C Pozzilli

Sapienza University of Rome, Roma, Latium, Italy

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Publications (325)1373.49 Total impact

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    ABSTRACT: Two simultaneously performed tasks may compete for common brain network resources in patients with multiple sclerosis (MS), suggesting the occurrence of a cognitive-motor interference. While this phenomenon has been well described for walking and gait, data on static balance are scarce. In this cross-sectional study, 92 patients and 46 sex/age-matched healthy controls (HCs) were tested by means of static posturography under eyes opened (single-task condition) and while performing the Stroop word-colour task (dual-task condition), to estimate the dual-task cost (DTC) of standing balance. The patient group also underwent the Expanded Disability Status Scale, 25-foot walking test, 12-item MS walking scale, Modified Fatigue Impact Scale, and Symbol Digit Modalities Test. Patients had larger postural sway under both single-task and dual-task conditions (p<0.001), as well as greater DTC of standing balance (p=0.021) than HCs. Although secondary progressive (SP) patients had larger sway in both conditions than relapsing-remitting (RR) patients (p<0.05), these latter ones exhibited a greater DTC of postural balance (p=0.045). Deficits in sustained attention and information processing speed, as assessed by the SDMT, were also independently associated with the magnitude of DTC of standing balance (p=0.005). The phenomenon of cognitive-motor interference might be unmasked by a dual-task posturography and was associated with impaired sustained attention and information processing speed, especially in RR patients. The smaller DTC of standing balance observed in SP patients may be due to the ceiling effect of postural sway, or alternatively to the lack of postural reserve which constrained the more disabled patients to prioritize the balance over the cognitive task. Copyright © 2015 Elsevier B.V. All rights reserved.
    Gait & Posture 02/2015; DOI:10.1016/j.gaitpost.2015.02.002 · 2.30 Impact Factor
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    ABSTRACT: The objective of this paper is to estimate the risk of reaching well-established disability milestones after withdrawal of natalizumab (NTZ) due to concern about the risk of progressive multifocal leukoencephalopathy in patients with multiple sclerosis (MS). Data from 415 patients with MS followed-up for six years after starting NTZ were collected from seven tertiary MS centers. The risk of disability worsening, i.e. reaching Expanded Disability Status Scale (EDSS) scores of 4.0 or 6.0, and the likelihood of experiencing a disability reduction of one EDSS point (or more), were assessed by propensity score-adjusted analyses in patients who discontinued and in those still on treatment at the end of follow-up. A total of 318 patients who received standard NTZ treatment without experiencing evidence of disability worsening in the first two years were included in the six-year follow-up analysis, with 196 (61.6%) still on treatment and 122 (38.4%) discontinuing after a median time of 3.5 years. Patients in the discontinuing group had a more than two-fold increased risk of disability worsening (p = 0.007), and a 68% decreased likelihood of experiencing disability reduction (p = 0.009) compared with the continuing group. While discussing the overall risk/benefit profile of NTZ, patients should be advised that, in case of treatment discontinuation, the risk of disability worsening is one in three, and increases to one in two if the EDSS score at NTZ start is above 3.0. © The Author(s), 2015.
    Multiple Sclerosis 02/2015; DOI:10.1177/1352458515570768 · 4.86 Impact Factor
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    ABSTRACT: The humanized monoclonal alpha4-integrin antibody Natalizumab (NTZ) (Tysabri(©) , Biogen Idec, Cambridge, MA, USA) has shown to be effective in multiple sclerosis (MS) therapy; however, the interruption of the drug has been related to a disease restart. This risk has to be carefully considered in case of accidental or desired pregnancies. To report the risk of disease restart in patients who interrupted NTZ because of pregnancy and discuss the implication of NTZ choice in female childbearing patients with MS. Clinical histories and MRI images of four pregnant women with MS who interrupted NTZ. Despite pregnancy is usually related with disease stability, the cases presented here showed an abrupt increase of disability with high number of MRI lesions, some of them with a mass effect. We recommend that female patients on childbearing age must be informed before starting NTZ treatment of the risk of a return of disease activity when the drug is discontinued. The risk occurs even during pregnancy a condition that is considered as protective for women with MS. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
    Acta Neurologica Scandinavica 01/2015; DOI:10.1111/ane.12364 · 2.44 Impact Factor
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    ABSTRACT: Dear Sirs,The so-called “far transfer effect” or “transfer of training” refers to the occurrence of transferring improved performance in a specific function to different untrained functional domains. This implies little overlap between situations, being the original and transfer settings dissimilar [1].Commercial video games may provide integrated and adaptable training paradigms in which a transfer effect to executive functions (e.g.: problem solving, planning, reasoning, working memory or multitasking) can be achievable [2-4].Task-specific training using video games is emerging as a feasible approach for enhancing multitasking skills in older adults, and even for recovering motor and cognitive functions in patients affected by neurological diseases, such as multiple sclerosis (MS). Emerging evidence supports the use of computer-assisted and video game-based cognitive rehabilitation to enhance working memory, complex attention function, visuo-constructive performance and even cognitiv ...
    Journal of Neurology 01/2015; 262(3). DOI:10.1007/s00415-015-7640-8 · 3.84 Impact Factor
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    ABSTRACT: Multiple sclerosis (MS) frequently affects women of childbearing age. While short-term effects of pregnancy on MS course are well-known, whether pregnancy may influence long-term disability progression is debated. A two-centre retrospective study to investigate long-term effect of pregnancy on disability was performed in a population of MS women. Survival analyses and multivariate Cox proportional regression models (including early predictors of MS severity and exposure to disease-modifying treatments) were performed to compare time to reach well-established disability milestones in nulliparous women and in those with pregnancies after MS onset ('parous'). Women with pregnancies before MS onset were excluded from analyses as they represent a heterogeneous group. Data about 445 women (261 nulliparous, 184 'parous') were analysed. A longer time to reach Expanded Disability Status Scale (EDSS) 4.0 and 6.0 was observed in parous women; Cox regression models revealed a lower risk for 'parous' than nulliparous women in reaching EDSS 4.0 and 6.0 (HR = 0.552, p = 0.008 and HR = 0.422, p = 0.012 respectively). Our findings suggest that pregnancy after MS onset is associated with a slower long-term disability progression. Whether this represents a biological/immunological effect, or reflects a higher propensity toward childbearing in women with milder disease, it remains uncertain deserving further investigations. © The Author(s), 2014.
    Multiple Sclerosis 12/2014; DOI:10.1177/1352458514561907 · 4.86 Impact Factor
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    ABSTRACT: Objective. To evaluate the effectiveness of a home-based cognitive rehabilitation (CR) program based on the video game Dr Kawashima's Brain Training (DKBT; Nintendo, Japan), in improving attention, processing speed, and working memory of patients with multiple sclerosis (MS). Methods. This was a randomized, wait-list control study. Patients with MS and failure in at least one between Stroop Test (ST), Paced Auditory Serial Addition Test (PASAT), and Symbol Digit Modalities Test (SDMT) were submitted to an 8-week home-based CR program playing DKBT. Patients were evaluated at baseline and after DKBT by the aforementioned tests, by the Modified Fatigue Impact Scale (MFIS) and by the MS Quality of Life-54 questionnaire (MSQoL-54). Results. Fifty-two 52 patients were screened for eligibility; 35 (mean [standard deviation] age of 43.9 [8.4] years, median Expanded Disability Status Scale score of 2.0 (range = 2.0-6.0) were randomly assigned to the intervention group (n = 18) or wait-list control group (n = 17). ANCOVA analysis showed a significant effect of DKBT on ST (F = 5.027; P = .034; F(2) = 0.210), SDMT (F = 4.240; P = .049; F(2) = 0.177), and on some subscales of MSQoL-54. The PASAT and cognitive subscale of MFIS also showed an improvement, but this was just not significant (F = 4.104, P = .054, F(2) = 0.171, and F = 4.226, P = .054, F(2) = 0.237, respectively). Conclusion. We suggest that a home-based DKBT program may improve cognitive functions, some aspects of QoL, and cognitive fatigue in patients with MS.
    Neurorehabilitation and neural repair 11/2014; DOI:10.1177/1545968314554623 · 4.62 Impact Factor
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    ABSTRACT: Background. Resting brain activity can be modulated by motor tasks to adapt to function. In multiple sclerosis (MS) patients, altered resting-state functional connectivity (RS-FC) has been reported and associated with impaired function and disability; little is known on how RS-FC is modulated by a simple repetitive motor task. Objective. To assess changes in RS-FC in early relapsing-remitting MS (RRMS) patients associated with repetitive thumb flexions (RTFs). Methods. A total of 20 right-handed patients with early RRMS and 14 healthy controls underwent a resting functional magnetic resonance imaging (fMRI) scan, before and after 25 minutes of alternate 30-s blocks of right RTF and rest. Dual-regression analysis of resting fMRI data followed the independent component analysis. Individual spatial maps of coherence between brain areas for 2 networks of interest, sensorimotor and cerebellar, were compared at the group level and correlated with measures of both clinical impairment and brain damage. Results. Significant RTF-induced differences in RS-FC were observed between groups in the cerebellar network because of increased RS-FC in patients but not in controls. In the sensorimotor network, the RS-FC after RTF increased in both groups, with no significant between-group differences. The sensorimotor and the cerebellar RS-FC were intercorrelated only in patients and only after the RTF. The sensorimotor RS-FC increase in patients correlated with structural MRI alterations. Conclusions. Our study unmasked RS-FC changes of motor-related networks occurring after a simple repetitive motor task in early RRMS patients only. Evaluation of altered RSN dynamics might prove useful for anticipating neuroplasticity and for MRI-informed neurorehabilitation.
    Neurorehabilitation and neural repair 11/2014; DOI:10.1177/1545968314558600 · 4.62 Impact Factor
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    ABSTRACT: The aim of the study was to perform a third cognitive assessment in our pediatric-onset multiple sclerosis (MS) patient cohort and determine predictors of the individual cognitive outcome. http://www.ncbi.nlm.nih.gov/pubmed/25217060
    Neurology 09/2014; DOI:10.1212/WNL.0000000000000885 · 8.30 Impact Factor
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    ABSTRACT: Purpose To determine if high-intensity, task-oriented, visual feedback training with a video game balance board (Nintendo Wii) induces significant changes in diffusion-tensor imaging (DTI) parameters of cerebellar connections and other supratentorial associative bundles and if these changes are related to clinical improvement in patients with multiple sclerosis. Materials and Methods The protocol was approved by local ethical committee; each participant provided written informed consent. In this 24-week, randomized, two-period crossover pilot study, 27 patients underwent static posturography and brain magnetic resonance (MR) imaging at study entry, after the first 12-week period, and at study termination. Thirteen patients started a 12-week training program followed by a 12-week period without any intervention, while 14 patients received the intervention in reverse order. Fifteen healthy subjects also underwent MR imaging once and underwent static posturography. Virtual dissection of white matter tracts was performed with streamline tractography; values of DTI parameters were then obtained for each dissected tract. Repeated measures analyses of variance were performed to evaluate whether DTI parameters significantly changed after intervention, with false discovery rate correction for multiple hypothesis testing. Results There were relevant differences between patients and healthy control subjects in postural sway and DTI parameters (P < .05). Significant main effects of time by group interaction for fractional anisotropy and radial diffusivity of the left and right superior cerebellar peduncles were found (F2,23 range, 5.555-3.450; P = .036-.088 after false discovery rate correction). These changes correlated with objective measures of balance improvement detected at static posturography (r = -0.381 to 0.401, P < .05). However, both clinical and DTI changes did not persist beyond 12 weeks after training. Conclusion Despite the low statistical power (35%) due to the small sample size, the results showed that training with the balance board system modified the microstructure of superior cerebellar peduncles. The clinical improvement observed after training might be mediated by enhanced myelination-related processes, suggesting that high-intensity, task-oriented exercises could induce favorable microstructural changes in the brains of patients with multiple sclerosis. © RSNA, 2014 Online supplemental material is available for this article.
    Radiology 08/2014; DOI:10.1148/radiol.14140168 · 6.21 Impact Factor
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    ABSTRACT: Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined. Open access full paper at //www.neurology.org/content/83/3/278.abstract
    Neurology 05/2014; DOI:10.1212/WNL.0000000000000560 · 8.30 Impact Factor
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    ABSTRACT: BackgroundMost of Multiple Sclerosis (MS) patients undergo disease modifying drug (DMD) therapy at childbearing age. The objective of this prospective, collaborative study, was to assess outcomes of pregnancies fathered by MS patients undergoing DMD.MethodsStructured interviews on pregnancies fathered by MS patients gathered in the Italian Pregnancy Dataset were collected; pregnancies were divided according to father exposure or unexposure to DMD at time of procreation. Treatment were compared with multivariable logistic and linear models.ResultsSeventy-eight pregnancies fathered by MS patients were tracked. Forty-five patients were taking DMD at time of conception (39 beta-interferons, 6 glatiramer acetate), while 33 pregnancies were unexposed to DMD. Seventy-five pregnancies ended in live-births, 44 in the exposed and 31 in the unexposed group. No significant differences between the two groups were found in the risk of spontaneous abortion or malformations (p > 0.454), mean gestational age (p = 0.513), frequency of cesarean delivery (p = 0.644), birth weight (p = 0.821) and birth length (p = 0.649). In comparison with data of the Italian general population, the proportion of spontaneous abortion and caesarean delivery in exposed pregnancies fell within the estimates, while the proportion of pre-term delivery in the exposed group was higher than expected.ConclusionsOur data indicate no association between paternal DMD exposure at time of conception and risk of spontaneous abortion, adverse fetal outcomes and congenital malformations. Further studies clarifying the role of DMD fathers intake prior and during pregnancy are desirable, to supply guidelines for clinical practice.
    BMC Neurology 05/2014; 14(1):114. DOI:10.1186/1471-2377-14-114 · 2.49 Impact Factor
  • Journal of neurology, neurosurgery, and psychiatry 04/2014; 86(2). DOI:10.1136/jnnp-2014-307786 · 5.58 Impact Factor
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    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.
    BMC Neurology 04/2014; 14(1):65. DOI:10.1186/1471-2377-14-65 · 2.49 Impact Factor
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    ABSTRACT: We report a 14-week post-marketing experience on 20 patients with multiple sclerosis (MS) who started prolonged-release (PR) oral dalfampridine 10 mg twice daily according to European Medicine Agency criteria. They underwent serial static posturography assessments and the dizziness handicap inventory (DHI) to investigate whether PR dalfampridine could impact standing balance and self-reported perception of balance. The incidence of accidental falls per person per month was also recorded throughout the study. Eight (40%) patients, who had a relevant improvement in walking speed, were defined as treatment responders. They showed a significant improvement of standing balance (with respect to pretreatment assessment) when contrasted with 12 (60%) nonresponders (F [4,15] = 3.959, P = 0.027). No significant changes in DHI score, as well as in its functional, physical, and emotional subscales, were found in both responders and nonresponders at the end of study (all P values are ≥0.2). Treatment response did not affect the incidence of accidental falls. Future studies based on larger sample sizes, and with longer followup, are required to confirm the beneficial effect of PR dalfampridine on standing balance.
    03/2014; 2014:802307. DOI:10.1155/2014/802307
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    ABSTRACT: This double-blind, placebo-controlled, dose-finding phase IIb study evaluated the efficacy and safety of ponesimod, an oral selective S1P1 receptor modulator, for the treatment of patients with relapsing-remitting multiple sclerosis (RRMS). 464 patients were randomised to receive once-daily oral ponesimod 10, 20 or 40 mg, or placebo for 24 weeks. The primary endpoint was the cumulative number of new T1 gadolinium-enhanced (T1 Gd+) lesions per patient recorded every 4 weeks from weeks 12 to 24 after study drug initiation. Secondary endpoints were the annualised confirmed relapse rate (ARR) and time to first confirmed relapse. Safety and tolerability were also evaluated. The mean cumulative number of new T1 Gd+ lesions at weeks 12-24 was significantly lower in the ponesimod 10 mg (3.5; rate ratio (RR) 0.57; p=0.0318), 20 mg (1.1; RR 0.17; p<0.0001) and 40 mg (1.4; RR 0.23; p<0.0001) groups compared with placebo (6.2). The mean ARR was lower with 40 mg ponesimod versus placebo, with a maximum reduction of 52% (0.25 vs 0.53; p=0.0363). The time to first confirmed relapse was increased with ponesimod compared with placebo. The proportion of patients with ≥1 treatment-emergent adverse events (AEs) was similar across ponesimod groups and the placebo group. Frequently reported AEs with higher incidence in the three ponesimod groups compared with placebo were anxiety, dizziness, dyspnoea, increased alanine aminotransferase, influenza, insomnia and peripheral oedema. Once-daily treatment with ponesimod 10, 20 or 40 mg significantly reduced the number of new T1 Gd+ lesions and showed a beneficial effect on clinical endpoints. Ponesimod was generally well tolerated, and further investigation of ponesimod for the treatment of RMMS is under consideration. NCT01006265.
    Journal of neurology, neurosurgery, and psychiatry 03/2014; 85(11). DOI:10.1136/jnnp-2013-307282 · 5.58 Impact Factor
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    ABSTRACT: Objectives: To investigate whether clinical and magnetic resonance imaging (MRI) outcomes of patients with multiple sclerosis (MS) who required a reduction of administration frequency of interferon-beta (IFNB) were similar to those of patients who did not. Methods: We identified three subgroups of patients under treatment for 24 months with subcutaneous (sc) high-frequency IFNB-1a or -1b: those continuing to receive IFNB according to the drug label (recommended frequency group), those reducing the administration frequency of sc IFNB-1a or -1b (reduced frequency group), and those switched to once weekly intramuscular (im) IFNB (switched group). All patients were followed for further 24 months. The occurrence of relapse, MRI activity and disability worsening were considered as outcome measures. Results: We identified 308 patients, 201 in the recommended frequency group, 70 in the reduced frequency group, and 37 in the switched group. Patients in the reduced frequency group had increased risk for relapses (HR = 1.95, p < 0.001) and MRI activity (HR = 1.41, p < 0.001), while patients in the switched group had increased risk for relapses (HR = 1.67, p = 0.012), but not for MRI activity (HR = 1.26, p = 0.08) than those in the recommended frequency group. Predictors for disease activity re-start after the reduction of IFNB administration frequency were younger age, higher pre-IFNB relapse rate, and reducing sc IFNB frequency to twice weekly rather than switching to im IFNB-1a once weekly. Conclusion: Our findings discourage the reduction of sc IFNB administration frequency, especially in younger patients with a higher pre-IFNB relapse rate. However, switching to im IFNB-1a may be considered in some selected cases. © 2014 S. Karger AG, Basel.
    European Neurology 01/2014; 71(5-6):135-143. DOI:10.1159/000356786 · 1.36 Impact Factor
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    ABSTRACT: Purpose To investigate, by using resting-state (RS) functional magnetic resonance (MR) imaging, thalamocortical functional connectivity (FC) and its correlations with cognitive impairment in multiple sclerosis (MS). Materials and Methods All subjects provided written informed consent; the study protocol was approved by the university institutional review board for this HIPAA-compliant study. Forty-eight patients with relapsing-remitting MS and 24 control subjects underwent multimodal MR imaging, including diffusion-tensor imaging, three-dimensional (3D) T1-weighted imaging, and functional MR imaging at rest and a neuropsychological examination with the Paced Auditory Serial Addition Test (PASAT). Functional MR imaging data were analyzed with tools from FMRIB Software Library, by using the seed-based method to identify the thalamic RS network (RSN). Results When compared with control subjects, patients showed gray matter and white matter atrophy, as well as diffusion-tensor imaging abnormalities (P < .01). Patients displayed significantly greater synchronization than control subjects in the cerebellum; basal ganglia; hippocampus; cingulum; and temporo-occipital, insular, frontal, and parietal cortices. They also exhibited significantly lower synchronization in the thalamus; cerebellum; cingulum; and insular, prefrontal, and parieto-occipital cortices (cluster level, P < .05, corrected for familywise error [FWE]). In patients, the PASAT score at 3 seconds significantly inversely correlated with the thalamus, cerebellum, and some cortical areas in all cerebral lobes; the PASAT score at 2 seconds significantly correlated, even more strongly, with all the aforementioned regions and, in addition, with the cingulum and the left hippocampus (cluster level, P < .05, corrected for FWE). Conclusion Thalamic RSN is disrupted in MS, and decreased performance in cognitive testing is associated with increased thalamocortical FC, thus suggesting that neuroplasticity changes are unable to compensate for tissue damage and to prevent cognitive dysfunction. © RSNA, 2014.
    Radiology 01/2014; 271(3):131688. DOI:10.1148/radiol.14131688 · 6.21 Impact Factor
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    ABSTRACT: The aim of the study was to identify the main factors that impact mobility impairment in multiple sclerosis (MS) patients in Italy. Clinicians from a large number of Italian MS centers took part in a Delphi process aimed at obtaining consensus statements among the participants. Large consensus was obtained for statements grouped under the following main MS themes: identification of the most useful scales to evaluate mobility, integration of objective evaluation with patient perceptions, impact of walking impairment on daily life, management of the disabled patient using a rehabilitative and pharmacological approach. The consensus statements developed by a large number of experts may be used as a practical reference tool to help physicians treat MS patients with motor impairment.
    Journal of Neurology 01/2014; 261(3). DOI:10.1007/s00415-013-7230-6 · 3.84 Impact Factor

Publication Stats

7k Citations
1,373.49 Total Impact Points

Institutions

  • 1988–2015
    • Sapienza University of Rome
      • • Department of Neurology and Psychiatry
      • • Department of Anatomical, Histological, Forensic Medicine and Orthopedic Science
      Roma, Latium, Italy
    • Istituto Nazionale Tumori "Fondazione Pascale"
      Napoli, Campania, Italy
    • National Institute of Radiological Sciences
      Tiba, Chiba, Japan
  • 2005–2012
    • University of Florence
      • Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino
      Florens, Tuscany, Italy
  • 2011
    • Sant´Andrea Hospital
      Roma, Latium, Italy
  • 1985–2011
    • The American University of Rome
      Roma, Latium, Italy
  • 2009
    • University of Rome Tor Vergata
      Roma, Latium, Italy
  • 2008
    • London School of Hygiene and Tropical Medicine
      • Department of Medical Statistics
      London, ENG, United Kingdom
  • 1997–2005
    • University of Milan
      • Department of Neurological Sciences
      Milano, Lombardy, Italy
  • 2003
    • VU University Medical Center
      • Department of Neurology
      Amsterdam, North Holland, Netherlands
  • 2001–2002
    • University College London
      • Institute of Neurology
      London, ENG, United Kingdom
    • London Research Institute
      Londinium, England, United Kingdom
  • 1999
    • San Raffaele Scientific Institute
      Milano, Lombardy, Italy
  • 1981
    • Medical Research Council (UK)
      Londinium, England, United Kingdom