Publications by authors named "Carlo Pozzilli"

164 Publications

Predictors of lymphocyte count recovery after dimethyl fumarate-induced lymphopenia in people with multiple sclerosis.

J Neurol 2021 Jan 26. Epub 2021 Jan 26.

Multiple Sclerosis Center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Largo Agostino Gemelli 8, 00168, Rome, Italy.

Background: Dimethyl fumarate (DMF) is an oral drug approved for Relapsing Multiple Sclerosis (RMS) patients. Grade III lymphopenia is reported in 5-10% DMF-treated patients. Data on lymphocyte count (ALC) recovery after DMF withdrawal following prolonged lymphopenia are still scarce.

Objectives: To characterize ALC recovery and to identify predictors of slower recovery after DMF interruption.

Methods: Multicenter data from RMS patients who started DMF and developed lymphopenia during treatment were collected. In patients with grade II-III lymphopenia, ALCs were evaluated from DMF withdrawal until reaching lymphocyte counts > 800/mm.

Results: Among 1034 patients who started DMF, we found 198 (19.1%) patients with lymphopenia and 65 patients (6.3%) who discontinued DMF due to persistent grade II-III lymphopenia. Complete data were available for 51 patients. All patients recovered to ALC > 800 cells/mm with a median time of 3.4 months. Lower ALCs at DMF suspension (HR 0.98; p = 0.005), longer disease duration (HR 1.29; p = 0.014) and prior exposure to MS treatments (HR 0.03; p = 0.025) were found predictive of delayed ALC recovery.

Conclusion: ALC recovery after DMF withdrawal is usually rapid, nevertheless it may require longer time in patients with lower ALC count at DMF interruption, longer disease duration and previous exposure to MS treatments, potentially leading to delayed initiation of a new therapy.
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http://dx.doi.org/10.1007/s00415-021-10412-0DOI Listing
January 2021

Alemtuzumab outcomes by age: Post hoc analysis from the randomized CARE-MS studies over 8 years.

Mult Scler Relat Disord 2020 Dec 24;49:102717. Epub 2020 Dec 24.

Manchester Centre for Clinical Neurosciences, Salford Royal NHS Foundation Trust, Stott Lane, Salford, M6 8HD, UK.

Background: Alemtuzumab significantly improved clinical and MRI outcomes vs. subcutaneous interferon beta-1a (SC IFNB-1a) in the CARE-MS trials (NCT00530348, NCT00548405), with sustained efficacy in 2 consecutive extensions (NCT00930553, NCT02255656 [TOPAZ]).

Methods: Post hoc analysis of 8-year alemtuzumab efficacy and safety in pooled CARE-MS patients (N=811) stratified by baseline age (≥18 to ≤25, >25 to ≤35, >35 to ≤45, >45 to ≤55 years).

Results: Compared with SC IFNB-1a over 2 years across age cohorts, alemtuzumab lowered annualized relapse rates (ARR; 0.22-0.24 vs. 0.38-0.51), improved or stabilized disability (freedom from 6-month confirmed disability worsening [CDW]: 85%-92% vs. 62%-88%; achievement of 6-month confirmed disability improvement [CDI]: 20%-31% vs. 13%-25%), increased proportions free of MRI disease activity (70%-86% vs. 42%-63% per year), and slowed brain volume loss (BVL; -0.45% to -0.87% vs. -0.50% to -1.39%). Through Year 2, the treatment effect with alemtuzumab did not significantly differ among age groups for ARR (p-interaction=0.6325), 6-month CDW-free (p-interaction=0.4959), 6-month CDI (p-interaction=0.9268), MRI disease activity-free (p-interaction=0.6512), and BVL (p-interaction=0.4970). Alemtuzumab remained effective on outcomes through Year 8 across age groups. Age-related increases in malignancies (≤45 years: 0.9%-2.2% vs. >45 years: 8.1%) and deaths (0%-1.7% vs. 7.0%) were observed. Serious infections also increased from the youngest (5.1%) to oldest (12.8%) age cohorts.

Conclusions: Alemtuzumab had greater efficacy than SC IFNB-1a over 2 years across comparable age groups, with no significant differences between alemtuzumab-treated age groups. Efficacy on relapse, disability, and MRI outcomes continued through Year 8 across age groups. Age-related increases in serious infections, malignancies, and deaths were observed.
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http://dx.doi.org/10.1016/j.msard.2020.102717DOI Listing
December 2020

Validation of the Italian version of the Multiple Sclerosis Intimacy and Sexuality Questionnaire-19.

Neurol Sci 2020 Nov 21. Epub 2020 Nov 21.

Department of Neurosciences, Reproductive and Odontostomatological Sciences, 'Federico II' University, Naples, Italy.

Background: People with multiple sclerosis (MS) may experience sexual dysfunction throughout the disease course. Validated scales to assess sexual dysfunction in MS for Italian patients are lacking. Hence, we aimed at validating Multiple Sclerosis Intimacy and Sexuality Questionnaire (MSISQ-19) for Italian MS patients.

Methods: We included both male and female MS patients. Each patient completed the Italian translation of the MSISQ-19. Construct validity was explored by the exploratory factor analysis and the Cronbach's alpha coefficient. Test-retest stability and concurrent internal and external validity were examined by Pearson' correlation coefficients.

Results: We enrolled 369 MS patients (323 female and 46 male). Italian MSISQ-19 showed a Cronbach's alpha of 0.92. MSISQ-19 test and retest total scores correlated between each other (r = 0.48, p = 0.01). MSISQ-19 total score also correlated with primary, secondary and tertiary subscales (p < 0.001).

Conclusion: The Italian Version of the MSISQ-19 showed satisfactory internal consistency and reliability with moderately adequate test-retest reproducibility, suggesting that it may be used as a valuable measure of sexual dysfunction in the Italian population.
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http://dx.doi.org/10.1007/s10072-020-04873-wDOI Listing
November 2020

Transition to secondary progression in relapsing-onset multiple sclerosis: Definitions and risk factors.

Mult Scler 2021 Mar 19;27(3):430-438. Epub 2020 Nov 19.

Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro," Bari, Italy.

Background: No uniform criteria for a sensitive identification of the transition from relapsing-remitting multiple sclerosis (MS) to secondary-progressive multiple sclerosis (SPMS) are available.

Objective: To compare risk factors of SPMS using two definitions: one based on the neurologist judgment (ND) and an objective data-driven algorithm (DDA).

Methods: Relapsing-onset MS patients ( = 19,318) were extracted from the Italian MS Registry. Risk factors for SPMS and for reaching irreversible Expanded Disability Status Scale (EDSS) 6.0, after SP transition, were estimated using multivariable Cox regression models.

Results: SPMS identified by the DDA ( = 2343, 12.1%) were older, more disabled and with a faster progression to severe disability ( < 0.0001), than those identified by the ND ( = 3868, 20.0%). In both groups, the most consistent risk factors ( < 0.05) for SPMS were a multifocal onset, an age at onset >40 years, higher baseline EDSS score and a higher number of relapses; the most consistent protective factor was the disease-modifying therapy (DMT) exposure. DMT exposure during SP did not impact the risk of reaching irreversible EDSS 6.0.

Conclusion: A DDA definition of SPMS identifies more aggressive progressive patients. DMT exposure reduces the risk of SPMS conversion, but it does not prevent the disability accumulation after the SP transition.
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http://dx.doi.org/10.1177/1352458520974366DOI Listing
March 2021

Disease-modifying drugs can reduce disability progression in relapsing multiple sclerosis.

Brain 2020 10;143(10):3013-3024

Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari 'Aldo Moro' Policlinico, Bari, Italy.

An ever-expanding number of disease-modifying drugs for multiple sclerosis have become available in recent years, after demonstrating efficacy in clinical trials. In the real-world setting, however, disease-modifying drugs are prescribed in patient populations that differ from those included in pivotal studies, where extreme age patients are usually excluded or under-represented. In this multicentre, observational, retrospective Italian cohort study, we evaluated treatment exposure in three cohorts of patients with relapsing-remitting multiple sclerosis defined by age at onset: paediatric-onset (≤18 years), adult-onset (18-49 years) and late-onset multiple sclerosis (≥50 years). We included patients with a relapsing-remitting phenotype, ≥5 years follow-up, ≥3 Expanded Disability Status Scale (EDSS) evaluations and a first neurological evaluation within 3 years from the first demyelinating event. Multivariate Cox regression models (adjusted hazard ratio with 95% confidence intervals) were used to assess the risk of reaching a first 12-month confirmed disability worsening and the risk of reaching a sustained EDSS of 4.0. The effect of disease-modifying drugs was assessed as quartiles of time exposure. We found that disease-modifying drugs reduced the risk of 12-month confirmed disability worsening, with a progressive risk reduction in different quartiles of exposure in paediatric-onset and adult-onset patients [adjusted hazard ratios in non-exposed versus exposed >62% of the follow-up time: 8.0 (3.5-17.9) for paediatric-onset and 6.3 (4.9-8.0) for adult-onset, P < 0.0001] showing a trend in late-onset patients [adjusted hazard ratio = 1.9 (0.9-4.1), P = 0.07]. These results were confirmed for a sustained EDSS score of 4.0. We also found that relapses were a risk factor for 12-month confirmed disability worsening in all three cohorts, and female sex exerted a protective role in the late-onset cohort. This study provides evidence that sustained exposure to disease-modifying drugs decreases the risk of disability accumulation, seemingly in a dose-dependent manner. It confirms that the effectiveness of disease-modifying drugs is lower in late-onset patients, although still detectable.
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http://dx.doi.org/10.1093/brain/awaa251DOI Listing
October 2020

Efficacy and Safety of Alemtuzumab Through 9 Years of Follow-up in Patients with Highly Active Disease: Post Hoc Analysis of CARE-MS I and II Patients in the TOPAZ Extension Study.

CNS Drugs 2020 09;34(9):973-988

MS Center for Innovations in Care, Missouri Baptist Medical Center, St. Louis, MO, USA.

Background: Alemtuzumab efficacy versus subcutaneous interferon-β-1a (SC IFNB-1a) was demonstrated over 2 years in patients with relapsing-remitting multiple sclerosis, with continued efficacy over 7 additional years. Alemtuzumab is included as a recommended treatment for patients with highly active disease (HAD) by the American Academy of Neurology Practice Guidelines, and the label indication in Europe was recently restricted to the treatment of HAD patients. There is currently no consensus definition for HAD, and alemtuzumab efficacy across various HAD definitions has not been explored previously.

Objectives: In this post hoc analysis, we assess the efficacy and safety of alemtuzumab in Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) trial patients who met criteria for at least one of four separate definitions of HAD (one primary and three alternatives). Over 2 years, alemtuzumab-treated HAD patients were compared with SC IFNB-1a-treated HAD patients, with additional 7-year follow-up in patients from the alemtuzumab arm.

Methods: Patients in the CARE-MS studies received either alemtuzumab (baseline: 5 days; 12 months later: 3 days) or SC IFNB-1a (3 times weekly). Alemtuzumab-treated patients who enrolled in the extensions could receive additional courses ≥ 12 months apart. Four definitions of HAD were applied to assess alemtuzumab efficacy: the pre-specified primary definition (two or more relapses in the year prior to baseline and at least one gadolinium [Gd]-enhancing lesion at baseline) and three alternative definitions that focused on relapse, magnetic resonance imaging (MRI), or prior treatment response criteria. Efficacy outcomes were annualized relapse rate, change in Expanded Disability Status Scale score, 6-month confirmed disability worsening, 6-month confirmed disability improvement, MRI disease activity, and brain volume change. Adverse events were summarized for HAD patients meeting the primary definition.

Results: In the pooled CARE-MS population, 208 alemtuzumab-treated patients met the primary HAD definition. Annualized relapse rate was 0.27 in years 0-2 and 0.16 in years 3-9. Over 9 years, 62% of patients were free of 6-month confirmed disability worsening, 50% had 6-month confirmed disability improvement, and median cumulative change in brain volume was - 2.15%. During year 9, 62% had no evidence of disease activity, and 69% were free of MRI disease activity. Similar efficacy outcomes were observed using an alternative relapse-driven HAD definition. For patients meeting alternative HAD definitions focused on either higher MRI lesion counts or disease activity while on prior therapy, reduced efficacy for some endpoints was seen. Safety was consistent with the overall CARE-MS population through year 9.

Conclusions: Over 9 years, alemtuzumab efficacy was maintained in CARE-MS HAD patients based on four HAD definitions. These results support intervention with alemtuzumab in patients with early indicators of HAD, including frequent relapse without high MRI activity. No safety signals were observed over 9 years that were unique to the HAD populations. CLINICALTRIALS.

Gov Identifiers: NCT00530348; NCT00548405; NCT00930553; NCT02255656.
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http://dx.doi.org/10.1007/s40263-020-00749-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447657PMC
September 2020

A Comprehensive Approach to Disentangle the Effect of Cerebellar Damage on Physical Disability in Multiple Sclerosis.

Front Neurol 2020 30;11:529. Epub 2020 Jun 30.

Department of Human Neurosciences, "Sapienza" Rome University, Rome, Italy.

Cerebellar damage occurs frequently in multiple sclerosis (MS) patients, with a wide exhibition of symptoms particularly as impairments of balance and gait. Recent studies implementing new postprocessing magnetic resonance imaging (MRI) techniques showed how cerebellar subregional atrophy provides an explanation of disability in MS. The aim of this work was to evaluate the relationship between quantitative measures of physical disability, cerebellar subregional atrophy, and cerebellar peduncle disruption. Forty-nine MS patients and 32 healthy subjects as controls (HS) underwent a 3-Tesla MRI including 3D T1-weighted and diffusion tensor imaging. Patients underwent static posturography to calculate the body's center of pressure (COP) displacement, Expanded Disability Status Scale (EDSS), and 25-ft walking test (25-FWT). Cerebellar lobular volumes were automatically calculated using the Spatially Unbiased Infratentorial Toolbox. Tract-based spatial statistics (TBSS) in FSL was used to process diffusion tensor imaging (DTI) Fit-generated fractional anisotropy (FA) maps to assess structural connectivity of cerebellar peduncles. Stepwise multivariate linear regression analyses were used to explore relationships between variables. Cerebellar volumes (anterior and posterior, as well as lobular volumes from I to X) were significantly lower in patients with MS than HS ( < 0.05). FA in all cerebellar peduncles was lower in MS patients than in HS ( < 0.05). EDSS and 25-FWT showed an association with atrophy of lobule VIIIb (β = -0.37, < 0.01, and β = -0.45, < 0.001, respectively) COP measures inversely correlated with volume of lobules I-IV (β = -0.37, < 0.01, and β = -0.36, < 0.01). Lower FA in the three cerebellar peduncles of MS patients positively correlated with cerebellar lobular volumes. Our findings show how sensorimotor cerebellum atrophy and disruption of both afferent and efferent cerebellar connections contribute to physical disability in MS patients.
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http://dx.doi.org/10.3389/fneur.2020.00529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338682PMC
June 2020

The introduction of new medications in pediatric multiple sclerosis: Open issues and challenges.

Mult Scler 2021 Mar 16;27(3):479-482. Epub 2020 Jun 16.

Istituto di Neurologia Sperimentale (INSPE), IRCCS Ospedale San Raffaele, Milan, Italy.

Disease-modifying drugs (DMDs) for multiple sclerosis (MS) have been evaluated in pediatric patients in observational studies demonstrating a similar, even better clinical effect compared to adults, with a similar safety. Only fingolimod has been tested in a randomized controlled trial (RCT) and is approved for pediatric multiple sclerosis (ped-MS). Numerous methodological, practical, and ethical issues underline that RCTs are difficult to conduct in ped-MS. This also creates a lack of safety information. To facilitate the availability of new agents in ped-MS, we encourage to develop a different approach based on pharmacokinetic/pharmacodynamic studies to yield information on optimal doses and implementation of obligatory registries to obtain information on safety as primary endpoint.
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http://dx.doi.org/10.1177/1352458520930620DOI Listing
March 2021

Resting-state functional connectivity of anterior and posterior cerebellar lobes is altered in multiple sclerosis.

Mult Scler 2020 May 28:1352458520922770. Epub 2020 May 28.

Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy/IRCCS Neuromed, Pozzilli, Italy.

Background: Damage to the cerebellar sensorimotor and cognitive domains may underlie physical and cognitive disability.

Objective: To investigate resting-state functional connectivity (FC) of sensorimotor and cognitive cerebellum, and clinical correlates in multiple sclerosis (MS).

Methods: A total of 119 patients with MS and 42 healthy subjects underwent multimodal 3T-magnetic resonance imaging (MRI). Patients were evaluated using the Expanded Disability Status Scale and Multiple Sclerosis Functional Composite Scale. After parcellation of sensorimotor (lobules I-V + VIII) and cognitive cerebellum (lobules VI, VII, IX, X), we calculated cerebellar resting-state FC using a seed-based approach.

Results: In patients with MS, the sensorimotor cerebellum showed increased FC mainly with cerebellar, thalamic, and cortical (frontal, parietal, temporal) areas and decreased FC with insular areas; the cognitive cerebellum showed increased FC mainly with thalamic and cortical (temporal-occipital) areas, and decreased FC with frontal-insular areas. Both sensorimotor and cognitive cerebellar FC negatively correlated with disability, and positively with cognitive scores. Cerebellar structural damage only partially influenced results.

Conclusion: The two neocerebellar circuits showed altered FC with subcortical and cortical areas. The association between increased sensorimotor and cognitive cerebellar FC and low levels of physical and cognitive disability suggests that altered FC might modulate the effects of cerebellar structural damage on clinical condition.
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http://dx.doi.org/10.1177/1352458520922770DOI Listing
May 2020

Multiple Sclerosis Treatment and Melanoma Development.

Int J Mol Sci 2020 Apr 22;21(8). Epub 2020 Apr 22.

I Dermatology Department, IDI-IRCCS, 00167 Rome, Italy.

Therapy of multiple sclerosis (MS) with disease-modifying agents such as natalizumab or fingolimod has been associated with the development of cutaneous melanoma. Here we briefly revise literature data and report of a case of a 48-year old woman who developed a melanoma and several atypical naevi after sub sequential treatment with natalizumab (1 year) and fingolimod (7 years). By immunohistochemistry we observed the presence of T cells and leukocyte infiltration as well as of vascular endothelial growth factor (VEGF)-A expression in the patient melanoma biopsy. Then, we analyzed proliferation, migration and VEGF-A expression in three melanoma cell lines and found out that both natalizumab and fingolimod inhibited tumor cell proliferation but promoted or blocked cell migration depending on the cell line examined. VEGF-A secretion was augmented in one melanoma cell line only after fingolimod treatment. In conclusion, our in vitro data do not support the hypothesis of a direct action of natalizumab or fingolimod on melanoma progression but acting on the tumor microenvironment these treatments could indirectly favor melanoma evolution.
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http://dx.doi.org/10.3390/ijms21082950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216218PMC
April 2020

Effectiveness of fingolimod in real-world relapsing-remitting multiple sclerosis Italian patients: the GENIUS study.

Neurol Sci 2020 Oct 21;41(10):2843-2851. Epub 2020 Apr 21.

Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari Aldo Moro, Bari, Italy.

Background: Fingolimod is the first oral agent approved for treatment of relapsing-remitting multiple sclerosis (RRMS). We aimed to evaluate fingolimod effectiveness in a real-world sample of RRMS patients.

Methods: A retrospective, multicentre study in patients treated with fingolimod, whom clinical and radiological data were collected in the 2 years preceding and following the initiation of fingolimod.

Results: Out of 414 patients, 56.8% received prior first-line injectable disease-modifying therapies, 25.4% were previously treated with natalizumab, 1.2% with immunosuppressant agents, and 16.7% were treatment naive. The annualized relapse rate decreased by 65% in the first year and by 70% after two years of treatment. Age ≤ 40 years, ≥ 1 relapse in the 24 months before fingolimod initiation and previous treatment with natalizumab were risk factors for relapses. Overall, 67.9% patients had no evidence of disease activity (NEDA-3) after 1 year and 54.6% after 2 years of treatment. A higher proportion of naïve (81.2% in 1 year and 66.7% after 2 years) or first-line injected patients (70.2% and 56.6%) achieved NEDA-3 than those previously treated with natalizumab (54.3% and 42.9%).

Conclusions: Fingolimod appeared to be effective in naive patients and after first-line treatment failure in reducing risk of relapse and disease activity throughout the 2-year follow-up.
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http://dx.doi.org/10.1007/s10072-020-04380-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479005PMC
October 2020

Multi-scale resting state functional reorganization in response to multiple sclerosis damage.

Neuroradiology 2020 Jun 18;62(6):693-704. Epub 2020 Mar 18.

Department of Human Neuroscience, Sapienza - University of Rome, Viale dell'Università 30, 00185, Rome, Italy.

Purpose: In multiple sclerosis (MS), how brain functional changes relate to clinical conditions is still a matter of debate. The aim of this study was to investigate how functional connectivity (FC) reorganization at three different scales, ranging from local to whole brain, is related to tissue damage and disability.

Methods: One-hundred-nineteen patients with MS were clinically evaluated with the Expanded Disability Status Scale and the Multiple Sclerosis Functional Composite. Patients and 42 healthy controls underwent a multimodal 3 T MRI, including resting-state functional MRI.

Results: We identified 16 resting-state networks via independent component analysis and measured within-network, between-network, and whole-brain (global efficiency and degree centrality) FC. Within-network FC was higher in patients than in controls in default mode, frontoparietal, and executive-control networks, and corresponded to low clinical impairment (default mode network versus Expanded Disability Status Scale r = - 0.31, p < 0.01; right frontoparietal network versus Paced Auditory Serial Addition Test r = 0.33, p < 0.01). All measures of between-network and whole-brain FC, except default mode network global efficiency, were lower in patients than in controls, and corresponded to high disability (i.e., basal ganglia global efficiency versus Timed 25-Foot Walk r = - 0.25, p < 0.03; default mode global efficiency versus Expanded Disability Status Scale r = - 0.44, p < 0.001). Altered measures of within-network, between-network, and whole-brain FC were combined in functional indices that were linearly related to disease duration, Paced Auditory Serial Addition Test and lesion load and non-linearly related to Expanded Disability Status Scale.

Conclusion: We suggest that the combined evaluation of functional alterations occurring at different levels, from local to whole brain, could exhaustively describe neuroplastic changes in MS, while increased within-network FC likely represents adaptive compensatory processes, decreased between-network and whole-brain FC likely represent loss of functional network integration consequent to structural disruption.
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http://dx.doi.org/10.1007/s00234-020-02393-0DOI Listing
June 2020

Minimal evidence of disease activity (MEDA) in relapsing-remitting multiple sclerosis.

J Neurol Neurosurg Psychiatry 2020 03 23;91(3):271-277. Epub 2020 Jan 23.

Multiple Sclerosis Center, San Camillo-Forlanini Hospital, Roma, Italy.

Objective: This study aimed to define the minimal evidence of disease activity (MEDA) during treatment that can be tolerated without exposing patients with relapsing-remitting multiple sclerosis at risk of long-term disability.

Methods: We retrospectively collected data of patients followed up to 10 years after starting interferon beta or glatiramer acetate. Survival analyses explored the association between the long-term risk of reaching an Expanded Disability Status Scale≥6.0 and early clinical and MRI activity assessed after the first and second year of treatment. Early disease activity was classified by the so-called 'MAGNIMS score' (: no relapses and <3 new T2 lesions; : no relapses and ≥3 new T2 lesions or 1 relapse and 0-2 new T2 lesions; : 1 relapse and ≥3 new T2 lesions or ≥2 relapses) and the absence or presence of contrast-enhancing lesions (CELs).

Results: At follow-up, 148/1036 (14.3%) patients reached the outcome: 61/685 (8.9%) with score (reference category), 57/241 (23.7%) with score (HR=1.94, p=0.002) and 30/110 (27.3%) with score (HR=2.47, p<0.001) after the first year of treatment. In the score subgroup, the risk was further reduced in the absence (49/607, 8.1%) than in the presence of CELs (12/78, 15.4%; HR=2.11, p=0.01). No evident disease activity and score in the absence of CELs shared the same risk (p=0.54). Similar findings were obtained even after the second year of treatment.

Conclusions: Early marginal MRI activity of one to two new T2 lesions, in the absence of both relapses and CELs, is associated with a minor risk of future disability, thus representing a simple and valuable definition for MEDA.
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http://dx.doi.org/10.1136/jnnp-2019-322348DOI Listing
March 2020

Dalfampridine to Improve Balance in Multiple Sclerosis: Substudy from a Randomized Placebo-Controlled Trial.

Neurotherapeutics 2020 04;17(2):704-709

S. Andrea Hospital, Sapienza University, Via di Grottarossa 1035, 00189, Rome, Italy.

This was a substudy of a randomized, double-blind, placebo-controlled trial originally designed to explore the effect of dalfampridine on information processing speed (2013-002558-64 EU Clinical Trials Register) in patients with multiple sclerosis (MS). A total of 120 patients were originally randomized in a 2:1 ratio to receive dalfampridine 10 mg or placebo twice daily for 12 weeks. Here, we sought to explore the effect of dalfampridine on static balance in single-task and dual-task conditions in a subgroup of 41 patients. They underwent static posturography in quiet standing (single-task) and while performing the Stroop test (dual-task) at randomization (baseline), after 12 weeks and after a 4-week wash-out period. Baseline characteristics of active group (n = 27) did not differ from those of placebo group (n = 14). Dalfampridine treatment was associated with better balance control than placebo in both single-task (F = 4.80, p = 0.034) and dual-task (F = 6.42, p = 0.015) conditions, with small-to-moderate effect sizes (Cohen's f = 0.122-0.162). The beneficial effect of dalfampridine was not retained 4 weeks after its discontinuation. The rate of accidental falls per month did not differ between the two groups (p = 0.12). Our preliminary findings suggest that dalfampridine can be considered a potential option to treat balance impairment due to MS. Larger sample sizes are needed to verify if the beneficial effect of dalfampridine on balance can be translated into a reduced risk of accidental falls.
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http://dx.doi.org/10.1007/s13311-019-00813-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283428PMC
April 2020

Cognitive fatigability is a quantifiable distinct phenomenon in multiple sclerosis.

J Neuropsychol 2020 09 14;14(3):370-383. Epub 2019 Nov 14.

Medicine Department, Neurology Unit, San Filippo Neri Hospital, Rome, Italy.

Cognitive fatigability in multiple sclerosis represents the decrease in cognitive performance over time. It is a frequent symptom that negatively affects quality of life and ability to work. There are no objective measures of cognitive fatigability. This study aimed at quantifying cognitive fatigability despite the learning effect and to clarify whether cognitive fatigability represents a free-standing phenomenon rather than an aspect of cognitive impairment. We measured information processing speed with the Symbol Digit Modalities Test, and the number of right answers was recorded every 30 s for 180 s. We approximated the number of right answers as function of time with two logarithmic models, one including a first-order term alone and the other adding also a second-order term. The coefficient of the latter (B) may quantify performance deflection and may represent cognitive fatigability. We tested 173 patients with multiple sclerosis, including 119 cognitively impaired and 54 cognitively preserved patients, and 35 healthy subjects. The performance of cognitively preserved patients showed a deflection at the end of task that was detected neither in controls nor in cognitively impaired patients and needed a second-order term to be approximated (p < .03, F = 14.02). B was explained neither by depression nor fatigue. We proposed for the first time a method to quantify cognitive fatigue via a second-order least square fit model, easily usable in the clinical practice. By using this novel approach, cognitive fatigability results to be a free-standing phenomenon that is more evident in cognitively preserved than in cognitive impaired patients.
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http://dx.doi.org/10.1111/jnp.12197DOI Listing
September 2020

Efficacy of alemtuzumab over 6 years in relapsing-remitting multiple sclerosis patients who relapsed between courses 1 and 2: Post hoc analysis of the CARE-MS studies.

Mult Scler 2020 11 1;26(13):1719-1728. Epub 2019 Nov 1.

University of Lille, INSERM U995, CHU Lille, FHU Imminent, Lille, France.

Background: Alemtuzumab is administered as two annual courses for relapsing-remitting multiple sclerosis (MS). Patients may relapse before completing the two-course regimen.

Objective: The objective was to evaluate 6-year outcomes in patients who relapsed between alemtuzumab Courses 1 and 2 (early relapsers).

Methods: Post hoc analysis of patients from the Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) studies who enrolled in the extension.

Results: Early relapsers (CARE-MS I: 15%; CARE-MS II: 24%) had more relapses in 1-2 years pre-alemtuzumab and higher mean baseline Expanded Disability Status Scale score than patients without relapse. Their annualized relapse rate declined from Year 1 (CARE-MS I: 1.3; CARE-MS II: 1.2) to Year 2 following Course 2 (0.3; 0.5) and remained low thereafter. Over 6 years, 60% remained free of 6-month confirmed disability worsening; 24% (CARE-MS I) and 34% (CARE-MS II) achieved 6-month confirmed disability improvement. During Year 6, 69% (CARE-MS I) and 68% (CARE-MS II) were free of magnetic resonance imaging (MRI) disease activity. Median percent yearly brain volume loss (Year 1: -0.67% (CARE-MS I); -0.47% (CARE-MS II)) declined after Course 2 (Year 6: -0.24%; -0.13%).

Conclusion: Early relapsers' outcomes improved after completing the second alemtuzumab course. These findings support administering the approved two-course regimen to maximize clinical benefit.

Clinicaltrials.gov Registration Numbers: CARE-MS I, II, extension: NCT00530348, NCT00548405, NCT00930553.
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http://dx.doi.org/10.1177/1352458519881759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604550PMC
November 2020

Retrospectively acquired cohort study to evaluate the long-term impact of two different treatment strategies on disability outcomes in patients with relapsing multiple sclerosis (RE.LO.DI.MS): data from the Italian MS Register.

J Neurol 2019 Dec 18;266(12):3098-3107. Epub 2019 Sep 18.

Department of Basic Medical Sciences, Neurosciences, and Sense Organs, Multiple Sclerosis Center, University of Bari "Aldo Moro", Bari, Italy.

Background: The increase in disease-modifying drugs (DMDs) allows individualization of treatment in relapsing multiple sclerosis (RMS); however, the long-term impact of different treatment sequences is not well established. This is particularly relevant for MS patients who may need to postpone more aggressive DMD strategies.

Objective: To evaluate different therapeutic strategies and their long-term outcomes, measured as relapses and confirmed disability progression (CDP), in MS 'real-world' settings.

Methods: Multicentre, observational, retrospectively acquired cohort study evaluating the long-term impact of different treatment strategies on disability outcomes in patients with RMS in the Italian MS Register.

Results: We evaluated 1152 RMS-naïve patients after propensity-score adjustment. Patients included were receiving: interferon beta-1a (IFN-β1a) 44 µg switching to fingolimod (FTY; IFN-switchers; n = 97); FTY only (FTY-stayers; n = 157); IFN-β1a only (IFN-stayers; n = 849). CDP and relapses did not differ between FTY-stayers and IFN-switchers [HR (95% CI) 0.99 (0.48-2.04), p = 0.98 and 0.81 (0.42-1.58), p = 0.55, respectively]. However, IFN-stayers showed increased risk of relapses compared with FTY-stayers [HR (95% CI) 1.46 (1.00-2.12), p = 0.05].

Conclusion: The ideal treatment option for MS is becoming increasingly complex, with the need to balance benefit and risks. Our results suggest that starting with FTY affects the long-term disease outcome similarly to escalating from IFN-β1a to FTY.
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http://dx.doi.org/10.1007/s00415-019-09531-6DOI Listing
December 2019

Drug Holiday of Interferon Beta 1b in Multiple Sclerosis: A Pilot, Randomized, Single Blind Study of Non-inferiority.

Front Neurol 2019 16;10:695. Epub 2019 Jul 16.

Neurosciences, Mental Health, and Sensory Organs (NESMOS) Department, Center for Experimental Neurological Therapies, S. Andrea Hospital-site, "Sapienza" University of Rome, Rome, Italy.

To compare a schedule with cyclic withdrawal (CW) of interferon beta (IFN-b) 1b, respect to the full regimen (FR), in relapsing-remitting MS (RR-MS). Participants were randomly assigned to CW or FR schedule and monthly monitored with brain MRI scans for 12 months (three of run-in and 9 of treatment). CW schedule included drug withdrawal for 1 month after two of treatment for a total of three quarters over the 9-month treatment period. The assessing neurologist and the expert neuroradiologists were blind. After the blind phase of the study all participants took their indicated disease modifying therapies in a prospectively planned, open-label extension phase (up to 120 months). Of 60 randomized subjects 56 (29 in FR and 27 in CW group) completed the single-blind phase: the two groups were comparable, except for a non-significant difference in the number of contrast-enhanced lesions (CEL) at the end of run-in. The two-sided 90% CI for the ratio between median number of cumulative CEL was 0.29-1.07, allowing to significantly reject the null hypothesis of a ratio ≥1.2 and to meet the primary end-point of non-inferiority (the threshold and the ratio between median were chosen according to the non-normal distribution of the data). The differences (CW vs. FR) were also non-significant for secondary end points: mean cumulative number of T2-weighted new and enlarging lesions (3.48 ± 5.34 vs. 3.86 ± 6.76); mean number and volume (cm) of black holes (1.24 ± 1.61 vs. 2.71 ± 4.56; 489.11 ± 1488.12 vs. 204.48 ± 396.98); number of patients with at least an active scan (21 vs. 22); mean relapse rate (0.52 ± 0.89 vs. 0.34 ± 0.66), relapse risk ratio adjusted for baseline variables (2.15 [0.64-7.18]), EDSS score (1.0 [1-1.56] vs. 1.5 [1-1.78]), proportion of patients with antibodies anti-IFN (5 [21%] vs. 8 [36%]). Fifty-four patients (27 for each study arm) completed the open-label phase. The annualized RR, EDSS, proportion of patients shifting to progressive disease and hazard ratio of shifting, adjusting for baseline covariates, were comparable between the two study groups. A calendar with CW was non-inferior than FR at the beginning of IFN-b therapy, and may not affect the long-term outcome. www.ClinicalTrials.gov, identifier: NCT00270816.
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http://dx.doi.org/10.3389/fneur.2019.00695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646514PMC
July 2019

The influence of physiotherapy intervention on patients with multiple sclerosis-related spasticity treated with nabiximols (THC:CBD oromucosal spray).

PLoS One 2019 30;14(7):e0219670. Epub 2019 Jul 30.

IRCCS Fondazione Don Carlo Gnocchi, Milan, Italy.

Background: Nabiximols (THC/CBD Oromucosal Spray, Sativex) is used as an add-on therapy to treat moderate to severe spasticity of Multiple Sclerosis (MS).

Objectives: To examine the impact of physiotherapy (PT) programs on effectiveness and persistence of nabiximols treatment in people with MS-related spasticity.

Methods: This is an observational multicenter study with a follow-up period of 12 weeks, conducted in routine care settings in Italy. Patients with moderate to severe MS-related spasticity who started nabiximols were included. Spasticity was evaluated by the patient-rated 0-10 numerical rating scale (NRS). Clinical data were collected at baseline (T0), 4 weeks (T1) and 12 weeks (T2) months after enrollment.

Results: A total of 297 MS patients were selected, 290 completed the 3 months follow-up period. Mean NRS scores were 7.6 ± 1.1 at T0, 5.8 ± 1.4 at T1 and 5.5 ± 1.5 at T2. At T1, 77% of patients reached ≥20% improvement (initial response, IR); 22% reached ≥30% improvement (clinically relevant response, CRR). At T1, patients undergoing PT had a higher probability to reach CRR (Odds Ratio = 2.6 95% CI 1.3-5.6, p = 0.01). Nabiximols was discontinued in 30/290 (10.3%) patients at T1 (early discontinuers) and in 71/290 (24.5%) patients at T2 (late discontinuers). The probability of being late discontinuers was reduced in patients undergoing PT (Hazard Ratio = 0.41; 95% CI 0.23-0.69, p = 0.001).

Conclusions: Our real-life study confirms nabiximols' effectiveness in MS-related spasticity and suggests that the association of a PT program may improve overall response and persistence to nabiximols treatment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0219670PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667203PMC
February 2020

Pharmacokinetics and pharmacodynamics of natalizumab in pediatric patients with RRMS.

Neurol Neuroimmunol Neuroinflamm 2019 09 1;6(5):e591. Epub 2019 Jul 1.

Multiple Sclerosis Study Center (A.G.), ASST Valle Olona, Gallarate Hospital (VA); Department of Neurology (G.C., L.M.), Institute of Experimental Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan; Department of Neurology (L.M.G.), Fondazione Istituto G. Giglio, Cefalù; Department of Neurology (C.P.), "La Sapienza" University, Rome; Biogen Italia (S.F.), Milan; and Department of Neuroscience DNS, Multiple Sclerosis Centre (P.G.), Università degli Studi di Padova, Italy.

Objective: This phase I study investigated pharmacokinetic (PK) and pharmacodynamic (PD) profiles of natalizumab in pediatric patients with relapsing-remitting MS (RRMS).

Methods: Pediatric patients with RRMS who were prescribed natalizumab 300 mg IV every 4 weeks were enrolled. Blood samples were collected on days 1, 2, 8, 15, and 22 and at weeks 4, 8, 12, and 16 to estimate PK parameters; PD properties were evaluated by measuring α4-integrin saturation and lymphocyte counts over time. Natalizumab's safety profile was also evaluated.

Results: PK parameters were similar to those reported in adult patients; natalizumab concentrations peaked approximately 1 day after infusion in most of the participants (Cmax 142.9 μg/mL, AUClast 47389.4 hr*μg/mL), followed by a biphasic decline with a rapid distribution phase and a slow elimination phase, with a terminal half-life of 215.1 hours. In terms of PD, both time course and magnitude of α4-integrin saturation and increase in lymphocyte counts were similar to those observed in adults. During the 16-week study follow-up, 3 adverse events attributed to natalizumab were observed; no unexpected safety events occurred.

Conclusions: PK profile, α4-integrin saturation, lymphocyte counts, and safety observed in these pediatric patients are comparable to those reported in adults.

Classification Of Evidence: This study provides Class I evidence that natalizumab PK/PD parameters and safety profile are similar in adults and pediatric patients in the short term. Longer studies, also including a larger number of younger subjects (aged 10-12 years), are required to further inform about long-term PK and PD parameters in pediatric patients with MS.
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http://dx.doi.org/10.1212/NXI.0000000000000591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624146PMC
September 2019

Effect of dalfampridine on information processing speed impairment in multiple sclerosis.

Neurology 2019 08 22;93(8):e733-e746. Epub 2019 Jul 22.

From the MS Center Sant'Andrea Hospital (L.D.G., F.G., G.B., C.P.), Department of Human Neuroscience (L.D.G., F.D.L., F.G., I.F., C.P.), and Department of Psychology (F.D.L.), Sapienza University of Rome; Department of Neuroscience San Camillo-Forlanini Hospital (L.P., E.Q., C.G.); and Neurological Center of Latium (G.B.), IRCCS Neuromed, Rome, Italy.

Objective: To test a possible benefit of dalfampridine on information processing speed (IPS), a key function for cognitive impairment (CogIm) in multiple sclerosis (MS).

Methods: In this randomized, double-blind, placebo-controlled trial, we included patients with a score on the Symbol Digit Modalities Test (SDMT) under the 10th percentile of the reference value. Patients were randomized in a 2:1 ratio to receive dalfampridine 10 mg or placebo twice daily for 12 weeks. They underwent a comprehensive neuropsychological evaluation at screening (T0), at the end of treatment (T1), and after a 4-week follow-up (T2). The primary endpoint was improvement in SDMT.

Results: Out of 208 patients screened, 120 were randomized to receive either dalfampridine (n = 80) or placebo (n = 40). At T1, the dalfampridine group presented an increase of SDMT scores vs placebo group (mean change 9.9 [95% confidence interval (CI) 8.5-11.4] vs 5.2 [95% CI 2.8-7.6], = 0.0018; = 0.60 for raw score; and 0.8 [95% CI 0.6-1] vs 0.3 [95% CI 0.0-0.5], = 0.0013; = 0.61 for scores; by linear mixed model with robust standard error). The improvement was not sustained at T2. A beneficial effect of dalfampridine was observed in the Paced Auditory Serial Addition Test and in cognitive fatigue.

Conclusion: Dalfampridine could be considered as an effective treatment option for IPS impairment in MS.

Trial Registration: 2013-002558-64 EU Clinical Trials Register.

Classification Of Evidence: This study provides Class I evidence that for patients with MS with low scores on the SDMT, dalfampridine improves IPS.
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http://dx.doi.org/10.1212/WNL.0000000000007970DOI Listing
August 2019

Advances in preventing adverse events during monoclonal antibody management of multiple sclerosis.

Expert Rev Neurother 2019 05 16;19(5):417-429. Epub 2019 May 16.

a MS Center Sant'Andrea Hospital, Sapienza University of Rome , Rome , Italy.

Introduction: Decades of pharmacological research in Multiple Sclerosis (MS) led to the development of therapeutic Monoclonal Antibodies (MAbs) with many different mechanisms of action (MoA), potentially able to improve disability outcome but also determining a more complex management of patients. Areas covered: When clinicians select MS treatments, they should consider adverse events (AEs) on individual basis to minimize patients' risks. Some AEs are common and can be easily handled, but rare complications should also be taken into account. The aim of this review is to summarize existing evidence and provide practical recommendations for the management of therapeutic MAbs in MS. Expert opinion: The introduction of MAbs revolutionized MS treatment with an improvement in effectiveness. Unfortunately, this has been coupled with a more complex array of AEs needing a tighter surveillance strategy. A close interaction between general practitioners, neurologists, and other specialists is the key for a safer use of such effective drugs.
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http://dx.doi.org/10.1080/14737175.2019.1610393DOI Listing
May 2019

Advances in spinal cord imaging in multiple sclerosis.

Ther Adv Neurol Disord 2019 22;12:1756286419840593. Epub 2019 Apr 22.

Queen Square MS Centre, NMR Research Unit, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK.

The spinal cord is frequently affected in multiple sclerosis (MS), causing motor, sensory and autonomic dysfunction. A number of pathological abnormalities, including demyelination and neuroaxonal loss, occur in the MS spinal cord and are studied with magnetic resonance imaging (MRI). The aim of this review is to summarise and discuss recent advances in spinal cord MRI. Advances in conventional spinal cord MRI include improved identification of MS lesions, recommended spinal cord MRI protocols, enhanced recognition of MRI lesion characteristics that allow MS to be distinguished from other myelopathies, evidence for the role of spinal cord lesions in predicting prognosis and monitoring disease course, and novel post-processing methods to obtain lesion probability maps. The rate of spinal cord atrophy is greater than that of brain atrophy (-1.78% -0.5% per year), and reflects neuroaxonal loss in an eloquent site of the central nervous system, suggesting that it can become an important outcome measure in clinical trials, especially in progressive MS. Recent developments allow the calculation of spinal cord atrophy from brain volumetric scans and evaluation of its progression over time with registration-based techniques. Fully automated analysis methods, including segmentation of grey matter and intramedullary lesions, will facilitate the use of spinal cord atrophy in trial designs and observational studies. Advances in quantitative imaging techniques to evaluate neuroaxonal integrity, myelin content, metabolic changes, and functional connectivity, have provided new insights into the mechanisms of damage in MS. Future directions of research and the possible impact of 7T scanners on spinal cord imaging will be discussed.
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http://dx.doi.org/10.1177/1756286419840593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6477770PMC
April 2019

Functional Connectivity Changes After Initial Treatment With Fingolimod in Multiple Sclerosis.

Front Neurol 2019 22;10:153. Epub 2019 Mar 22.

Department of Radiology, IRCCS NEUROMED, Pozzilli, Italy.

On the basis of recent functional MRI studies, Multiple Sclerosis (MS) has been interpreted as a multisystem disconnection syndrome. Compared to normal subjects, MS patients show alterations in functional connectivity (FC). However, the mechanisms underlying these alterations are still debated. The aim of the study is to investigate resting state (RS) FC changes after initial treatment with fingolimod, a proven anti-inflammatory and immunomodulating agent for MS. We studied 32 right-handed relapsing-remitting MS patients (median Expanded Disability Status Scale: 2.0, mean disease duration: 8.8 years) who underwent both functional and conventional MRI with a 3 Tesla magnet. All assessments were performed 3 weeks before starting fingolimod, then, at therapy-initiation stage and at month 6. Each imaging session included scans at baseline (run1) and after (run2) a 25-min, within-session, motor-practice task, consisting of a paced right-thumb flexion. FC was assessed using a seed on the left primary motor cortex to obtain parametric maps at run1 and task-induced FC change (run2-run1). Comparison between 3-week before- and fingolimod start sessions accounted for a test-retest effect. The main outcome was the changes in both baseline and task-induced changes in FC, between initiation and 6 months. MRI contrast enhancement was detected in 14 patients at initiation and only in 3 at month 6. There was a significant improvement ( < 0.05) in cognitive function, as measured by the Paced Auditory Serial Addition Task, at month 6 compared to initiation. After accounting for test-retest effect, baseline FC significantly decreased at month 6, with respect to initiation ( < 0.05, family-wise error corrected) in bilateral occipito-parietal areas and cerebellum. A task-induced change in FC at month 6 showed a significant increment in all examined sessions, involving not only areas of the sensorimotor network, but also posterior cortical areas (cuneus and precuneus) and areas of the prefrontal and temporal cortices ( < 0.05, family-wise error corrected). Cognitive improvement at month 6 was significantly ( < 0.05) related to baseline FC reduction in posterior cortical areas. This study shows significant changes in functional connectivity, both at baseline and after the execution of a simple motor task following 6 months of fingolimod therapy.
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http://dx.doi.org/10.3389/fneur.2019.00153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438876PMC
March 2019

Unraveling treatment response in multiple sclerosis: A clinical and MRI challenge.

Neurology 2019 01 26;92(4):180-192. Epub 2018 Dec 26.

From the Department of Neurosciences (C.G., L.P.), San Camillo-Forlanini Hospital, Rome, Italy; Centre d'Esclerosi Multiple de Catalunya (Cemcat), Department of Neurology/Neuroimmunology (M.T., J.R., J.S.-G., X.M.), and Magnetic Resonance Unit, Department of Radiology (A.R.), Hospital Universitari Vall d'Hebron, Universitat Autonoma de Barcelona, Spain; Biostatistics Unit (M.P.S.), Department of Health Sciences, University of Genoa; Neuroimaging Research Unit (M.F., M.A.R.), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy; Nuffield Department of Clinical Neurosciences (J.P.), West Wing, John Radcliffe Hospital, Oxford; Institutes of Neurology & Healthcare Engineering (O.C., F.B.), University College London (O.C.), UK; Amsterdam Neuroscience and Department of Radiology and Nuclear Medicine (F.B., H.V.), VU University Medical Center, Amsterdam, the Netherlands; Department of Neurology (J.L.F.), Rigshospitalet Glostrup and University of Copenhagen, Denmark; Neuroradiological Academic Unit (T.A.Y.), Institute of Neurology, London, UK; Department of Neurology (C.E.), Medical University of Graz, Austria; Neurologic Clinic and Policlinic, Department of Medicine (L.K.), Clinical Research, Biomedicine and Biomedical Engineering, University Hospital Basel, University of Basel, Switzerland; Department of Neurology and Psychiatry (C.P.), Sapienza University, Rome; and Neurology and Neurometabolic Unit, Department of Neurological and Behavioral Sciences (N.D.S.), University of Siena, Italy.

Over the last few decades, the improved diagnostic criteria, the wide use of MRI, and the growing availability of effective pharmacologic treatments have led to substantial advances in the management of multiple sclerosis (MS). The importance of early diagnosis and treatment is now well-established, but there is still no consensus on how to define and monitor response to MS treatments. In particular, the clinical relevance of the detection of minimal MRI activity is controversial and recommendations on how to define and monitor treatment response are warranted. An expert panel of the Magnetic Resonance Imaging in MS Study Group analyzed and discussed published studies on treatment response in MS. The evolving concept of no evidence of disease activity and its effect on predicting long-term prognosis was examined, including the option of defining a more realistic target for daily clinical practice: minimal evidence of disease activity. Advantages and disadvantages associated with the use of MRI activity alone and quantitative scoring systems combining on-treatment clinical relapses and MRI active lesions to detect treatment response in the real-world setting were also discussed. While most published studies on this topic involved patients treated with interferon-β, special attention was given to more recent studies providing evidence based on treatment with other and more efficacious oral and injectable drugs. Finally, the panel identified future directions to pursue in this research field.
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http://dx.doi.org/10.1212/WNL.0000000000006810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345120PMC
January 2019

Impact of early diagnosis on clinical characteristics of an Italian sample of people with multiple sclerosis recruited online.

Mult Scler Relat Disord 2019 Jan 5;27:239-246. Epub 2018 Nov 5.

First Clinic of Neurology, University of Campania "Luigi Vanvitelli", Piazza Miraglia 2, Naples 80138, Italy.

Background: In order to anticipate the diagnosis of Multiple Sclerosis (MS), the diagnostic criteria had been reviewed several times in the last years.

Objective: We wanted to understand whether earlier diagnoses of MS have impacted on therapeutic management of the disease.

Methods: We designed a 22-item survey posted on SMsocialnetwork, a webplatform with a medical supervision, dedicated to Italian MS patients. We collected socio-demographic data, disease and treatment-related information of 1000 patients.

Results: The median age at diagnosis significantly decreased over years. In the last decades the time delay between disease onset and diagnosis reduced, the disease phenotypes at diagnosis shifted from progressive form to relapsing ones and clinically isolated syndrome, the number of early treated patients increased over time.

Conclusion: We showed, verifying a large sample of patients in a reallife setting, that the improvement of the diagnostic process allowed the anticipation of MS diagnosis over years and had a huge impact in terms of treatment approach.
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http://dx.doi.org/10.1016/j.msard.2018.10.113DOI Listing
January 2019

Prolonged-release fampridine in multiple sclerosis: clinical data and real-world experience. Report of an expert meeting.

Ther Adv Neurol Disord 2018 5;11:1756286418803248. Epub 2018 Oct 5.

Center of Clinical Neuroscience, Department of Neurology, MS Center Dresden, University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany.

Prolonged-release (PR) fampridine is the only approved medication to improve walking in multiple sclerosis (MS), having been shown to produce a clinically meaningful improvement in walking ability in the subset of MS patients with Expanded Disability Status Scale 4-7. Recent responder subgroup analyses in the phase III ENHANCE study show a large effect size in terms of an increase of 20.58 points on the patient-reported 12-item MS Walking Scale in the 43% of patients classified as responders to PR-fampridine, corresponding to a standardized response mean of 1.68. Use of PR-fampridine in clinical practice varies across Europe, depending partly on whether it is reimbursed. A group of European MS experts met in June 2017 to discuss their experience with using PR-fampridine, including their views on the patient population for treatment, assessment of treatment response, re-testing and re-treatment, and stopping criteria. This article summarizes the experts' opinions on how PR-fampridine can be used in real-world clinical practice to optimize the benefits to people with MS with impaired walking ability.
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http://dx.doi.org/10.1177/1756286418803248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174649PMC
October 2018

Relation between functional connectivity and disability in multiple sclerosis: a non-linear model.

J Neurol 2018 Dec 1;265(12):2881-2892. Epub 2018 Oct 1.

Department of Human Neuroscience, Sapienza University of Rome, Viale dell'Università, 30, 00185, Rome, Italy.

Objective: To characterize the relation between brain functional connectivity and disability in patients with multiple sclerosis; to investigate the existence of critical values of both disability and functional connectivity corresponding to exhaustion of functional adaptive mechanisms.

Methods: Hundred-and-nineteen patients with no-to-severe disability and 42 healthy subjects were studied via 3T resting state functional MRI. Out of 116 regions extracted from Automated Anatomical Labeling atlas, pairs of regions whose functional connectivity correlated with Expanded Disability Status Score were identified. In patients, mathematical modeling was applied to find the best models describing Expanded-Disability-Status-Score vs structural or functional measures. Functional vs structural models intersecting points were identified.

Results: Disability had direct linear relation with lesion load (r = 0.40, p < 5E-6), inverse of thalamic volume (r = 0.31 p < 1E-3) and functional connectivity in bi-frontal pairs of regions (r > 0.40, p < 0.04), while being non-linearly associated with functional connectivity in cerebello-temporal and cerebello-frontal pairs of regions (F > 1.73, p < 0.02). Structural vs functional models intersecting points corresponded to Expanded Disability Status Score of 3.0. 85% of patients scoring more than 3.0 showed functional connectivity in cerebello-temporal and cerebello-frontal pairs of regions below confidence intervals (z = [2.28-2.88] 95% CI) measured in healthy subjects.

Conclusions: Functional brain connectivity changes may represent mechanisms of adaptation to structural damage and inflammation and may be not always clinically beneficial. Functional connectivity decreases in comparison with structural measure at Expanded Disability Status Score greater than 3.0, which may be critical and indicate exhaustion of compensatory mechanisms.
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http://dx.doi.org/10.1007/s00415-018-9075-5DOI Listing
December 2018

Comparable efficacy and safety of dimethyl fumarate and teriflunomide treatment in Relapsing-Remitting Multiple Sclerosis: an Italian real-word multicenter experience.

Ther Adv Neurol Disord 2018 10;11:1756286418796404. Epub 2018 Sep 10.

Department G. Ingrassia, Policlinico G. Rodolico, V. Santa Sofia 78, 95123, Catania, Italy.

Background: The aim of the study was to evaluate the achievement of 'no evidence of disease activity' (NEDA) over a 12-month period in a large multicenter population with relapsing remitting multiple sclerosis (RRMS) treated with delayed-release dimethyl fumarate (DMF) and teriflunomide (TRF) using a propensity-score adjustment.

Methods: A time-to-event method was used to determine the percentages of patients with RRMS (pwRRMS) in both groups achieving NEDA 3 (no relapses, no 12-week confirmed disability progression, and no new T2/gadolinium-enhancing brain lesions). We described the safety profile of the investigated drugs.

Results: Of the 587 pwRRMS treated with DMF and the 316 pwRRMS treated with TRF, 468 pwRRMS were successfully paired by propensity score: 234 on DMF and 234 on TRF. The percentages of pwRRMS who achieved NEDA 3 were 80.3% in the DMF group and 77.2% in the TRF group. Serious adverse events occurred in four (1.9%) pwRRMS on DMF and in three (1.3%) pwRRMS on TRF.

Conclusions: DMF and TRF significantly impacted RRMS disease activity in our study. Serious safety concerns were recorded in less than 2% of the studied population.
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http://dx.doi.org/10.1177/1756286418796404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131312PMC
September 2018