[Show abstract][Hide abstract] ABSTRACT: Patients with Multiple Sclerosis (PwMS) with severe sensorimotor and cognitive deficits show reduced ability in motor sequence learning. Conversely, in PwMS with minimal disability (EDSS≤2), showing only subtle neurological impairments and no particular deficits in everyday life activities, motor sequence learning has been poorly addressed. Here, we investigated whether PwMS with minimal disability already show a specific impairment in motor sequence learning and which component of this process can be first affected in MS.
We implemented a serial reaction time task based on thumb-to-finger opposition movements in response to visual stimuli. Each session included 14 blocks of 120 stimuli presented randomly or in ten repetitions of a 12-item sequence. Random (R) and sequence (S) blocks were temporally alternated (R1, R2, S1÷S5, R3, S6÷S10, R4). Random blocks were designed to evaluate the motor component; sequence blocks, beside the motor component, allowed to discriminate the procedural performance.
Twenty-two PwMS and 22 control healthy subjects were asked to perform the task under implicit or explicit instructions (11 subjects for each experimental condition).
PwMS with minimal disability improved motor performance in random blocks reducing response time with practice with a trend similar to control subjects, suggesting that short-term learning of simple motor tasks is nearly preserved at this disease stage. Conversely, they found difficulties in sequence-specific learning in implicit and explicit condition, with more pronounced impairment in the implicit condition. These findings could suggest an involvement of different circuits in implicit and explicit sequence learning that could deteriorate at different disease stages.
[Show abstract][Hide abstract] ABSTRACT: Optimal patient selection would improve the risk-benefit ratio of natalizumab treatment for relapsing-remitting multiple sclerosis (RR MS). Clinical features of subjects responding to natalizumab have not been univocally recognized.
[Show abstract][Hide abstract] ABSTRACT: In patients with relapsing-remitting MS (RRMS) fingolimod prevents disease relapses and delays disability progression. First dose administration of fingolimod is associated with a transient, dose-dependent decrease in heart rate (HR) in the 6 hours after drug intake.The aim of the study is to to assess safety and tolerability of the first dose of fingolimod in a cohort of Italian patients with RRMS without alternative therapeutic options.
Open-label, single arm, multicentre study. After the first dose of fingolimod, patients were observed for 6 hours and had their vital signs monitored hourly. Extended on-site monitoring was provided when required.
Of the 906 patients enrolled in the study, most (95.2%) did not experience any adverse event (AE) following fingolimod administration. Cardiovascular AEs occurred in 18 patients and included bradycardia (1.3%), first-and second-degree atrioventricular block (0.1% and 0.2%), palpitations (0.1%), sinus arrhythmia (0.1%) and ventricular premature beats (0.1%). All events were self-limiting and did not require any intervention. Extended monitoring was required in 34 patients.
These results, in a population who better resembled real-world clinical practice in terms of concomitant diseases and medications, are consistent with previous clinical trials and confirmed that the first dose administration of fingolimod is generally safe and well tolerated.Trial registration: EudraCT 2011-000770-60.
[Show abstract][Hide abstract] ABSTRACT: In the last few years, several imaging methods, such as magnetic resonance imaging (MRI) and computed tomography, have been used to investigate the degree of blood–brain barrier (BBB) permeability in patients with neurological diseases including multiple sclerosis, ischemic stroke, and brain tumors. One promising MRI method for assessing the BBB permeability of patients with neurological diseases in vivo is T1-weighted dynamic contrast-enhanced (DCE)-MRI. Here we review the technical issues involved in DCE-MRI in the study of human brain tumors. In the first part of this paper, theoretical models for the DCE-MRI analysis will be described, including the Toft–Kety models, the adiabatic approximation to the tissue homogeneity model and the two-compartment exchange model. These models can be used to estimate important kinetic parameters related to BBB permeability. In the second part of this paper, details of the data acquisition, issues related to the arterial input function, and procedures for DCE-MRI image analysis are illustrated.
[Show abstract][Hide abstract] ABSTRACT: Upper limb impairments can occur in patients with multiple sclerosis, affecting daily living activities; however there is at present no definite agreement on the best rehabilitation treatment strategy to pursue. Moreover, motor training has been shown to induce changes in white matter architecture in healthy subjects. This study aimed at evaluating the motor behavioral and white matter microstructural changes following a 2-month upper limb motor rehabilitation treatment based on task-oriented exercises in patients with multiple sclerosis. Thirty patients (18 females and 12 males; age=43.3±8.7years) in a stable phase of the disease presenting with mild or moderate upper limb sensorimotor deficits were randomized into two groups of 15 patients each. Both groups underwent twenty 1-hour treatment sessions, three times a week. The "treatment group" received an active motor rehabilitation treatment, based on voluntary exercises including task-oriented exercises, whilst the "control group" underwent passive mobilization of the shoulder, elbow, wrist and fingers. Before and after the rehabilitation protocols, motor performance was evaluated in all patients with standard tests. Additionally, finger motor performance accuracy was assessed by an engineered glove. In the same sessions, every patient underwent diffusion tensor imaging to obtain parametric maps of fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity. The mean value of each parameter was separately calculated within regions of interest including the fiber bundles connecting brain areas involved in voluntary movement control: the corpus callosum, the corticospinal tracts and the superior longitudinal fasciculi. The two rehabilitation protocols induced similar effects on unimanual motor performance, but the bimanual coordination task revealed that the residual coordination abilities were maintained in the treated patients whilst they significantly worsened in the control group (p=0.002). Further, in the treatment group white matter integrity in the corpus callosum and corticospinal tracts was preserved whilst a microstructural integrity worsening was found in the control group (fractional anisotropy of the corpus callosum and corticospinal tracts: p=0.033 and p=0.022; radial diffusivity of the corpus callosum and corticospinal tracts: p=0.004 and p=0.008). Conversely, a significant increase of radial diffusivity was observed in the superior longitudinal fasciculi in both groups (p=0.02), indicating a lack of treatment effects on this structure, showing damage progression likely due to a demyelination process. All these findings indicate the importance of administering, when possible, a rehabilitation treatment consisting of voluntary movements. We also demonstrated that the beneficial effects of a rehabilitation treatment are task-dependent and selective in their target; this becomes crucial towards the implementation of tailored rehabilitative approaches.
[Show abstract][Hide abstract] ABSTRACT: Concerning intravenous thrombolysis, only inconclusive data are available for patients older than 90. We retrospectively evaluated 11 such patients whom we treated with thrombolysis from June 2007 through April 2012, comparing them to 41 patients of the same age whom we treated conventionally in the same period. Baseline clinical data were superimposable, except for shorter onset-to-hospital time for thrombolyzed patients. Mortality and hemorrhagic transformation did not differ. Functional status (modified Rankin scale) 3 months after was better in treated patients, even when compared to controls who arrived early in the hospital. Treated patients were more often discharged home or to intensive rehabilitation, less often to a nursing home. We conclude that safety and effectiveness of intravenous thrombolysis in eligible nonagenarians are evident in a setting of everyday practice, and that patients 90 years or older should not be denied thrombolysis solely on the basis of their age.
European Neurology 07/2013; 70(1-2):84-87. · 1.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Subjective fatigue is a typical symptom in Multiple Sclerosis (MS) even in the earliest stages of the disease. The relationship between persistent fatigue and motor task performance is still unclear. Aim of this study was to better investigate this relationship at both the motor behavioral and neuroanatomical levels. Towards this goal, we combined a quantitative evaluation of an undemanding finger motor task with concurrent brain functional magnetic resonance imaging (fMRI) in a group of MS patients with minimal disability but reporting persistent subjective fatigue. We found an unexpected significant positive correlation between persistent subjective fatigue and task-related temporal accuracy, revealing a "fatigue-motor performance paradox". fMRI analysis indicated that this association is potentially mediated by cerebellar and orbitofrontal cortex activity, suggesting a role of these regions in developing subjective fatigue. Our data point to a possible adaptive role for fatigue as the subjective correlate of increased resource demand for motor activities.
[Show abstract][Hide abstract] ABSTRACT: To address the disability impact on fine hand motor functions in patients with Multiple Sclerosis (MS) by quantitatively measuring finger opposition movements, with the aim of providing a new "score" integrating current methods for disability assessment.
40 MS patients (Expanded Disability Status Scale (EDSS): 0-7) and 80 healthy controls (HC) performed a repetitive finger-to-thumb opposition sequence with their dominant hand at spontaneous and maximal velocity, and uni- and bi-manually metronome-paced. A sensor-engineered glove was used to measure finger motor performance. Twenty-seven HC were tested twice, one month apart, to assess test-retest reliability.
The motor parameters showed a good reproducibility in HC and demonstrated significantly worse performance in MS patients with respect to HC. A multivariate model revealed that rate of movement in the spontaneous velocity condition and inter-hand interval (IHI), indicating bimanual coordination, contributed independently to differentiate the two groups. A finger motor impairment score based on these two parameters was able to discriminate HC from MS patients with very low EDSS scores (p<0.001): a significant difference was already evident for patients with EDSS = 0. Further, in the MS group, some motor performance parameters correlated with the clinical scores. In particular, significant correlations were found between IHI and EDSS (r = 0.56; p<0.0001), MS Functional Composite (r = -0.40; p = 0.01), Paced Auditory Serial Addition (r = -0.38; p = 0.02). No motor performance parameter correlated with Timed 25-Foot Walk.
A simple, quantitative, objective method measuring finger motor performance could be used to define a score discriminating healthy controls and MS patients, even with very low disability. This sensitivity might be of crucial importance for monitoring the disease course and the treatment effects in early MS patients, when changes in the EDSS are small or absent.
PLoS ONE 05/2013; 8(5):e65225. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Multiple sclerosis (MS) is a complex neurological disease where, in genetically predisposed individuals, the unbalanced interplay between pathogenic and regulatory T cells will result in the progression of the autoimmune assault to neural antigens. Fingolimod (FTY720), an oral sphingosine 1-phosphate modulator recently approved for the treatment of MS, inhibits the egress of T cells from lymph nodes acting specifically on naïve and memory T cells and sparing effector T cells. Here we characterized IL-17 and IFNγ producing effector CD4 and CD8 positive T cells as well as CD4 positive CD25(high)CD127(low) regulatory T cells in MS patients before and 1 month after treatment was started. We observed that fingolimod did not significantly affect the percentage of CCR6 and CD161 positive T cells in both CD4 and CD8 compartments. In contrast, it significantly reduced the levels of both CD4+ CCR6+ CD161+ and CD8+ CCR6+ CD161+ producing IFNγ alone or in combination with IL-17. The percentage of IL-17 secreting cells in both subsets was affected by the treatment to a lesser extent. Finally, we observed that CD4+ CD25(high)CD127(low) regulatory T cells were decreased in MS patients compared to healthy controls and fingolimod significantly increased their frequencies. All together these findings demonstrate that fingolimod functionally modulates the ability of potentially pathogenic effector cells to produce relevant pro-inflammatory cytokines and increases the number of circulating regulatory T cells possibly contributing in restoring a balance between these populations.
Journal of Neuroimmune Pharmacology 05/2013; 8(5). · 3.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to assess the feasibility of measuring different permeability parameters with T1-weighted dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) in order to investigate the blood brain-barrier permeability associated with different brain tumors. The Patlak algorithm and the extended Tofts-Kety model were used to this aim. Twenty-five adult patients with tumors of different histological grades were enrolled in this study. MRI examinations were performed at 1.5 T. Multiflip angle, fast low-angle shot, and axial 3D T1-weighted images were acquired to calculate T1 maps, followed by a DCE acquisition. A region of interest was placed within the tumor of each patient to calculate the mean value of different permeability parameters. Differences in permeability measurements were found between different tumor grades, with higher histological grades characterized by higher permeability values. A significant difference in transfer constant () values was found between the two methods on high-grade tumors; however, both techniques revealed a significant correlation between the histological grade of tumors and their values. Our results suggest that DCE acquisition is feasible in patients with brain tumors and that maps can be easily obtained by these two algorithms, even if the theoretical model adopted could affect the final results.
[Show abstract][Hide abstract] ABSTRACT: Motor performance recovery after a demanding finger motor task does not follow the excitability dynamics of primary motor cortex (M1), which remains depressed also when performance is restored. Thus, other neural circuits are supposed to cope with central fatigue, re-establishing adequate motor performance levels. A hint that the basal ganglia (BG) can be involved in this process is provided by studies showing an association of central fatigue with the BG. To investigate this possibility, we conducted an fMRI study with simultaneous motor performance recording in 20 healthy volunteers at different stages of a demanding finger motor task: baseline, central fatigue induced by 5-min sequence repetition, performance recovery after a short rest period. When motor performance was recovered, we observed a significant activation with respect to baseline in subcortical structures belonging to different BG circuits (putamen and globus pallidus), involving the limbic system functionally interacting with the BG (amygdala). Then, to assess whether the BG activation was exclusively related to the fatigue and recovery processes or to increasing automatism in motor performance, a control fMRI experiment based on a shorter motor task duration was carried out on 14 healthy subjects. In this case, the task repetition did not induce decreased performance, and no significant effect on the BOLD signal change was found in BG regions of interest with respect to baseline. All these findings suggest that motor and non-motor BG circuits run parallel and converge in a common motor path to successfully compensate motor performance deterioration in a central fatigue condition.
[Show abstract][Hide abstract] ABSTRACT: Abstract Our objective was to assess the incidence and trends of amyotrophic lateral sclerosis (ALS) in Liguria, a north-west region of Italy, utilizing a prospective design. Liguria (1,615,064 residents in 2010) is the site of a multicentre-multisource prospective population based registry called LIGALS (Liguria Amyotrophic Lateral Sclerosis Registry). All incident ALS cases during the period 2009-2010 were enrolled and followed up. Cases were identified using several concurrent sources. ALS diagnosis was based on the revised El Escorial criteria. One hundred and four cases were enrolled, generating an annual crude incidence of 3.22/100,000 (95% CI 2.66-3.90), with a male/female ratio of 1.34. The annual standardized incidence, age and gender adjusted to the 2001 Italian population, was 2.51. At last observation on 1 March 2012, 45% of patients registered in the LIGALS had died, with a median survival of 45 months from symptoms onset. According to capture-recapture estimation, three patients were unobserved. For both genders, demographic and clinical features were collected. In conclusion, comparing these data to those of epidemiological studies with a similar prospective design, the occurrence of ALS is similar. The observed crude incidence was higher compared to other Italian studies, due in part to a very careful case ascertainment and in part to a high percentage of the elderly in Liguria.
[Show abstract][Hide abstract] ABSTRACT: The risk of progressive multifocal leukoencephalopathy (PML) in patients treated with natalizumab for multiple sclerosis (MS) is a serious concern. The presence of anti-JC virus antibodies is a risk factor for PML development, but 2.5 % of the patients result falsely-negative, while the prognostic relevance of testing JCV-DNA in biological fluids of treated patients is debated. Aim of this work was to evaluate the utility of testing JCV-DNA, together with anti-JCV antibodies, in biological samples of treated patients as a tool for PML risk stratification. 126 subjects from 5 MS Centers in Italy were included in the study. We performed a cross-sectional study in 63 patients testing JCV-DNA in blood, peripheral blood cells and urine. We longitudinally assessed the presence of JCV-DNA in a cohort of 33 subjects, one of which developed PML. We could test retrospectively serum samples from another PML case occurred during natalizumab therapy. Anti-JCV antibodies and urinary JCV-DNA were both tested in 73 patients. No changes in JCV-DNA status occurred during natalizumab treatment. The subject who developed PML in the longitudinal cohort had detectable JCV-DNA in urine at all time-points while serum or blood from both PML patients were always negative before the onset of disease and, in one case, after. Four subjects with JCV-DNA in urine and undetectable anti-JCV antibodies were retested for anti-JCV antibodies and three out of four resulted positive. In conclusion, testing JCV-DNA in urine is complementary to testing anti-JCV antibodies in identifying patients at risk of PML.
Journal of Neuroimmune Pharmacology 05/2012; 7(3):665-72. · 3.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Haematopoietic stem cell transplantation (HSCT) has been tried in the last 15 years as a therapeutic option in patients with poor-prognosis autoimmune disease who do not respond to conventional treatments. Worldwide, more than 600 patients with multiple sclerosis (MS) have been treated with HSCT, most of them having been recruited in small, single-centre, phase 1-2 uncontrolled trials. Clinical and magnetic resonance imaging outcomes from case series reports or Registry-based analyses suggest that a major response is achieved in most patients; quality and duration of response are better in patients transplanted during the relapsing-remitting phase than in those in the secondary progressive stage.
An interdisciplinary group of neurologists and haematologists has been formed, following two international meetings supported by the European and American Blood and Marrow Transplantation Societies, for the purpose of discussing a controlled clinical trial, to be designed within the new scenarios of evolving MS treatments.
Objectives of the trial, patient selection, transplant technology and outcome assessment were extensively discussed. The outcome of this process is summarized in the present paper, with the goal of establishing the background and advancing the development of a prospective, randomized, controlled multicentre trial to assess the clinical efficacy of HSCT for the treatment of highly active MS.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
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.