribution of controls. We find that of these six patients, five of them qualitatively differ from the normative distribution which suggests this technique could be used in the future to distinguish between optic neuritis patients and healthy controls.

Robust optic nerve segmentation on clinically acquired computed tomography.

The optic nerve (ON) plays a critical role in many devastating pathological conditions. Segmentation of the ON has the ability to provide understanding of anatomical development and progression of diseases of the ON. Recently, methods have been proposed to segment the ON but progress toward full automation has been limited. We optimize registration and fusion methods for a new multi-atlas framework for automated segmentation of the ONs, eye globes, and muscles on clinically acquired computed tomography (CT) data. Briefly, the multi-atlas approach consists of determining a region of interest within each scan using affine registration, followed by nonrigid registration on reduced field of view atlases, and performing statistical fusion on the results. We evaluate the robustness of the approach by segmenting the ON structure in 501 clinically acquired CT scan volumes obtained from 183 subjects from a thyroid eye disease patient population. A subset of 30 scan volumes was manually labeled to assess accuracy and guide method choice. Of the 18 compared methods, the ANTS Symmetric Normalization registration and nonlocal spatial simultaneous truth and performance level estimation statistical fusion resulted in the best overall performance, resulting in a median Dice similarity coefficient of 0.77, which is comparable with inter-rater (human) reproducibility at 0.73.