Advances in peripheral nerve MR imaging : The application of diffusion MRI in neurological disorders

The peripheral nervous system is a network of nerves which transmits signals from the central nervous system to the body and vice versa. It regulates and controls body functions and activity. Damage to (part of) the nerves may cause distortion in transmission of the signal from the central nervous system to the innervated area and vice versa, which in turn may lead to muscle weakness or muscle wasting. The underlying pathophysiological processes leading to nerve degeneration are not always evident. New insights regarding these processes are needed to better understand disease mechanisms. Furthermore, there is a need for non-invasive imaging modalities that can diagnose and monitor disease progression, or therapeutic effects in neurological disorders. A non-invasive imaging technique that allows for the visualization of nerve tissue is magnetic resonance imaging (MRI). Diffusion tensor imaging (DTI) is an MRI technique which is sensitive to the random motion of water molecules and can be used to measure the diffusion of water molecules in tissue. In nerve tissue this diffusion is more oriented along the nerve than perpendicular to it (anisotropic diffusion). This makes it a potential valuable method to investigate peripheral nerve tissue in neurological disorders. In this thesis MRI and DTI are applied in different neurological disorders to explore the potential value in a clinical setting. To determine the potential value of DTI to investigate peripheral nerves in a clinical setting, first the reproducibility of DTI in the lumbosacral nerves was investigated. DTI was found to be reproducible and can therefore be reliably used in cross-sectional studies in a clinical setting. Small differences in inter-week comparison highlight that one needs to be careful when interpreting diffusion measures in longitudinal studies, since small differences can also be caused by factors other than disease progression or therapy response. Then DTI was applied in multiple neurological disorders including spina bifida, compressed nerves of lumbar disc herniated patients, multifocal motor neuropathy, spinal muscular atrophy and single-sided deafness. In general DTI showed differences in diffusion values such as in the fractional anisotropy, mean diffusivity, axial diffusivity and radial diffusivity. With fiber tractography it was possible to reconstruct the nerves in 3D. In for example the spina bifida patients the lumbosacral nerves showed asymmetry and disorganization compared to healthy controls. The various studies in this thesis show that MRI and DTI are promising techniques in the evaluation of peripheral nerve tissue in neurological disorders. The evaluated methods may contribute to the improvement of diagnosis and prognosis of different neurological disorders. However, in some patient groups the hypothesized intra-subject differences were not found. Furthermore, in the longitudinal follow-up of patients, one should be careful with the interpretation, since differences in diffusion values may also be caused by other factors than disease progression or therapeutic effects

Advances in peripheral nerve MR imaging : The application of diffusion MRI in neurological disorders

The peripheral nervous system is a network of nerves which transmits signals from the central nervous system to the body and vice versa. It regulates and controls body functions and activity. Damage to (part of) the nerves may cause distortion in transmission of the signal from the central nervous system to the innervated area and vice versa, which in turn may lead to muscle weakness or muscle wasting. The underlying pathophysiological processes leading to nerve degeneration are not always evident. New insights regarding these processes are needed to better understand disease mechanisms. Furthermore, there is a need for non-invasive imaging modalities that can diagnose and monitor disease progression, or therapeutic effects in neurological disorders. A non-invasive imaging technique that allows for the visualization of nerve tissue is magnetic resonance imaging (MRI). Diffusion tensor imaging (DTI) is an MRI technique which is sensitive to the random motion of water molecules and can be used to measure the diffusion of water molecules in tissue. In nerve tissue this diffusion is more oriented along the nerve than perpendicular to it (anisotropic diffusion). This makes it a potential valuable method to investigate peripheral nerve tissue in neurological disorders. In this thesis MRI and DTI are applied in different neurological disorders to explore the potential value in a clinical setting. To determine the potential value of DTI to investigate peripheral nerves in a clinical setting, first the reproducibility of DTI in the lumbosacral nerves was investigated. DTI was found to be reproducible and can therefore be reliably used in cross-sectional studies in a clinical setting. Small differences in inter-week comparison highlight that one needs to be careful when interpreting diffusion measures in longitudinal studies, since small differences can also be caused by factors other than disease progression or therapy response. Then DTI was applied in multiple neurological disorders including spina bifida, compressed nerves of lumbar disc herniated patients, multifocal motor neuropathy, spinal muscular atrophy and single-sided deafness. In general DTI showed differences in diffusion values such as in the fractional anisotropy, mean diffusivity, axial diffusivity and radial diffusivity. With fiber tractography it was possible to reconstruct the nerves in 3D. In for example the spina bifida patients the lumbosacral nerves showed asymmetry and disorganization compared to healthy controls. The various studies in this thesis show that MRI and DTI are promising techniques in the evaluation of peripheral nerve tissue in neurological disorders. The evaluated methods may contribute to the improvement of diagnosis and prognosis of different neurological disorders. However, in some patient groups the hypothesized intra-subject differences were not found. Furthermore, in the longitudinal follow-up of patients, one should be careful with the interpretation, since differences in diffusion values may also be caused by other factors than disease progression or therapeutic effects

Belief Elicitation to Populate Health Economic Models of Medical Diagnostic Devices in Development

Background and Objective Bayesian methods can be used to elicit experts’ beliefs about the clinical value of healthcare technologies. This study investigates a belief–elicitation method for estimating diagnostic performance in an early stage of development of photoacoustic mammography (PAM) imaging versus magnetic resonance imaging (MRI) for detecting breast cancer. Research Design Eighteen experienced radiologists ranked tumor characteristics regarding their importance to detect malignancies. With reference to MRI, radiologists estimated the true positives and negatives of PAM using the variable interval method. An overall probability density function was determined using linear opinion pooling, weighted for individual experts’ experience. Result The most important tumor characteristics are mass margins and mass shape. Respondents considered MRI the better technology to visualize these characteristics. Belief elicitation confirmed this by providing an overall sensitivity of PAM ranging from 58.9 to 85.1 % (mode 75.6 %) and specificity ranging from 52.2 to 77.6 % (mode 66.5 %). Conclusion Belief elicitation allowed estimates to be obtained for the expected diagnostic performance of PAM, although radiologists expressed difficulties in doing so. Heterogeneity within and between experts reflects this uncertainty and the infancy of PAM. Further clinical trials are required to validate the extent to which this belief–elicitation method is predictive for observed test performanc

Identification of discrete vascular lesions in the extremities using post-mortem computed tomography angiography – Case reports

In this case report, we introduced post-mortem computed tomography angiography (PMCTA) in three cases suffering from vascular lesions in the upper extremities. In each subject, the third part of the axillary arteries and veins were used to catheterize the arms. The vessels were filled with a barium sulfate based contrast agent using a syringe. A CT scan was performed before and after filling of the vessels. Partial PMCTA provided information about the exact location and the severity of lesions. In one subject, partial PMCTA was essential to identify the cause of death. The substantial benefit of partial PMCTA is that the procedure is easily performed using standard clinically available CT systems without the use of pumps or other advanced equipment. These findings demonstrated the feasibility of PMCTA for identification of vascular lesions in the upper extremities. We expect that partial PMCTA can be of great value in cases where the subjects are suspected to have lesions in the extremities

Post-mortem computed tomography angiography utilizing barium sulfate to identify microvascular structures : a preliminary phantom model and case study

We investigated the use of computer tomography angiography (CTA) to visualize microvascular structures in a vessel-mimicking phantom and post-mortem (PM) bodies. A contrast agent was used based on 22% barium sulfate, 20% polyethylene glycol and 58% distilled water. A vessel-mimicking phantom identified small vessels. Intercostal arteries and veins were visualized in four males and one female without known vascular lesions. Histology confirmed the filling of vascular structures down to 8 µm without extravasation

Diffusion tensor imaging of peripheral nerves in non-fixed post-mortem subjects

Purpose: While standard magnetic resonance imaging (MRI) sequences are increasingly employed in post-mortem (PM) examinations, more advanced techniques such as diffusion tensor imaging (DTI) remain unexplored in forensic sciences. Therefore, we studied the temporal stability and reproducibility of DTI and fiber tractography (FT) in non-fixed PM subjects. In addition, we investigated the lumbosacral nerves with PMDTI and compared their tissue characteristics to in vivo findings. Methods: MRI data were acquired on a 1.5 T MRI scanner in seven PM subjects, consisting of six non-trauma deaths and one chronic trauma death, and in six living subjects. Inter-scan (within one session) and inter-session (between days) reproducibility of diffusion parameters, fractional anisotropy (FA), and mean diffusivity (MD), were evaluated for the lumbosacral nerves using Bland-Altman and Jones plots. Diffusion parameters in nerves L3-S2 were compared to living subjects using the non-parametric Mann-Whitney U test. Results: Reproducibility of diffusion values of inter-scan 95% limits of agreement ranged from -0.058 to 0.062 for FA, and (-0.037 to 0.052) × 10-3 mm2/s for MD. For the inter-session this was -0.0423 to 0.0423, and (-0.0442 to 0.0442) × 10-3 mm2/s for FA, and MD, respectively. Although PM subjects showed approximately four-fold lower diffusivity values compared to living subjects, FT results were comparable. The chronic trauma case showed disorganization and asymmetry of the nerves. Conclusion: We demonstrated that DTI was reproducible in characterizing nervous tissue properties and FT in reconstructing the architecture of lumbosacral nerves in PM subjects. We showed differences in diffusion values between PM and in vivo and showed the ability of PMDTI and FT to reconstruct nerve lesions in a chronic trauma case. We expect that PMDTI and FT may become valuable in identification and documentation of PM nerve trauma or pathologies in forensic sciences

Multicenter reproducibility study of diffusion MRI and fiber tractography of the lumbosacral nerves

BACKGROUND: Diffusion tensor imaging (DTI) has been applied in the lumbar and sacral nerves in vivo, but information about the reproducibility of this method is needed before DTI can be used reliably in clinical practice across centers. PURPOSE: In this multicenter study the reproducibility of DTI of the lumbosacral nerves in healthy volunteers was investigated. STUDY TYPE: Prospective control series. SUBJECTS: Twenty healthy subjects. FIELD STRENGTH/SEQUENCE: 3T MRI. 3D turbo spin echo, and 3.0 mm isotropic DTI scan. ASSESSMENT: The DTI scan was performed three times (twice in the same session, intrascan reproducibility, and once after an hour, interscan reproducibility). At site 2, 1 week later, the protocol was repeated (interweek reproducibility). Fiber tractography (FT) of the lumbar and sacral nerves (L3-S2) was performed to obtain values for fractional anisotropy, mean, axial, and radial diffusivity. STATISTICAL TESTS: Reproducibility was determined using the intraclass correlation coefficient (ICC), and power calculations were performed. RESULTS: FT was successful and reproducible in all datasets. ICCs for all diffusion parameters were high for intrascan (ranging from 0.70-0.85), intermediate for interscan (ranging from 0.61-0.73), and interweek reliability (ranging from 0.58-0.62). There were small but significant differences between the interweek diffusivity values (P < 0.0005). Depending on the effect size, nerve location, and parameter of interest, power calculations showed that sample sizes between 10 and 232 subjects are needed for cross-sectional studies. DATA CONCLUSION: We found that DTI and FT of the lumbosacral nerves have intermediate to high reproducibility within and between scans. Based on these results, 10-58 subjects are needed to find a 10% change in parameters in cross-sectional studies of the lumbar and sacral nerves. The small significant differences of the interweek comparison suggest that results from longitudinal studies need to be interpreted carefully, since small differences may also be caused by factors other than disease progression or therapeutic effects. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018

Post-mortem diffusion MRI of the cervical spine and its nerve roots

Purpose: The aim of this work is to examine the architectural configuration and the microstructural substrate of the cervical spine and its nerve roots with post-mortem (PM) diffusion tensor imaging (DTI) in non-fixed subjects and to compare these findings with histology. Methods: Magnetic resonance imaging (MRI) data were acquired on a 1.5 T MRI scanner in five non-fixed non-trauma deaths. Two different areas were evaluated: 1) the cervical spinal cord and ventral and dorsal nerve roots with a "high in-plane" DTI and a multi-echo fast field echo protocol, and 2) the cervical peripheral nerves with an "isotropic" DTI and a 3D turbo spin echo protocol. Histology samples were obtained matching the anatomical level of the slices of the 'high in-plane' DTI protocol. Results: We were able to show detailed reconstructions of the dorsal and ventral nerve roots with the 'high in-plane' protocol and identified a low fractional anisotropy (FA = 0.30 ± 0.08) in the grey matter and a high FA (0.51 ± 0.13) in the white matter. Both grey and white matter configurations correlated with the anatomical MRI, the diffusion MRI, and with the histological sections. Using the 'isotropic' DTI protocol, it was feasible to reconstruct the spinal cord, cervical nerves, and nerve roots in all PM subjects. Conclusion: We were able to generate detailed architectural configurations of the ventral and dorsal nerve roots. Anatomical and diffusion MR scans showed good qualitative agreement with histology. We believe that PMDTI will be helpful in the assessment of head and neck injuries in a forensic setting