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Tauhid, Shahamat

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.

Background: The reliable and efficient measurement of spinal cord atrophy is of growing interest in monitoring disease progression in multiple sclerosis (MS). Methods: We compared T1- and T2-weighted MRI for measuring cervical spinal cord volume in 31 patients with MS and 18 age-matched controls (NC) from T1-weighted gradient recalled echo and T2-weighted fast spin-echo 1.5 T axial acquisitions. The two sequences were matched on slice thickness, signal averages and voxel size. An active surface software tool determined the normalized mean cervical cord cross-sectional area. Results: T1-derived cord areas were higher than T2 areas in the whole cohort (estimated mean difference = 7.03 mm2 (8.89 %); 95 % Confidence Interval (CI): 5.91, 8.14; p < 0.0001) and in both groups separately. There were trends for lower spinal cord areas in MS vs. NC with both sequences. For the T1 cord area, the mean difference was 3.7 mm2 (4.55 %) (95 % CI: −1.36, 8.78; p = 0.15). For the T2 cord area, the difference was larger [mean difference 4.9 mm2 (6.52 %) (95 % CI: −0.83, 10.67); p = 0.091]. The T1 and T2 cord areas showed similar weak to moderate correlations with measures of clinical status and T2 spinal cord lesion volume in the MS group. Superficial spinal cord T2 lesions had no apparent confounding effect on the outlining tool. The mean intra-rater and inter-rater coefficients of variation ranged from 0.27 to 0.91 % for T1- and 0.66 to 0.99 % for T2-derived cord areas. Conclusion: T2-weighted images may prove efficient for measuring cervical spinal cord atrophy in MS, with the added advantage of lesion detectability.

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.

Assess the sensitivity of the Magnetic Resonance Disease Severity Scale (MRDSS), based on cerebral lesions and atrophy, for treatment monitoring of glatiramer acetate (GA) in relapsing-remitting multiple sclerosis (MS). This retrospective non-randomized pilot study included patients who started daily GA [n = 23, age (median, range) 41 (26.2, 53.1) years, Expanded Disability Status Scale (EDSS) score 1.0 (0, 3.5)], or received no disease-modifying therapy (noDMT) [n = 21, age 44.8 (28.2, 55.4), EDSS 0 (0, 2.5)] for 2 years. MRDSS was the sum of z-scores (normalized to a reference sample) of T2 hyperintense lesion volume (T2LV), the ratio of T1 hypointense LV to T2LV (T1/T2), and brain parenchymal fraction (BPF) multiplied by negative 1. The two groups were compared by Wilcoxon rank sum tests; within group change was assessed by Wilcoxon signed rank tests. Glatiramer acetate subjects had less progression than noDMT on T1/T2 [(median z-score change (range), 0 (−1.07, 1.20) vs. 0.41 (−0.30, 2.51), p = 0.003)] and MRDSS [0.01 (−1.33, 1.28) vs. 0.46 (−1.57, 2.46), p = 0.01]; however, not on BPF [0.12 (−0.18, 0.58) vs. 0.10 (−1.47,0.50), p = 0.59] and T2LV [−0.03 (−0.90, 0.57) vs. 0.01 (−1.69, 0.34), p = 0.40]. While GA subjects worsened only on BPF [0.12 (−0.18, 0.58), p = 0.001], noDMT worsened on BPF [0.10 (−1.47, 0.50), p = 0.002], T1/T2 [0.41 (−0.30, 2.51), p = 0.0002], and MRDSS [0.46 (−1.57, 2.46), p = 0.0006]. These preliminary findings show the potential of two new cerebral MRI metrics to track MS therapeutic response. The T1/T2, an index of the destructive potential of lesions, may provide particular sensitivity to treatment effects.

Multiple sclerosis (MS) commonly affects occupational function. We investigated the link between brain MRI and employment status. Patients with MS (n = 100) completed a Work Productivity and Activity Impairment (WPAI) (general health version) survey measuring employment status, absenteeism, presenteeism, and overall work and daily activity impairment. Patients “working for pay” were considered employed; “temporarily not working but looking for work,” “not working or looking for work due to age,” and “not working or looking for work due to disability” were considered not employed. Brain MRI T1 hypointense (T1LV) and T2 hyperintense (T2LV) lesion volumes were quantified. To assess lesional destructive capability, we calculated each subject’s ratio of T1LV to T2LV (T1/T2). Normalized brain parenchymal volume (BPV) assessed brain atrophy. The mean (SD) age was 45.5 (9.7) years; disease duration was 12.1 (8.1) years; 75 % were women, 76 % were relapsing-remitting, and 76 % were employed. T1LV, T1/T2, Expanded Disability Status Scale (EDSS) scores, and activity impairment were lower and BPV was higher in the employed vs. not employed group (Wilcoxon tests, p < 0.05). Age, disease duration, MS clinical subtype, and T2LV did not differ between groups (p > 0.05). In multivariable logistic regression modeling, adjusting for age, sex, and disease duration, higher T1LV predicted a lower chance of employment (p < 0.05). Pearson correlations showed that EDSS was associated with activity impairment (p < 0.05). Disease duration, age, and MRI measures were not correlated with activity impairment or other WPAI outcomes (p > 0.05). We report a link between brain atrophy and lesions, particularly lesions with destructive potential, to MS employment status.

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.

Purpose We tested the validity of a freely available segmentation pipeline to measure compartmental brain volumes from 3T MRI in patients with multiple sclerosis (MS). Our primary focus was methodological to explore the effect of segmentation corrections on the clinical relevance of the output metrics. Methods: Three-dimensional T1-weighted images were acquired to compare 61 MS patients to 30 age- and gender-matched normal controls (NC). We also tested the within patient MRI relationship to disability (eg, expanded disability status scale [EDSS] score) and cognition. Statistical parametric mapping v. 8 (SPM8)-derived gray matter (GMF), white matter (WMF), and total brain parenchyma fractions (BPF) were derived before and after correcting errors from T1 hypointense MS lesions and/or ineffective deep GM contouring. Results: MS patients had lower GMF and BPF as compared to NC (P<.05). Cognitively impaired patients had lower BPF than cognitively preserved patients (P<.05). BPF was related to EDSS; BPF and GMF were related to disease duration (all P<.05). Errors caused bias in GMFs and WMFs but had no discernable influence on BPFs or any MRI-clinical associations. Conclusions: We report the validity of a segmentation pipeline for the detection of MS-related brain atrophy with 3T MRI. Longitudinal studies are warranted to extend these results.

Background/Purpose: To assess correlation between brain lesions and clinical status with 1.5T and 3T magnetic resonance imaging (MRI). Methods: Brain MRI fluid-attenuated inversion-recovery (FLAIR) sequences were performed in 32 multiple sclerosis (MS) patients. Expanded Disability Status Scale (EDSS) score (mean ± standard deviation) was 2 ± 2.0 (range 0-8), disease duration 9.3 ± 8.0 (range .8-29) years. Results: FLAIR lesion volume (FLLV) at 3T was higher than at 1.5T (P= .01). Correlation between 1.5T FLLV and EDSS score was poor, while 3T FLLV correlated moderately and significantly (rs= .39, P= .03). When controlling for age and depression, correlations between FLLV and cognitive measures were significant at 1.5T for the Judgment of Line Orientation test (JLO) (rs=−.44, P= .05), the Symbol Digit Modalities Test (SDMT) (rs=−.49, P= .02), and the California Verbal Learning Test Delayed Free Recall (CVLT DR) (rs=−.44, P= .04). Correlations at 3T were also significant for these tests, but of greater magnitude: JLO (rs=−.70, P= .0005), SDMT (rs=−.73, P= .0001), CVLT DR (rs=−.061, P= .003). Additional significant correlations obtained only at 3T included the 2 second-paced auditory serial addition test (rs=−.55, P= .01), the Brief Visuospatial Memory Test-Delayed Free Recall (rs=−.56, P= .007), and the California Verbal Learning Test Total Recall (rs=−.42, P= .05). Conclusion: MRI at 3T may boost sensitivity and improve validity in MS brain lesion assessment.

BACKGROUND: Brain lesions converting to chronic T1 hypointensities (“chronic black holes” [CBH]), indicate severe tissue destruction (axonal loss and irreversible demyelination) in multiple sclerosis (MS). Two mechanisms by which fingolimod could limit MS lesion evolution include sequestration of lymphocytes in the periphery or direct neuroprotective effects. We investigated the effect of fingolimod on the evolution of acute gadolinium-enhancing (Gd+) brain lesions to CBH in patients with MS. METHODS: This was a retrospective nonrandomized comparison of patients with Gd+ brain lesions at the time of starting oral fingolimod [.5 mg/day, n = 26, age (mean ± SD) 39.2 ± 10.6 years, Expanded Disability Status Scale (EDSS) score - median (range): 1.75 (0, 6.5)] to those on no therapy [n = 30, age 41.7 ± 9.3 years; EDSS 1.0 (0, 6)]. Each lesion was classified by whether it converted to a CBH in the year following treatment. RESULTS: In the fingolimod group, 99 Gd+ baseline lesions (mean ± SD, range: 3.8 ± 5.1; 1, 21 per patient) were identified of which 25 (25%) evolved to CBH (1.0 ± 2.0; 0, 10 per patient). The untreated group had 62 baseline Gd + lesions (2.1 ± 2.3; 1, 13), 26 (42%) of which evolved to CBH (.9 ± 1.4; 0, 7) (P = .063). Thirteen patients (50%) receiving fingolimod and 17 untreated patients (57%) developed CBH (P = .79). CONCLUSION: This pilot study shows a trend of fingolimod on reducing the conversion rate from acute to chronic destructive MS lesions. Such an effect awaits verification in larger randomized prospective studies.

Background: Spinal cord atrophy occurs early in multiple sclerosis (MS) and impacts disability. The therapeutic effect of interferon beta-1a (IFNβ-1a) on spinal cord atrophy in patients with relapsing-remitting (RR) MS has not been explored. Methods: We retrospectively identified 16 consecutive patients receiving weekly intramuscular IFNβ-1a for 2 years [baseline age (mean ± SD) 47.7 ± 7.5 years, Expanded Disability Status Scale score median (range) 1.5 (0–2.5), timed 25-foot walk 4.6 ± 0.7 seconds; time on treatment 68.3 ± 59.9 months] and 11 sex- and age-matched normal controls (NC). The spinal cord was imaged at baseline, 1 and 2 years later with 3T MRI. C1-C5 spinal cord volume was measured by an active surface method, from which normalized spinal cord area (SCA) was calculated. Results: SCA showed no change in the MS or NC group over 2 years [mean annualized difference (95 % CI) MS: −0.604 mm2 (−1.352, 0.144), p = 0.106; NC: −0.360 mm2 (−1.576, 0.855), p = 0.524]. Between group analysis indicated no differences in on-study SCA change [MS vs. NC; year 1 vs. baseline, mean annualized difference (95 % CI) 0.400 mm2 (−3.350, 2.549), p = 0.780; year 2 vs. year 1: −1.196 mm2 (−0.875, 3.266), p = 0.245; year 2 vs. baseline −0.243 mm2 (−1.120, 1.607), p = 0.712]. Conclusion: Established IFNβ-1a therapy was not associated with ongoing spinal cord atrophy or any difference in the rate of spinal cord volume change in RRMS compared to NC over 2 years. These results may reflect a treatment effect. However, due to sample size and study design, these results should be considered preliminary and await confirmation.