Corpus callosum (CC) is involved in the performance of bimanual motor tasks. We asked whether its functional role could be investigated by combining a motor behavioral study on bimanual movements in multiple sclerosis (MS) patients with a quantitative magnetic resonance diffusion tensor imaging (DTI) analysis of CC, which is shown to be damaged in this disease. MS patients and normal subjects were asked to perform sequences of bimanual finger opposition movements at different metronome rates; then we explored the structural integrity of CC by means of DTI. Significant differences in motor performance, mainly referred to timing accuracy, were observed between MS patients and control subjects. Bimanual motor coordination was impaired in MS patients as shown by the larger values of the interhand interval observed at all the tested metronome rates with respect to controls. Furthermore, DTI revealed a significant reduction of fractional anisotropy (FA), indicative of microstructural tissue damage, in the CC of MS patients. By correlating the mean FA values with the different motor behavior parameters, we found that the degree of damage in the anterior callosal portions mainly influences the bimanual coordination and, in particular, the movement phase preceding the finger touch. Finally, the described approach, which correlates quantitative measures of tissue damage obtained by advanced magnetic resonance imaging tools with appropriate behavioral measurements, may help the exploration of different aspects of motor performance impairment attributable to the disease.

Background: Over recent years numerous patients with severe forms of multiple sclerosis (MS) refractory to conventional therapies have been treated with intense immunosuppression followed by autologous haematopoietic stem cell transplantation (AHSCT). The clinical outcome and the toxicity of AHSCT can be diverse, depending on the various types of conditioning protocols and on the disease phase. Objectives: To report the Italian experience on all the consecutive patients with MS treated with AHSCT with an intermediate intensity conditioning regimen, named BEAM/ATG, in the period from 1996 to 2008. Methods: Clinical and magnetic resonance imaging outcomes of 74 patients were collected after a median follow-up period of 48.3 (range = 0.8–126) months. Results: Two patients (2.7%) died from transplant-related causes. After 5 years, 66% of patients remained stable or improved. Among patients with a follow-up longer than 1 year, eight out of 25 subjects with a relapsing–remitting course (31%) had a 6–12 months confirmed Expanded Disability Status Scale improvement > 1 point after AHSCT as compared with one out of 36 (3%) patients with a secondary progressive disease course ( p = 0.009). Among the 18 cases with a follow-up longer than 7 years, eight (44%) remained stable or had a sustained improvement while 10 (56%), after an initial period of stabilization or improvement with median duration of 3.5 years, showed a slow disability progression. Conclusions: This study shows that AHSCT with a BEAM/ATG conditioning regimen has a sustained effect in suppressing disease progression in aggressive MS cases unresponsive to conventional therapies. It can also cause a sustained clinical improvement, especially if treated subjects are still in the relapsing–remitting phase of the disease.

Objective: To evaluate whether the effects on potential surrogate endpoints, such as MRI markers and relapses, observed in trials of experimental treatments are able to predict the effects of these treatments on disability progression as defined in relapsing-remitting multiple sclerosis (RRMS) trials. Methods: We used a pooled analysis of all the published randomized controlled clinical trials in RRMS reporting data on Expanded Disability Status Scale (EDSS) worsening and relapses or MRI lesions or both. We extracted data on relapses, MRI lesions, and the proportion of progressing patients. A regression analysis weighted on trial size and duration was performed to study the relationship between the treatment effect observed in each trial on relapses and MRI lesions and the observed treatment effect on EDSS worsening. Results: A set of 19 randomized double-blind controlled trials in RRMS were identified, for a total of 44 arms, 25 contrasts, and 10,009 patients. A significant correlation was found between the effect of treatments on relapses and the effect of treatments on EDSS worsening: the adjusted R² value of the weighted regression was 0.71. The correlation between the treatment effect on MRI lesions and EDSS worsening was slightly weaker (R² = 0.57) but significant. Conclusions: These findings support the use of commonly used surrogate markers of EDSS worsening as endpoints in multiple sclerosis clinical trials. Further research is warranted to validate surrogate endpoints at the individual level rather than at the trial level, to draw important conclusions in the management of the individual patient.

Fatigue, an overwhelming lack of physical or mental energy, is a common complaint in patients affected by multiple sclerosis (MS). Although different mechanisms have been proposed to explain MS-related fatigue, injury of distinct anatomical networks seems to be relevant in fatigue etiology. Particularly, theories point to fronto-striatal network pathological changes as a possible neural basis of fatigue. To investigate the role of fronto-striatal white matter structural alterations in fatigue perception we prospectively recruited 40 relapsing remitting patients with MS and 15 healthy controls. In patients with MS, fatigue was assessed using a validated measure, the Modified Fatigue Impact Scale (MFIS; Kos et al., 2005). Brain MRI scans were acquired for each subject enrolled with diffusion tensor imaging. Diffusion tensor data were correlated with MFIS scores using voxel-wise analysis of fractional anisotropy maps and fiber tractography algorithms. A significant cluster of voxels correlating with fatigue scores located in the deep left frontal white matter was identified. Fiber tractography revealed the cluster to be included in a complex fronto-frontal, fronto-striatal, fronto-occipital, and fronto-limbic network. Structural properties of the traced white matter fiber bundles correlated with fatigue perception and patients with clinically relevant fatigue were found to present reduced white matter integrity in the aforementioned tracts compared to those with lower levels of fatigue. Our observations show a significant involvement of different frontal networks in the pathophysiology of fatigue, thus accounting for the multifaceted nature of this disabling symptom.

To describe the occurrence of abnormal hyperintensity in the dentate nucleus on T1-weighted magnetic resonance (MR) images in patients with multiple sclerosis (MS) as a neuroradiologic sign of gray matter involvement. Presence of the finding was evaluated for association with disability, clinical MS subtype, total lesion volume on T1- and T2-weighted MR images (lesion load), and brain atrophy. Written informed consent was waived by the Ethics Committee because of the retrospective nature of this single-center Institutional Review Board-approved study. MR examinations of 185 patients with MS were reviewed, and 119 patients were included for analysis. Two neuroimagers, who were blinded to clinical data, assessed the presence of a hyperintense dentate nucleus on T1-weighted MR images. The presence of this radiologic alteration was then evaluated in relation to MS subtype, clinical disability, T1 and T2 lesion load, and whole-brain atrophy measurements. Fisher exact, chi(2), and Mann-Whitney U tests were used to evaluate differences in clinical and imaging features between patients with and those without a T1 hyperintense dentate nucleus. Twenty-three (19.3%) of the 119 patients had a hyperintense dentate nucleus on unenhanced T1-weighted MR images. This finding was related to the secondary progressive subtype of the disease, a higher score on the Expanded Disability Status Scale, a higher brain lesion load, and tissue loss. None of the patients with primary progressive MS had a hypterintense dentate nucleus. Hyperintensity of the dentate nucleus may be present on unenhanced T1-weighted MR images of patients with MS and is associated with the secondary progressive disease subtype and with increased clinical disability, lesion load, and brain atrophy.