Validation of mean upper cervical cord area (MUCCA) measurement techniques in multiple sclerosis (MS): High reproducibility and robustness to lesions, but large software and scanner effects.

INTRODUCTION: Atrophy of the spinal cord is known to occur in multiple sclerosis (MS). The mean upper cervical cord area (MUCCA) can be used to measure this atrophy. Currently, several (semi-)automated methods for MUCCA measurement exist, but validation in clinical magnetic resonance (MR) images is lacking. METHODS: Five methods to measure MUCCA (SCT-PropSeg, SCT-DeepSeg, NeuroQLab, Xinapse JIM and ITK-SNAP) were investigated in a predefined upper cervical cord region. First, within-scanner reproducibility and between-scanner robustness were assessed using intra-class correlation coefficient (ICC) and Dice's similarity index (SI) in scan-rescan 3DT1-weighted images (brain, including cervical spine using a head coil) performed on three 3 T MR machines (GE MR750, Philips Ingenuity, Toshiba Vantage Titan) in 21 subjects with MS and 6 healthy controls (dataset A). Second, sensitivity of MUCCA measurement to lesions in the upper cervical cord was assessed with cervical 3D T1-weighted images (3 T GE HDxT using a head-neck-spine coil) in 7 subjects with MS without and 14 subjects with MS with cervical lesions (dataset B), using ICC and SI with manual reference segmentations. RESULTS: In dataset A, MUCCA differed between MR machines (p < 0.001) and methods (p < 0.001) used, but not between scan sessions. With respect to MUCCA values, Xinapse JIM showed the highest within-scanner reproducibility (ICC absolute agreement = 0.995) while Xinapse JIM and SCT-PropSeg showed the highest between-scanner robustness (ICC consistency = 0.981 and 0.976, respectively). Reproducibility of segmentations between scan sessions was highest in Xinapse JIM and SCT-PropSeg segmentations (median SI ≥ 0.921), with a significant main effect of method (p < 0.001), but not of MR machine or subject group. In dataset B, SI with manual outlines did not differ between patients with or without cervical lesions for any of the segmentation methods (p > 0.176). However, there was an effect of method for both volumetric and voxel wise agreement of the segmentations (both p < 0.001). Highest volumetric and voxel wise agreement was obtained with Xinapse JIM (ICC absolute agreement = 0.940 and median SI = 0.962). CONCLUSION: Although MUCCA is highly reproducible within a scanner for each individual measurement method, MUCCA differs between scanners and between methods. Cervical cord lesions do not affect MUCCA measurement performance.

Cervical cord and ventricle affection in neuromyelitis optica.

OBJECTIVES: Cervical cord involvement is common in neuromyelitis optica (NMO) and multiple sclerosis (MS), but its impact on disability in NMO has rarely been studied. Recent publications on NMO examined the periventricular system, areas of high aquaporin-4 expression, but not yet by using ventricle volumetry. PURPOSE: To compare cervical cord atrophy, ventricular widening, and supra- and infratentorial brain measures between NMO and MS, and study their impact on clinical disability. METHODS: Magnet resonance imaging-based volumetry of upper cervical cord, third and fourth lateral ventricles, grey matter, white matter, brainstem, cerebellum and clinical status of 18 NMO and 20 MS patients, was compared between the groups and with 26 healthy controls. Patterns of ventricular widening relative to healthy controls were inspected by voxel-based morphometry of the cerebrospinal fluid. RESULTS: Cervical cord atrophy was similar in NMO and MS (75.2 ± 10.0 mm2 , respectively, 76.5 ± 9.5 mm2 vs 84.1 ± 8.6 mm2 in controls).Third ventricle increase in both groups, and specific fourth ventricle widening in MS were detected. Patient groups differed in third to fourth ventricle ratio (P = 0.002). In NMO, white matter correlated inversely with the affected cord segments (P = 0.001) and with cervical cord area (P = 0.043). The disability status was explained by cervical cord area and third ventricle volume (R2 =0.524) in NMO, and by grey matter and fourth ventricle volume (R2 =0.565) in MS. CONCLUSION: Cervical cord atrophy and third ventricular enlargement are both clinically relevant in NMO. Third and fourth ventricle volumetry shows differences between NMO and MS regarding the involvement of periventricular structures.

Cervical cord area is associated with infratentorial grey and white matter volume predominantly in relapsing-remitting multiple sclerosis: A study using semi-automated cord volumetry and voxel-based morphometry.

BACKGROUND AND PURPOSE: Atrophy of the brain and the upper cervical cord, which both have major impact on the severity of clinical symptoms in multiple sclerosis (MS), may be interrelated by neuraxonal degeneration. Aiming to identify possible spatially remote effects of neuraxonal brain damage on spinal cord atrophy, we studied regional and global brain volumes and the upper cervical cord area (UCCA) in a large group of MS patients and a healthy control group. METHODS: In a group of 132 MS patients (71 relapsing-remitting MS; 61 secondary progressive MS; median [range] of EDSS: 5 [0-7], respectively 6 [2-8.5] and mean±standard deviation of age/disease duration: 37±11 years/6.7±6.3 years; respectively: 49±8 years/14.5±8.0 years) and 45 healthy subjects UCCA, regional and global brain volumes, and brain lesion load were assessed. Associations between MRI results and clinical parameters in the entire cohort and differentiated according to MS-subtype were investigated using t-tests, partial correlation analyses, voxel-based morphometry and statistical parametric mapping. RESULTS: Exclusively in RRMS, a significant positive correlation of UCCA with cerebellar cortical grey matter (GM) in the vermis and with regional white matter volume in the entire brainstem, corresponding to the corticospinal tracts, was detected. Although SPMS patients were considerably more affected by disability and decrease of UCCA (RRMS:75.2±10.4 mm(2); SPMS: 66.0±11.8 mm(2),controls: 84.5±8.7mm(2)), brain grey matter (RRMS:585.8±53.6 ml; SPMS: 528.2±61.5 ml, controls: 608.7±48.1 ml) and total brain volume (RRMS:1162.9±41.8 ml; SPMS: 1117.9±51.2 ml, controls: 1194.1±19.5 ml) than RRMS patients, significant positive associations in this group were found only between UCCA and a cluster of white matter in the medulla, but not in grey matter. CONCLUSION: Cervical cord and brain atrophy were present in both, RRMS and even more severe in SPMS. Still, spatial associations between cervical cord area and remote cerebellar and brainstem volume, possibly driven by neuraxonal degeneration, were detected mostly in RRMS patients with predominantly short disease durations. Future longitudinal studies may elucidate the interplay between affection of spinal cord and infratentorial structures in MS, and contribute to the understanding of the conversion processes from relapsing-remitting to secondary progressive MS.

Quantitative assessment of brain stem and cerebellar atrophy in spinocerebellar ataxia types 3 and 6: impact on clinical status.

BACKGROUND AND PURPOSE: Cerebellar and brain stem atrophy are important features in SCA3, whereas SCA6 has been regarded as a "pure" cerebellar disease. However, recent neuropathologic studies have described additional brain stem involvement in SCA6. We, therefore, aimed to investigate the occurrence and impact of regional infratentorial brain volume differences in patients with SCA3 and SCA6. MATERIALS AND METHODS: Thirty-four patients with genetically proved SCA (SCA3, n = 17; SCA6, n = 17) and age-matched healthy control subjects (n = 51) were included. In all subjects, high-resolution T1-weighted images were acquired with a 1.5T MR imaging scanner. Individual brain stem and cerebellar volumes were calculated by using semiautomated volumetry approaches. For all patients with SCA, clinical dysfunction was scored according to the ICARS. Multiple regression analysis was used to identify the contribution of regional volumes to explain the variance in clinical dysfunction in each SCA genotype. RESULTS: Cerebellar volumes were lower in patients with SCA6 compared with controls and with those with SCA3. In contrast to controls, brain stem volume loss was observed in patients with SCA3 (P < .001) and, to a lesser extent, in those with SCA6 (P = .027). Significant linear dependencies were found between ICARS and cerebellum volume (SCA3: R(2) = 0.29, P = .02; SCA6: R(2) = 0.29, P = .03) and between ICARS and brain stem volume (SCA3: R(2) = 0.49, P = .002; SCA6: R(2) = 0.39, P < .01) in both subtypes. Both cerebellar and brain stem atrophy contributed independently to the variance in clinical dysfunction in SCA6, while in SCA3, only brain stem atrophy was of relevance. CONCLUSIONS: Our current findings in accordance with recent neuroradiologic and pathoanatomic studies suggest brain stem and cerebellar volume loss as attractive surrogate markers of disease severity in SCA3 and SCA6.

Diffusion tensor imaging-based fractional anisotropy quantification in the corticospinal tract of patients with amyotrophic lateral sclerosis using a probabilistic mixture model.

BACKGROUND AND PURPOSE: In amyotrophic lateral sclerosis (ALS), fiber degeneration within the corticospinal tract (CST) can be quantified by diffusion tensor imaging (DTI) as an indirect marker of upper motor neuron involvement. A new method of measuring quantitative DTI parameters using a probabilistic mixture model for fiber tissue and background in the corticospinal tract of patients with ALS is evaluated. MATERIALS AND METHODS: Axial echo-planar imaging (EPI) DTI datasets (6 gradient directions, 10 repetitions) were acquired for 10 patients and 20 healthy control subjects. The diffusion tensor was visualized in a multiplanar viewer using a unique color coding method. Pure fiber tissue inside a region is separated from background and mixture voxels using a probabilistic mixture model. This allows for a reduction of errors as a result of partial volume effects and measurement variability. RESULTS: Fractional anisotropy (FA) was measured within the CST at levels ranging from internal capsule to pons. Mean coefficients of variation of intrarater, scan-rescan, and inter-rater reproducibility were 2.4%, 3.0%, and 5.7%, respectively. Optimal measurement positions along the CST with respect to minimum variability and maximum difference between patients and healthy subjects were identified in the caudal half of the internal capsule. Moreover, a negative correlation between the age-corrected FA and the disease duration but not the ALS Severity scale score was found. CONCLUSION: The new software for fiber integrity quantification is suited to assess FA in the corticospinal tract with high reproducibility. Thus, this tool can be useful in future studies for monitoring disease status and potential treatment efficiency.

Oral fumaric acid esters for the treatment of active multiple sclerosis: an open-label, baseline-controlled pilot study.

An exploratory, prospective, open-label study of fumaric acid esters (FAE, Fumaderm(R)) was conducted in patients with relapsing-remitting multiple sclerosis (RRMS). The study consisted of the following four phases: 6-week baseline, 18-week treatment (target dose of 720 mg/day), 4-week washout, and a second 48-week treatment phase (target dose of 360 mg/day). Ten patients with an Expanded Disability Status Scale (EDSS) score of 2.0-6.0 and at least one gadolinium-enhancing (Gd+) lesion on T1-weighted magnetic resonance imaging (MRI) brain scans participated in the study. Safety was assessed by adverse events (AEs), blood chemistry/hematology, electrocardiogram, and urinalysis. The primary efficacy outcomes were number and volume of Gd+ lesions. Other clinical outcomes included EDSS score, ambulation index (AI), and nine-hole peg test (9-HPT). Effects of FAE on intracellular cytokine profiles, T-cell apoptosis, and soluble adhesion molecules were also assessed. Three patients withdrew during the first 3 weeks of the study because of side effects, non-compliance, and follow-up loss. The most common AEs were gastrointestinal symptoms and flushing; all AEs were reported as mild and reversible. FAE produced significant reductions from baseline in number (P < 0.05) and volume (P < 0.01) of Gd+ lesions after 18 weeks of treatment; this effect persisted during the second treatment phase at half the target dose after the 4-week washout period. EDSS scores, AI, and 9-HPT remained stable or slightly improved from baseline in all patients. Measures of T-cell function demonstrated alterations in cytokines and circulating tumor necrosis factor. The results of this exploratory study suggest that further studies of FAE in patients with MS are warranted.

Non-invasive temperature imaging of muscles with magnetic resonance imaging using spin-echo sequences.

The application of spin-echo magnetic resonance imaging sequences on non-invasive temperature imaging for temperature mapping of human limbs is investigated. In an in vitro experiment performed on a meat sample, the equilibrium magnetisation P and the spin-lattice relaxation time T1 are calculated from the values for the repetition time TR and the signal intensities obtained by a spin-echo sequence at different tissue temperatures as measured by a fibre-optic probe. T1 is linearly correlated to the tissue temperature, and P is linearly correlated to the reciprocal value of the absolute temperature. Both effects, taken together, lead to a non-linear dependency of the signal intensity on temperature. Therefore a TR leading to maximum temperature dependency of the signal intensity is calculated and used in the further experiments. In the in vivo experiments, the lower legs of two volunteers are cooled from outside. Images are acquired with a spin-echo sequence (1.5 T, TR = 1200 ms, TE = 10 ms). A rise in signal intensity in the muscle with falling skin temperature is observed, particularly in more peripheral muscle layers. This study shows that spin-echo sequences can be used to monitor temperature changes and temperature differences in living muscle tissue.

[The MR phase contrast method. Determination of blood flow velocity and flow profile of intracranial arteries]. / MR-Phasenkontrastmethode. Bestimmung von Flussgeschwindigkeiten und Flussprofile in intrakraniellen Arterien.

2D-phase-contrast mapping is a MR method that allows for quantitative measurements of blood flow velocity in intracranial vessels. Using a modified FISP-Sequence with a 1.5 T MR scanner, flow studies were carried out on a phantom. Two matrix sizes (256 x 256 vs. 256 x 512) were compared. In 20 healthy volunteers blood flow velocity and profile of the basal (BA), middle cerebral (MCA), and anterior cerebral artery (ACA) were compared with the corresponding findings of transcranial Doppler (TCD) sonography. 2DPK and TCD yielded equivalent velocity data and profiles of the BA. The blood flow velocity in the MCA determined by 2DPK was lower than the TCD values. Using a 256 x 512 matrix, the acquired data were in better accordance with the TCD findings. Due to significant noise measurements of the ACA and PCA were frequently degraded.