The Contribution of Cortical Lesions to a Composite MRI Scale of Disease Severity in Multiple Sclerosis

Objective: To test a new version of the Magnetic Resonance Disease Severity Scale (v.3 = MRDSS3) for multiple sclerosis (MS), incorporating cortical gray matter lesions (CLs) from 3T magnetic resonance imaging (MRI). Background: MRDSS1 was a cerebral MRI-defined composite scale of MS disease severity combining T2 lesion volume (T2LV), the ratio of T1 to T2LV (T1/T2), and whole brain atrophy [brain parenchymal fraction (BPF)]. MRDSS2 expanded the scale to include cerebral gray matter fraction (GMF) and upper cervical spinal cord area (UCCA). We tested the contribution of CLs to the scale (MRDSS3) in modeling the MRI relationship to clinical status. Methods: We studied 51 patients [3 clinically isolated syndrome, 43 relapsing-remitting, 5 progressive forms, age (mean ± SD) 40.7 ± 9.1 years, Expanded Disability Status Scale (EDSS) score 1.6 ± 1.7] and 20 normal controls by high-resolution cerebrospinal MRI. CLs required visibility on both fluid-attenuated inversion-recovery (FLAIR) and modified driven equilibrium Fourier transform sequences. The MACFIMS battery defined cognitively impaired (n = 18) vs. preserved (n = 33) MS subgroups. Results: EDSS significantly correlated with only BPF, UCCA, MRDSS2, and MRDSS3 (all p < 0.05). After adjusting for depressive symptoms, the cognitively impaired group had higher severity of MRI metrics than the cognitively preserved group in regard to only BPF, GMF, T1/T2, MRDSS1, and MRDSS2 (all p < 0.05). CL number was not significantly related to EDSS score or cognition status. Conclusion: CLs from 3T MRI did not appear to improve the validity of the MRDSS. Further studies employing advanced sequences or higher field strengths may show more utility for the incorporation of CLs into composite scales

Dual‐Sensitivity Multiple Sclerosis Lesion and CSF Segmentation for Multichannel 3T Brain MRI

ABSTRACT BACKGROUND AND PURPOSE A pipeline for fully automated segmentation of 3T brain MRI scans in multiple sclerosis (MS) is presented. This 3T morphometry (3TM) pipeline provides indicators of MS disease progression from multichannel datasets with high‐resolution 3‐dimensional T1‐weighted, T2‐weighted, and fluid‐attenuated inversion‐recovery (FLAIR) contrast. 3TM segments white (WM) and gray matter (GM) and cerebrospinal fluid (CSF) to assess atrophy and provides WM lesion (WML) volume. METHODS To address nonuniform distribution of noise/contrast (eg, posterior fossa in 3D‐FLAIR) of 3T magnetic resonance imaging, the method employs dual sensitivity (different sensitivities for lesion detection in predefined regions). We tested this approach by assigning different sensitivities to supratentorial and infratentorial regions, and validated the segmentation for accuracy against manual delineation, and for precision in scan‐rescans. RESULTS Intraclass correlation coefficients of .95, .91, and .86 were observed for WML and CSF segmentation accuracy and brain parenchymal fraction (BPF). Dual sensitivity significantly reduced infratentorial false‐positive WMLs, affording increases in global sensitivity without decreasing specificity. Scan‐rescan yielded coefficients of variation (COVs) of 8% and .4% for WMLs and BPF and COVs of .8%, 1%, and 2% for GM, WM, and CSF volumes. WML volume difference/precision was .49 ± .72 mL over a range of 0–24 mL. Correlation between BPF and age was r = .62 (P = .0004), and effect size for detecting brain atrophy was Cohen's d = 1.26 (standardized mean difference vs. healthy controls). CONCLUSIONS This pipeline produces probability maps for brain lesions and tissue classes, facilitating expert review/correction and may provide high throughput, efficient characterization of MS in large datasets

An expanded composite scale of MRI-defined disease severity in multiple sclerosis: MRDSS2

The objective of this study was to test a new version of the Magnetic Resonance Disease Severity Scale (MRDSS2), incorporating cerebral gray matter (GM) and spinal cord involvement from 3 T MRI, in modeling the relationship between MRI and physical disability or cognitive status in multiple sclerosis (MS). Fifty-five MS patients and 30 normal controls underwent high-resolution 3 T MRI. The patients had an Expanded Disability Status Scale score of 1.6±1.7 (mean±SD). The cerebral normalized GM fraction (GMF), the T2 lesion volume (T2LV), and the ratio of T1 hypointense LV to T2LV (T1/T2) were derived from brain images. Upper cervical spinal cord area (UCCA) was obtained from spinal cord images. A within-subject d-score (difference of MS from normal control) for each MRI component was calculated, equally weighted, and summed to form MRDSS2. With regard to the relationship between physical disability and MRDSS2 or its individual components, MRI–Expanded Disability Status Scale correlations were significant for MRDSS2 (r=0.33, P=0.013) and UCCA (r=−0.33, P=0.015), but not for GMF (P=0.198), T2LV (P=0.707), and T1/T2 (P=0.240). The inclusion of UCCA appeared to drive this MRI–disability relationship in MRDSS2. With regard to cognition, MRDSS2 showed a larger effect size (P=0.035) than its individual components [GMF (P=0.081), T2LV (P=0. 179), T1/T2 (P=0.043), and UCCA (P=0.818)] in comparing cognitively impaired with cognitively preserved patients (defined by the Minimal Assessment of Cognitive Function in MS). Both cerebral lesions (T1/T2) and atrophy (GMF) appeared to drive this relationship. We describe a new version of the MRDSS, which has been expanded to include cerebral GM and spinal cord involvement. MRDSS2 has concurrent validity with clinical status

A 3T MR Imaging Investigation of the Topography of Whole Spinal Cord Atrophy in Multiple Sclerosis

Background and Purpose: Spinal cord atrophy is a common feature of MS. However, it is unknown which cord levels are most susceptible to atrophy. We performed whole cord imaging to identify the levels most susceptible to atrophy in patients with MS versus controls and also tested for differences among MS clinical phenotypes. Materials and Methods: Thirty-five patients with MS (2 with CIS, 27 with RRMS, 2 with SPMS, and 4 with PPMS phenotypes) and 27 healthy controls underwent whole cord 3T MR imaging. The spinal cord contour was segmented and assigned to bins representing each C1 to T12 vertebral level. Volumes were normalized, and group comparisons were age-adjusted. Results: There was a trend toward decreased spinal cord volume at the upper cervical levels in PPMS/SPMS versus controls. A trend toward increased spinal cord volume throughout the cervical and thoracic cord in RRMS/CIS versus controls reached statistical significance at the T10 vertebral level. A statistically significant decrease was found in spinal cord volume at the upper cervical levels in PPMS/SPMS versus RRMS/CIS. Conclusions: Opposing pathologic factors impact spinal cord volume measures in MS. Patients with PPMS demonstrated a trend toward upper cervical cord atrophy. However patients with RRMS showed a trend toward increased volume at the cervical and thoracic levels, which most likely reflects inflammation or edema-related cord expansion. With the disease causing both expansion and contraction of the cord, the specificity of spinal cord volume measures for neuroprotective therapeutic effect may be limited

Automated segmentation of cerebral deep gray matter from MRI scans: effect of field strength on sensitivity and reliability

Background: The cerebral subcortical deep gray matter nuclei (DGM) are a common, early, and clinically-relevant site of atrophy in multiple sclerosis (MS). Robust and reliable DGM segmentation could prove useful to evaluate putative neuroprotective MS therapies. The objective of the study was to compare the sensitivity and reliability of DGM volumes obtained from 1.5T vs. 3T MRI. Methods: Fourteen patients with MS [age (mean, range) 50.2 (32.0–60.8) years, disease duration 18.4 (8.2–35.5) years, Expanded Disability Status Scale score 3.1 (0–6), median 3.0] and 15 normal controls (NC) underwent brain 3D T1-weighted paired scan-rescans at 1.5T and 3T. DGM (caudate, thalamus, globus pallidus, and putamen) segmentation was obtained by the fully automated FSL-FIRST pipeline. Both raw and normalized volumes were derived. Results: DGM volumes were generally higher at 3T vs. 1.5T in both groups. For raw volumes, 3T showed slightly better sensitivity (thalamus: p = 0.02; caudate: p = 0.10; putamen: p = 0.02; globus pallidus: p = 0.0004; total DGM: p = 0.01) than 1.5T (thalamus: p = 0.05; caudate: p = 0.09; putamen: p = 0.03; globus pallidus: p = 0.0006; total DGM: p = 0.02) for detecting DGM atrophy in MS vs. NC. For normalized volumes, 3T but not 1.5T detected atrophy in the globus pallidus in the MS group. Across all subjects, scan-rescan reliability was generally very high for both platforms, showing slightly higher reliability for some DGM volumes at 3T. Raw volumes showed higher reliability than normalized volumes. Raw DGM volume showed higher reliability than the individual structures. Conclusions: These results suggest somewhat higher sensitivity and reliability of DGM volumes obtained from 3T vs. 1.5T MRI. Further studies should assess the role of this 3T pipeline in tracking potential MS neurotherapeutic effects

The Effect of Glatiramer Acetate on Spinal Cord Volume in Relapsing‐Remitting Multiple Sclerosis

ABSTRACT BACKGROUND Spinal cord atrophy occurs early in the multiple sclerosis (MS) disease course, is closely related to physical disability, and is a putative neuroprotective therapeutic outcome measure. OBJECTIVE This pilot study explored glatiramer acetate (GA)’s effect on spinal cord volume in patients with relapsing‐remitting MS (RRMS). METHODS Fifteen patients receiving daily subcutaneous GA were prospectively followed. At baseline, age was 43.6 ± 7.4 years, Expanded Disability Status Scale (EDSS) score was 1.4 ± 1.5, timed 25‐foot walk (T25FW) was 4.7 ± 1.1 seconds, and time on GA was 2.1 ± 3.1 years. Healthy controls (n = 10) with similar age and sex to the patients were also enrolled. The spinal cord was imaged at baseline and one year later with 3T magnetic resonance imaging. An active surface method measured the C1–C7 spinal cord volume from which we calculated the normalized area. RESULTS The spinal cord area showed no significant change in the MS group over one year (P = .19). Furthermore, the change in the spinal cord area did not differ significantly between the MS and control groups over one year (P = .26). In the MS group, the EDSS score (P = .44) and T25FW (P = .92) did not change significantly on‐study. CONCLUSION In this pilot study of RRMS, GA therapy was not associated with any ongoing spinal cord atrophy or any difference in the one‐year rate of spinal cord area change versus healthy controls. These results paralleled the lack of clinical worsening and may reflect a treatment effect of GA. Further studies are needed to confirm these preliminary findings

MRI phenotypes based on cerebral lesions and atrophy in patients with multiple sclerosis

Background: While disease categories (i.e. clinical phenotypes) of multiple sclerosis (MS) are established, there remains MRI heterogeneity among patients within those definitions. MRI-defined lesions and atrophy show only moderate inter-correlations, suggesting that they represent partly different processes in MS. We assessed the ability of MRI-based categorization of cerebral lesions and atrophy in individual patients to identify distinct phenotypes. Methods: We studied 175 patients with MS [age (mean ± SD) 42.7 ± 9.1 years, 124 (71%) women, Expanded Disability Status (EDSS) score 2.5 ± 2.3, n = 18 (10%) clinically isolated demyelinating syndrome (CIS), n = 115 (66%) relapsing-remitting (RR), and n = 42 (24%) secondary progressive (SP)]. Brain MRI measures included T2 hyperintense lesion volume (T2LV) and brain parenchymal fraction (to assess whole brain atrophy). Medians were used to create bins for each parameter, with patients assigned a low or high severity score. Results: Four MRI phenotype categories emerged: Type I = low T2LV/mild atrophy [n = 67 (38%); CIS = 14, RR = 47, SP = 6]; Type II = high T2LV/mild atrophy [n = 21 (12%); RR = 19, SP = 2]; Type III = low T2LV/high atrophy [n = 21 (12%); CIS = 4, RR = 16, SP = 1]; and Type IV = high T2LV/high atrophy [n = 66 (38%); RR = 33, SP = 33]. Type IV was the most disabled and was the only group showing a correlation between T2LV vs. BPF and MRI vs. EDSS score (all p < 0.05). Conclusions: We described MRI-categorization based on the relationship between lesions and atrophy in individual patients to identify four phenotypes in MS. Most patients have congruent extremes related to the degree of lesions and atrophy. However, many have a dissociation. Longitudinal studies will help define the stability of these patterns and their role in risk stratification