Publications by authors named "Giuseppe Fenu"

60 Publications

Risk of Persistent Disability in Patients With Pediatric-Onset Multiple Sclerosis.

JAMA Neurol 2021 May 3. Epub 2021 May 3.

Multiple Sclerosis Center, Gallarate Hospital, ASST Valle Olona, Gallarate (VA), Italy.

Importance: Availability of new disease-modifying therapies (DMTs) and changes of therapeutic paradigms have led to a general improvement of multiple sclerosis (MS) prognosis in adults. It is still unclear whether this improvement also involves patients with pediatric-onset MS (POMS), whose early management is more challenging.

Objective: To evaluate changes in the prognosis of POMS over time in association with changes in therapeutic and managing standards.

Design, Setting, And Participants: Retrospective, multicenter, observational study. Data were extracted and collected in May 2019 from the Italian MS Registry, a digital database including more than 59 000 patients. Inclusion criteria were MS onset before age 18 years, diagnosis before January 2014, and disease duration of at least 3 years. Exclusion criteria were primary progressive MS, Expanded Disability Status Scale (EDSS) score of at least 8 one year after onset, unavailability of diagnosis date, and less than 2 EDSS score evaluations. Eligible patients were 4704 patients with POMS. According to these criteria, we enrolled 3198 patients, excluding 1506.

Exposures: We compared time to reach disability milestones by epoch of MS diagnosis (<1993, 1993-1999, 2000-2006, and 2007-2013), adjusting for possible confounders linked to EDSS evaluations and clinical disease activity. We then analyzed the difference among the 4 diagnosis epochs regarding demographic characteristics, clinical disease activity at onset, and DMTs management.

Main Outcomes And Measures: Disability milestones were EDSS score 4.0 and 6.0, confirmed in the following clinical evaluation and in the last available visit.

Results: We enrolled 3198 patients with POMS (mean age at onset, 15.2 years; 69% female; median time to diagnosis, 3.2 years; annualized relapse rate in first 1 and 3 years, 1.3 and 0.6, respectively), with a mean (SD) follow-up of 21.8 (11.7) years. Median survival times to reach EDSS score of 4.0 and 6.0 were 31.7 and 40.5 years. The cumulative risk of reaching disability milestones gradually decreased over time, both for EDSS score of 4.0 (hazard ratio [HR], 0.70; 95% CI, 0.58-0.83 in 1993-1999; HR, 0.48; 95% CI, 0.38-0.60 in 2000-2006; and HR, 0.44; 95% CI, 0.32-0.59 in 2007-2013) and 6.0 (HR, 0.72; 95% CI, 0.57-0.90; HR, 0.44; 95% CI, 0.33-0.60; and HR, 0.30; 0.20-0.46). In later diagnosis epochs, a greater number of patients with POMS were treated with DMTs, especially high-potency drugs, that were given earlier and for a longer period. Demographic characteristics and clinical disease activity at onset did not change significantly over time.

Conclusions And Relevance: In POMS, the risk of persistent disability has been reduced by 50% to 70% in recent diagnosis epochs, probably owing to improvement in therapeutic and managing standards.
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http://dx.doi.org/10.1001/jamaneurol.2021.1008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094039PMC
May 2021

Defining the course of tumefactive multiple sclerosis: A large retrospective multicentre study.

Eur J Neurol 2021 Apr 12;28(4):1299-1307. Epub 2021 Jan 12.

Department of Clinical and Experimental Epilepsy, Queen Square, UCL Queen Square Institute of Neurology, London, UK.

Background And Purpose: Tumefactive multiple sclerosis (TuMS) (i.e., MS onset presenting with tumefactive demyelinating lesions [TDLs]) is a diagnostic and therapeutic challenge. We performed a multicentre retrospective study to describe the clinical characteristics and the prognostic factors of TuMS.

Methods: One hundred two TuMS patients were included in this retrospective study. Demographic, clinical, magnetic resonance imaging (MRI), laboratory data and treatment choices were collected.

Results: TuMS was found to affect women more than men (female:male: 2.4), with a young adulthood onset (median age: 29.5 years, range: 11-68 years, interquartile range [IQR]: 38 years). At onset, 52% of TuMS patients presented with the involvement of more than one functional system and 24.5% of them with multiple TDLs. TDLs most frequently presented with an infiltrative MRI pattern (38.7%). Cerebrospinal fluid immunoglobulin G oligoclonal bands were often demonstrated (76.6%). In 25.3% of the cases, more than one acute-phase treatment was administered, and almost one-half of the patients (46.6%) were treated with high-efficacy treatments. After a median follow-up of 2.3 years (range: 0.1-10.7 years, IQR: 3.4 years), the median Expanded Disability Status Scale (EDSS) score was 1.5 (range: 0-7, IQR: 2). Independent risk factors for reaching an EDSS score ≥3 were a higher age at onset (odds ratio [OR]: 1.08, 95% confidence interval [CI]: 1.03-1.14, p < 0.01), a higher number of TDLs (OR: 1.67, 95% CI: 1.02-2.74, p < 0.05) and the presence of infiltrative TDLs (OR: 3.34, 95% CI: 1.18-9.5, p < 0.001) at baseline.

Conclusions: The management of TuMS might be challenging because of its peculiar characteristics. Large prospective studies could help to define the clinical characteristics and the best treatment algorithms for people with TuMS.
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http://dx.doi.org/10.1111/ene.14672DOI Listing
April 2021

Seed Diversity in Two Close but Extremely Different Populations: Just a Case of Intraspecific Variability?

Plants (Basel) 2020 Nov 23;9(11). Epub 2020 Nov 23.

Department of Life and Environmental Sciences, University of Cagliari, Via Sant'Ignazio da Laconi 13, 09123 Cagliari, CA, Italy.

Analysis of the seed morphology is a widely used approach in ecological and taxonomic studies. In this context, intraspecific variability with respect to seed morphology (size, weight, and density) was assessed in two close Pau. populations sharing the same ecological conditions, except for the soil pollution distinguishing one of them. Larger and heavier seeds were found in plants growing on the heavy metal polluted site, while no differences in seed density were detected between seeds produced by plants growing on the contaminated and the control site. Moreover, seed coats and embryos varying together in their dimensions were described in the control population, while coats varying in their size independently from embryos were described in plants growing on the polluted site. Seeds from the two studied populations significantly differed in several parameters suggesting that intraspecific seed variability occurred in the case study.
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http://dx.doi.org/10.3390/plants9111625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700554PMC
November 2020

Cladribine vs other drugs in MS: Merging randomized trial with real-life data.

Neurol Neuroimmunol Neuroinflamm 2020 11 14;7(6). Epub 2020 Aug 14.

From the Department of Health Sciences (A. Signori, M.P.S.), Section of Biostatistics, University of Genoa; Department of Neurosciences (F.S., R.L., C.V.R.), Reproductive Sciences and Odontostomatology, Multiple Sclerosis Center, Federico II University, Naples; Neurological Clinic and Multiple Sclerosis Center of "AORN A.Cardarelli" (G.T.M.), Naples; Centro di Sclerosi Multipla (E.S.), II Clinica Neurologica, Università della Campania "Luigi Vanvitelli," Napoli; 2nd Neurology Unit and CRRSM (Regional Referral Multiple Sclerosis Center) (A.M.R.), Careggi University Hospital, University of Florence; Multiple Sclerosis Study Center (P.A., D.B.), ASST Valle Olona, PO di Gallarate (VA); Clinical and Biological Sciences Department (M.C.), Neurology Unit, University of Torino, San Luigi Gonzaga Hospital, Orbassano; Centro SM (E.B.), Dipartimento di Neuroscienze, Ospedale Universitario Città della Salute e della Scienza di Torino; Neurological Clinic (R.C.), Department of Experimental and Clinical Medicine, Marche Polytechnic University, Ancona; Policlinic Tor Vergata (G.M., D.L.), Rome; The Multiple Sclerosis Center of the Veneto Region (P.P.), Department of Neurosciences, University of Padua; Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences (S. Bonavita, L.L., S.E., D.I.), University of Campania Luigi Vanvitelli, Naples; Department of Clinical and Experimental Medicine (I.R.Z.), University of Sassari; Department Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (A.L.), Center of Excellence for Biomedical Research (CEBR), University of Genova; Neuroimmunology and Neuromuscular Diseases Unit (L.P.-G., V.T.C.), IRCCS Foundation Carlo Besta Neurological Institute, Milan; Centro Sclerosi Multipla ASST Papa Giovanni XXIII di Bergamo (S.L.G., B.F., V.B.); Department of Medical Science and Public Health (J.F., E.C., G.F.), University of Cagliari; Neurology Clinic (A. Sartori), Department of Medical, Surgical, and Health Sciences, University of Trieste; Multiple Sclerosis Center (S.R., C.C.), ASST Spedali Civili, PO di Montichiari (BS); Department of Medicine, Surgery and Neuroscience (M.L.S.), University of Siena; 2nd Neurology Unit and CReSM (Regional Referral Multiple Sclerosis Center) (A.D.S.), AOU San Luigi Gonzaga, Orbassano, Torino; Regina Montis Regalis Hospital (A.D.S.), Mondovì; Department of Neurology and Psychiatry (S.P.), Sapienza University, Rome; Neurologia Universitaria OORR (R.G.), Foggia; Institute of Neurology (S. Barone), University Magna Graecia of Catanzaro; Department of Neurology (C.B.), Valduce Hospital, Como; Merck Serono S.p.A. (A.V.), Rome; and IRCCS Ospedale Policlinico San Martino (A.L., M.P.S.), Genova, Italy.

Objective: Cladribine tablets were tested against placebo in randomized controlled trials (RCTs). In this study, the effectiveness of cladribine vs other approved drugs in patients with relapsing-remitting MS (RRMS) was compared by matching RCT to observational data.

Methods: Data from the pivotal trial assessing cladribine tablets vs placebo (CLARITY) were propensity score matched to data from the Italian multicenter database i-MuST. This database included 3,150 patients diagnosed between 2010 and 2018 at 24 Italian MS centers who started a disease-modifying drug. The annualized relapse rate (ARR) over 2 years from treatment start and the 24-week confirmed disability progression were compared between patients treated with cladribine and other approved drugs (interferon, glatiramer acetate, fingolimod, natalizumab, and dimethyl fumarate), with comparisons with placebo as a reference. Treatment effects were estimated by the inverse probability weighting negative binomial regression model for ARR and Cox model for disability progression. The treatment effect has also been evaluated according to baseline disease activity.

Results: All weighted baseline characteristics were well balanced between groups. All drugs tested had an effect vs placebo close to that detected in the RCT. Patients treated with cladribine had a significantly lower ARR compared with interferon (relapse ratio [RR] = 0.48; < 0.001), glatiramer acetate (RR = 0.49; < 0.001), and dimethyl fumarate (RR = 0.6; = 0.001); a similar ARR to that with fingolimod (RR = 0.74; = 0.24); and a significantly higher ARR than natalizumab (RR = 2.13; = 0.014), confirming results obtained by indirect treatment comparisons from RCTs (network meta-analyses). The relative effect of cladribine tablets 10 mg (cumulative dose 3.5 mg/kg over 2 years) was higher in patients with high disease activity vs all treatments except fingolimod and natalizumab. Effects on disability progression were largely nonsignificant, probably due to lack of power for such analysis.

Conclusion: In patients with RRMS, cladribine tablets showed lower ARR compared with matched patients who started interferon, glatiramer acetate, or dimethyl fumarate; was similar to fingolimod; and was higher than natalizumab. The beneficial effect of cladribine tablets was generally amplified in the subgroup of patients with high disease activity.

Classification Of Evidence: This study provides Class III evidence that for patients with RRMS, cladribine-treated patients had lower ARR compared with interferon, glatiramer acetate, or dimethyl fumarate; similar ARR compared with fingolimod; and higher ARR compared with natalizumab.
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http://dx.doi.org/10.1212/NXI.0000000000000878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641098PMC
November 2020

So Uncommon and so Singular, but Underexplored: An Updated Overview on Ethnobotanical Uses, Biological Properties and Phytoconstituents of Sardinian Endemic Plants.

Plants (Basel) 2020 Jul 29;9(8). Epub 2020 Jul 29.

Department of Life and Environmental Sciences, University of Cagliari, Via Sant'Ignazio da Laconi 13, 09123 Cagliari, Italy.

The last decades have recorded an increase of plant-based drug discovery processes. Indeed, natural products possess a superior chemical diversity as compared to synthetic ones, leading to a renewal in searching for new therapeutic agents from the plant kingdom. In particular, since the structural variety of natural compounds reflects the biodiversity of their source organisms, regions of the world with high biodiversity and endemism deserve particular interest. In this context, Sardinia Island (Italy), with 290 endemic taxa (12% of the total flora), is expected to provide unique and structurally diverse phytochemicals for drug development. Several research groups built up a large program dedicated to the analysis of Sardinian endemic species, highlighting their peculiar features, both in respect of phytochemical and biological profiles. On this basis, the aim of this review is to provide an up-to-date and comprehensive overview on ethnobotanical uses, biological properties and phytoconstituents of Sardinian endemic plants in order to support their beneficial potential and to provide input for future investigations. We documented 152 articles published from 1965 to June 2020 in which a broad range of biological activities and the identification of previously undescribed compounds have been reported, supporting their great value as sources of therapeutic agents.
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http://dx.doi.org/10.3390/plants9080958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465485PMC
July 2020

Multi-Platform Characterization of Cerebrospinal Fluid and Serum Metabolome of Patients Affected by Relapsing-Remitting and Primary Progressive Multiple Sclerosis.

J Clin Med 2020 Mar 21;9(3). Epub 2020 Mar 21.

Department of Biomedical Sciences, Clinical Metabolomics Unit, University of Cagliari, 09121 Cagliari, Italy.

Background: Multiple sclerosis (MS) is a chronic immunemediated disease of the central nervous system with a highly variable clinical presentation and disease progression. In this study, we investigate the metabolomics profile of patients affected by relapsing-remitting MS (RRMS)and primary progressive MS (PPMS), in order to find potential biomarkers to distinguish between the two forms.

Methods: Cerebrospinal Fluid CSF and blood samples of 34 patients (RRMS = 22, PPMS = 12) were collected. Nuclear magnetic resonance (H-NMR) and mass spectrometry (coupled with a gas chromatography and liquid chromatography) were used as analytical techniques. Subsequently, a multivariate statistical analysis was performed; the resulting significant variables underwent U-Mann-Whitney test and correction for multiple comparisons. Receiver Operating Characteristic ROC curves were built and the pathways analysis was conducted.

Results: The analysis of the serum and the CSF of the two classes, allowed the identification of several altered metabolites (lipids, biogenic amines, and amino acids). The pathways analysis indicated the following pathways were affected: Glutathione metabolism, nitrogen metabolism, glutamine-glutamate metabolism, arginine-ornithine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis etc. Conclusion: The analysis allowed the identification of a set of metabolites able to classify RRMS and PPMS patients, each of whom express different patterns of metabolites in the two biofluids.
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http://dx.doi.org/10.3390/jcm9030863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141510PMC
March 2020

The impact of modifiable risk factors on lesion burden in patients with early multiple sclerosis.

Mult Scler Relat Disord 2019 Dec 9;39:101886. Epub 2019 Dec 9.

MS Centre, Department of Medical Sciences and Public Health, University of Cagliari, Italy.

Introduction: Some studies have indicated the importance of considering smoking, vitamin D deficiency and obesity as negative prognostic factors for clinical and MRI outcomes in multiple sclerosis (MS). This study aimed to evaluate the possible effects of these modifiable risk factors on brain MRI lesion burden of patients with early MS, also exploring the influence on initial clinical features.

Methods: MS patients were enrolled at diagnosis time and examined for smoking, body mass index (BMI), serum level of lipids and 25(OH) vitamin D. Brain MRIs' were acquired and lesion volume assessed by Jim software. Clinical data (disease course, disease duration, and EDSS score) were also collected.

Results: 64 patients were enrolled, of these 4 (6.2%) had a primary progressive course. Mean age was 39.8 ± 11.1 years and mean EDSS 1.5 ± 1.1. Forty (62.5%) patients were smokers and 40 (62.5%) were overweight (BMI>25). Insufficient levels of vitamin D (<20 ng/mL) were reported in 36 (56.2%) patients, while 24 (37.5%) patients had an altered lipid profile with total cholesterol >200 mg/dl and LDL >100 mg/dl. No association between early clinical features and modifiable risk factors were reported. Multiple regression analysis showed an association between lesion burden and smoking status (p 0.003), while no association was reported with BMI, altered lipid profile and vitamin D insufficiency.

Conclusions: Several risk factors may play a role in evolution of MS. Our results show that smoking status, probably due to chronic vascular and neurotoxic effects of the cigarette components, can affect the brain damage from the early stages of MS. No association was observed with the other explored modifiable risk factors, although an effect due to the small sample size cannot be excluded.
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http://dx.doi.org/10.1016/j.msard.2019.101886DOI Listing
December 2019

Is There Any Relationship between Upper and Lower Limb Impairments in People with Multiple Sclerosis? A Kinematic Quantitative Analysis.

Mult Scler Int 2019 9;2019:9149201. Epub 2019 Oct 9.

Department of Mechanical, Chemical and Materials Engineering, University of Cagliari, Cagliari, Italy.

Background: In people with multiple sclerosis (pwMS), disability is generally assessed on the basis of ambulation abilities, whereas upper limb motor dysfunctions are less frequently considered. Nevertheless, they can severely affect the quality of life of pwMS. To date, it remains mostly unknown whether a relationship exists between upper and lower limb impairments.

Aim: To investigate the existence of a relationship between upper and lower limb impairments in pwMS based on two fundamental motor tasks, namely walking and hand-to-mouth (HTM) movement.

Methods: Twenty-eight pwMS with Expanded Disability Status Scale (EDSS) scores in the range of 1-6, and 21 healthy controls (HC) underwent a kinematic analysis of gait and HTM movement performed with a motion capture system. The spatiotemporal parameters for the two tasks were calculated and correlated using Spearman's rank correlation coefficients.

Results: The pwMS performed worse than HC on both tasks. Small to large correlations were found between the total HTM movement duration and most of the gait parameters (rho, 0.35-0.68; < 0.05).

Conclusions: Both upper and lower limb motor abilities in pwMS worsen as disability increases. Nevertheless, their relationship is only moderate. This finding emphasizes the need for specific tests to quantify disability considering the overall motor function in pwMS.
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http://dx.doi.org/10.1155/2019/9149201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6803720PMC
October 2019

Efficacy of different rituximab therapeutic strategies in patients with neuromyelitis optica spectrum disorders.

Mult Scler Relat Disord 2019 Nov 4;36:101430. Epub 2019 Oct 4.

Ospedale Policlinico San Martino - IRCCS, Genoa, Italy; Department of Health Sciences (DISSAL), Section of Biostatistics, University of Genova, Genova, Italy. Electronic address:

Objective: To evaluate disease activity according to rituximab (RTX) induction and maintenance regimens in a multicenter real-life dataset of NMOSD patients.

Methods: This is an observational-retrospective multicentre study including patients with NMOSD treated with RTX in 21 Italian and 1 Swiss centers. Demographics, relapse rate and adverse events over the follow-up were summarized taking into account induction strategy (two-1 g infusions at a 15-day interval (IND-A) vs. 375 mg/m2/week infusions for one month (IND-B)) and maintenance therapy (regimen A (M-A) with fixed time-points infusions vs. regimen B (M-B) based on cytofluorimetric driven reinfusion regimens, the least further subdivided according to CD19+ B cells (M-B1) or CD27+ memory B cells (M-B2) monitoring).

Results: 131 subjects were enrolled, 127 patients completed the induction regimen and 119 patients had at least one follow-up visit and were included in the outcome analysis. Median follow-up was 1.7 years (range 0.1-11.6). Annualized relapse rate (ARR) was 1.7 in the year before RTX start and decreased to 0.19 during the follow-up. Both ARR and Time to first relapse (TTFR) analysis showed a trend toward an increased disease activity for IND-B and M-A. No patients with MT-B2 experienced relapses during the follow-up. Number of relapses in the year before RTX initiation and having received a previous treatment were significantly associated with higher ARR and reduced TTFR in the multivariate analysis.

Interpretation: We confirm RTX efficacy in NMOSD patients. Use of specific induction and maintenance protocols is warranted in order to foster RTX efficacy and to reduce costs and side effects.
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http://dx.doi.org/10.1016/j.msard.2019.101430DOI Listing
November 2019

Treatment of multiple sclerosis with rituximab: A multicentric Italian-Swiss experience.

Mult Scler 2020 10 1;26(12):1519-1531. Epub 2019 Oct 1.

SCDO Neurologia e Centro di Riferimento Regionale Sclerosi Multipla, AOU San Luigi, Orbassano, Italy.

Background: Rituximab, an anti-CD20 monoclonal antibody leading to B lymphocyte depletion, is increasingly used as an off-label treatment option for multiple sclerosis (MS).

Objective: To investigate the effectiveness and safety of rituximab in relapsing-remitting (RR) and progressive MS.

Methods: This is a multicenter, retrospective study on consecutive MS patients treated off-label with rituximab in 22 Italian and 1 Swiss MS centers. Relapse rate, time to first relapse, Expanded Disability Status Scale (EDSS) progression, incidence of adverse events, and radiological outcomes from 2009 to 2019 were analyzed.

Results: A total of 355/451 enrolled subjects had at least one follow-up visit and were included in the outcome analysis. Annualized relapse rate significantly decreases after rituximab initiation versus the pre-rituximab start year in RRMS (from 0.86 to 0.09,  < .0001) and in secondary-progressive (SP) MS (from 0.34 to 0.06,  < .0001) and had a slight decrease in primary-progressive (PP) MS patients (from 0.12 to 0.07,  = 0.45). After 3 years from rituximab start, the proportion of patients with a confirmed EDSS progression was 14.6% in the RRMS group, 24.7% in the SPMS group, and 41.5% in the PPMS group. No major safety concerns arose.

Conclusion: Consistently with other observational studies, our data show effectiveness of rituximab in reducing disease activity in patients with MS.
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http://dx.doi.org/10.1177/1352458519872889DOI Listing
October 2020

Outcomes after fingolimod to alemtuzumab treatment shift in relapsing-remitting MS patients: a multicentre cohort study.

J Neurol 2019 Oct 17;266(10):2440-2446. Epub 2019 Jun 17.

Department of Medical Sciences and Public Health, Multiple Sclerosis Centre, University of Cagliari-ATS Sardegna, Via Is Guadazzonis 2, 09126, Cagliari, Italy.

Background: A high reactivation of multiple sclerosis (MS) was reported in patients treated with alemtuzumab after fingolimod. We aimed to understand whether this shift enhanced the risk for reactivation in a real-life cohort.

Methods: Subjects with relapsing MS, shifting from fingolimod to alemtuzumab were enrolled. We collected the following data: age, sex, disease duration, relapses after fingolimod withdrawal, new T2/gadolinium (Gd)-enhancing lesions in the last magnetic resonance imaging (MRI) during fingolimod and in the first, while on alemtuzumab, lymphocyte counts at alemtuzumab start, and Expanded Disability Status Scale (EDSS) before and after alemtuzumab.

Results: We enrolled 77 patients (women 61 (79%); mean age 36.2 years (SD 9.6), and disease duration 12.3 years (SD 6.8) at fingolimod discontinuation; median washout 1.8 months). The annualised relapse rate was 0.89 during fingolimod, 1.32 during washout, and 0.15 after alemtuzumab (p = 0.001). The EDSS changed from a median of 3 (IQR 2-4) at the end of fingolimod to 2.5 after alemtuzumab (IQR 1.5-4) (p = 0.013). The washout length and the lymphocyte count before alemtuzumab were not associated with EDSS change after alemtuzumab (p = 0.59 and p = 0.33, respectively). MRI activity decreased after alemtuzumab compared to that during fingolimod (p = 0.001). At alemtuzumab start, lymphocyte counts were < 0.8 × 10/mL in 21 patients.

Conclusions: In our cohort, alemtuzumab reduced relapse, new T2/Gd-enhancing lesions, and EDSS score, as compared to the previous periods (fingolimod/washout). These results were not related to washout length or lymphocyte counts. Therefore, a rapid initiation of alemtuzumab after fingolimod does not seem to be a risk factor for MS reactivation.
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http://dx.doi.org/10.1007/s00415-019-09424-8DOI Listing
October 2019

An early evaluation of translocation actions for endangered plant species on Mediterranean islands.

Plant Divers 2019 Apr 21;41(2):94-104. Epub 2019 Mar 21.

Mediterranean Plant Specialist Group (IUCN/SSC), Switzerland.

conservation is widely considered a primary conservation strategy. Plant translocation, specifically, represents an important tool for reducing the extinction risk of threatened species. However, thus far, few documented translocations have been carried out in the Mediterranean islands. The Care-Mediflora project, carried out on six Mediterranean islands, tackles both short- and long-term needs for the insular endangered plants through and conservation actions. The project approach is based on using activities as a tool to improve conservation of threatened plant species. Fifty island plants (representing 45 taxa) were selected for translocations using common criteria. During the translocations, several approaches were used, which differed in site selection method, origin of genetic material, type of propagative material, planting method, and more. Although only preliminary data are available, some general lessons can be learned from the experience of the Care-Mediflora project. Among the factors restricting the implementation of translocations, limited financial resources appear to be the most important. Specific preliminary management actions, sometimes to be reiterated after translocation, increase the overall cost, but often are necessary for translocation success. Translocation using juvenile/reproductive plants produces better results over the short term, although seeds may provide good results over the long run (to be assessed in the future). Regardless, plant translocation success can only be detected over long periods; therefore, proper evaluation of plant translocations requires a long-term monitoring protocol. Care-Mediflora project represents the first attempt to combine the existing approaches in a common plant conservation strategy specifically focusing on the Mediterranean islands.
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http://dx.doi.org/10.1016/j.pld.2019.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520489PMC
April 2019

Phylogenetically informed spatial planning as a tool to prioritise areas for threatened plant conservation within a Mediterranean biodiversity hotspot.

Sci Total Environ 2019 May 11;665:1046-1052. Epub 2019 Feb 11.

Department of Agricultural and Environmental Sciences - Production, Landscape, Agroenergy, University of Milan, Milan, Italy.

Global plant diversity is at risk due to anthropogenic changes to ecosystems, but given severely limited conservation resources, a reliable prioritisation strategy for species and sites is needed. Our objective was to identify key areas for conserving the phylogenetic diversity (PD) of threatened vascular plants in Italy, one of the most species-rich regions in the Mediterranean Basin. We used spatial data and the conservation status of 995 threatened vascular plants and applied a phylogenetically informed spatial planning to minimize conservation costs. We then determined the degree of overlap with existing protected areas and evaluated whether this PD-based prioritisation of areas provides adequate protection for threatened phylogenetically distinctive species (EDGE). The cost-effective procedure identified as priority for conservation 12% of the study territory, while achieving over 90% of conservation targets (total PD). We showed that priority areas and protected areas are moderately spatially mismatched. We also showed that not all top-EDGE species were met by the procedure applied, hence we conclude that the PD-based model indicated key areas for protection, but nevertheless additional attention is needed to protect top-EDGE species. This study represents one of the most comprehensive analyses, to date, for the conservation of the native flora in the Mediterranean, incorporating both spatial distribution and evolutionary relationships. Our work on the prioritisation of threatened plant species across Italy can serve as a guide for future conservation applications.
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http://dx.doi.org/10.1016/j.scitotenv.2019.02.127DOI Listing
May 2019

Efficacy and safety of alemtuzumab in a real-life cohort of patients with multiple sclerosis.

J Neurol 2019 Jun 12;266(6):1405-1411. Epub 2019 Mar 12.

Multiple Sclerosis Center, University of Cagliari/ATS Sardegna, Via Is Guadazzonis, 2, 09126, Cagliari, Italy.

Background: No postmarketing randomised clinical trials are available about alemtuzumab, and real-world data are limited. We aimed to analyse the efficacy and safety of alemtuzumab in a single-centre cohort of patients with relapsing-remitting MS.

Methods: Patients who took alemtuzumab were enrolled. We collected the following data: age, sex, MS history, expanded disability status scale (EDSS), relapses, magnetic resonance imaging (MRI) parameters after alemtuzumab, and adverse events. EDSS scores before alemtuzumab and at the last follow-up were compared by Wilcoxon test. Time to first relapse was analysed after dividing the cohort on the basis of previous treatment.

Results: Ninety patients were enrolled [women 74.4%; naïve 7; mean follow-up 27 months (SD 23)]. The EDSS was reduced from a median of 2.5 (IQR 1.5-4) before alemtuzumab to 2.0 (IQR 1.5-3.5) after (p = 0.025). The time to first relapse was shorter in patients shifting from a second-line therapy (p = 0.011). Over 2 years, 43.7% had no evidence of disease activity. We observed infusion-related reactions in 95.5% patients, including 11.1% with pneumonitis, thyroiditis in 11%, and thrombocytopenia in 3.3%.

Conclusions: We confirmed the clinical and MRI efficacy of alemtuzumab in the clinical setting and the frequency of infusion-related reactions. Compared with that in clinical trials, higher number of patients developed pneumonitis during infusion.
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http://dx.doi.org/10.1007/s00415-019-09272-6DOI Listing
June 2019

Assessing the Metabolomic Profile of Multiple Sclerosis Patients Treated with Interferon Beta 1a by H-NMR Spectroscopy.

Neurotherapeutics 2019 07;16(3):797-807

Multiple Sclerosis Centre, Department of Medical Sciences and Public Health, Binaghi Hospital, University of Cagliari, via Is Guadazzonis 2, 09126, Cagliari, Italy.

Metabolomic research has emerged as a promising approach to identify potential biomarkers in multiple sclerosis (MS). The aim of the present study was to determine the effect of interferon beta (IFN ß) on the metabolome of MS patients to explore possible biomarkers of disease activity and therapeutic response. Twenty-one MS patients starting IFN ß therapy (Rebif® 44 μg; s.c. 3 times per week) were enrolled. Blood samples were obtained at baseline and after 6, 12, and 24 months of IFN ß treatment and were analyzed by high-resolution nuclear magnetic resonance spectroscopy. Changes in metabolites were analyzed. After IFN ß exposure, patients  were divided into responders and nonresponders according to the "no evidence of disease activity" (NEDA-3) definition (absence of relapses, disability progression, and magnetic resonance imaging activity), and samples obtained at baseline were analyzed to evaluate the presence of metabolic differences predictive of IFN ß response. The results of the investigation demonstrated differential distribution of baseline samples compared to those obtained during IFN ß exposure, particularly after 24 months of treatment (RX = 0.812, RY = 0.797, Q = 0.613, p = 0.003). In addition, differences in the baseline metabolome between responder and nonresponder patients with respect to lactate, acetone, 3-OH-butyrate, tryptophan, citrate, lysine, and glucose levels were found (RX = 0.442, RY = 0.768, Q = 0.532, p = 0.01). In conclusion, a metabolomic approach appears to be a promising, noninvasive tool that could potentially contribute to predicting the efficacy of MS therapies.
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http://dx.doi.org/10.1007/s13311-019-00721-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694336PMC
July 2019

Quantifying gait impairment in individuals affected by Charcot-Marie-Tooth disease: the usefulness of gait profile score and gait variable score.

Disabil Rehabil 2020 03 18;42(5):737-742. Epub 2018 Oct 18.

Centro Sclerosi Multipla, Department of Medical Science and Public Health, University of Cagliari, Cagliari, Italy.

Gait analysis is a reliable tool to characterise ambulation in Charcot-Marie-Tooth, the obtained are complex data makes its use scarce in clinical practice. The use of synthetic measures may enable the clinician to easily interpret gait kinematics in Charcot-Marie-Tooth. To test the usefulness of Gait Profile Score as a method to quantify and monitor kinematic gait alterations in Charcot-Marie-Tooth. A group of patients with Charcot-Marie-Tooth and a control group underwent Gait Analysis. Neurological impairment was evaluated by means of the Charcot Marie Tooth neuropathy score in his original form and in the Rasch Analysis revised form. Differences in Kinematics scores induced by the pathology were assessed using the Mann-Whitney U test. The relationship between gait parameters and Charcot Marie Tooth neuropathy score was assessed by means of the Spearman correlation. Twenty patients were enrolled. Mann-Whitney U test revealed a significant effect of the pathology on Gait Profile Score (p < 0.001). Charcot Marie Tooth neuropathy score was positively correlated with Gait Profile Score (Rho = 0.708, p = 0.001). Gait profile score can differentiate Charcot Marie Tooth from unaffected people and to quantify ambulation impairment, also identifying the joints more affected by the disease.Implications for rehabilitationPhysiotherapy and orthotics constitute the sole possible clinical approach for Charcot Marie Tooth, but the clinical scales are scarcely effective for assessing the rehabilitative outcome.Synthetic measures are able to summarize Charcot Marie tooth kinematics in a single score, and Gait Profile Score is able to differentiate patients with Charcot Marie tooth from healthy controls.Gait Profile Score is related to clinical disability as measured by the Charcot Marie tooth neuropathy score.
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http://dx.doi.org/10.1080/09638288.2018.1506946DOI Listing
March 2020

Association between brain atrophy and cognitive motor interference in multiple sclerosis.

Mult Scler Relat Disord 2018 Oct 31;25:208-211. Epub 2018 Jul 31.

Multiple Sclerosis Center, Department of Medical Science and Public Health, University of Cagliari, Via Is Guadazzonis 2, Cagliari 09126, Italy.

Introduction: Cognitive motor interference (CMI) is performance impairment due to simultaneuous task execution and is measured using the dual task cost (DTC). No pathological feature of MS has to date been associated with CMI.

Aim: To assess the relationship between brain volumes and CMI, as measured using the DTC, in a cross-sectional study.

Methods: A group of persons with MS (pwMS) and an age- and sex-matched healthy control (HC) group underwent 3D gait analysis during using the dual task paradigm. Brain volumes were measured on T1-weighted gradient echo scans using SIENAX software. The relationships between brain volumes and the DTCs of spatial temporal parameters were evaluated using Pearson correlation. A multiple regression model was used to evaluate the ability to predict the DTC of cadence based on brain volume and grey matter (GM) volume.

Results: Forty-four patients and 16 HCs underwent MRI and gait analysis. The mean expanded disability status scale (EDSS) was 2.4 ± 1.5. Significant relationships between brain volumes and DTC were found only in the pwMS group, with higher rho scores for the DTC of mean velocity, DTC of cadence, and DTC of stride time. A statistically significant regression equation with an R value of 0.684 was found using GM and Z-score on the Stroop test as predictors of the DTC of cadence (p < 0.001).

Conclusion: Brain atrophy, especially than in the GM, is a major determinant of DTC, although other pathological markers also contribute to CMI in patients with MS.
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http://dx.doi.org/10.1016/j.msard.2018.07.045DOI Listing
October 2018

Determinants of therapy switch in multiple sclerosis treatment-naïve patients: A real-life study.

Mult Scler 2019 08 25;25(9):1263-1272. Epub 2018 Jul 25.

2nd Neurology Unit and CRRSM (Regional Referral Multiple Sclerosis Center), AOU San Luigi Gonzaga, Torino, Italy; Regina Montis Regalis Hospital, Mondovì, Italy.

Background: With many options now available, first therapy choice is challenging in multiple sclerosis (MS) and depends mainly on neurologist and patient preferences.

Objectives: To identify prognostic factors for early switch after first therapy choice.

Methods: Newly diagnosed relapsing-remitting MS patients from 24 Italian centers were included. We evaluated the association of baseline demographics, clinical, and magnetic resonance imaging (MRI) data to the switch probability for lack of efficacy or intolerance/safety with a multivariate Cox analysis and estimated switch rates by competing risks models.

Results: We enrolled 3025 patients. The overall switch frequency was 48% after 3 years. Switch risk for lack of efficacy was lower with fingolimod (hazard ratio (HR) = 0.50;  = 0.009), natalizumab (HR = 0.13;  < 0.001), dimethyl-fumarate (HR = 0.60;  = 0.037), teriflunomide (HR = 0.21;  = 0.031) as compared to interferons. Younger age (HR = 0.96;  < 0.001), diagnosis delay (HR = 1.23;  = 0.021), higher baseline Expanded Disability Status Scale (HR = 1.17;  = 0.001), and spinal cord lesions (HR = 1.46;  = 0.001) were independently associated with higher inefficacy switch rates. We found lower switch for intolerance/safety with glatiramer acetate (HR = 0.61;  = 0.001), fingolimod (HR = 0.35;  = 0.002), and dimethyl-fumarate (HR = 0.57;  = 0.022) as compared to interferons, while it increased with natalizumab (HR = 1.43;  = 0.022). Comorbidities were associated with intolerance switch (HR = 1.28;  = 0.047).

Conclusion: Several factors are associated with higher switch risk in patients starting a first-line therapy and could be integrated in the decision-making process of first treatment choice.
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http://dx.doi.org/10.1177/1352458518790390DOI Listing
August 2019

Estimating land market values from real estate offers: A replicable method in support of biodiversity conservation strategies.

Ambio 2019 Mar 10;48(3):313-323. Epub 2018 Jul 10.

Centro Conservazione Biodiversità (CCB), Dipartimento di Scienze della Vita e dell'Ambiente, Università degli Studi di Cagliari, Viale Sant'Ignazio da Laconi 13, 09123, Cagliari, Italy.

While cost estimation is a very positive tool for spatial conservation prioritisation, there are few examples where costs (in monetary terms) are applied. We present a repeatable method to estimate and map field values in monetary terms using common correlative models. We modelled, with a resolution of 1 km, the information obtained by several real estate's agencies with a set of eleven environmental, climatic, and anthropogenic variables. Land cover was the main influencing factor, but further variables were affecting bids on field sales according to the socio-economic specificity of each administrative province. The estimated values were related to endemic plant species richness, their conservation status and altitudinal ranges. Richest areas in endemics have lower values given current market conditions and, within these endemic rich areas, values near the coast were generally higher than the rest of endemic-rich territories. Despite their limits, our method offers an alternative perspective on the challenges of simplifying the extrapolation of useful information for planning and disseminating the conservation of many ecosystem services providers.
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http://dx.doi.org/10.1007/s13280-018-1074-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374228PMC
March 2019

Does focal inflammation have an impact on cognition in multiple sclerosis? An MRI study.

Mult Scler Relat Disord 2018 Jul 16;23:83-87. Epub 2018 May 16.

Multiple Sclerosis Centre, Binaghi Hospital, Department of medical sciences and public health, University of Cagliari, Cagliari, 09126, Italy.

Objective: Cognitive impairment concerns a significant percentage of patients with multiple sclerosis (MS). A transient impairment of cognition with a simultaneous presence of non-symptomatic gadolinium (Gd)-enhancing lesions in patients with MS was previously described. Our study aimed to evaluate modifications in cognitive function before and after the occurrence of asymptomatic MRI gadolinium (Gd)-enhancing lesions in relapsing MS patients.

Patients And Methods: All patients underwent a neuropsychological evaluation before (30-60 days) and after (30-60 days) brain MRI with Gd administration. Patients were classified as Gd positive (presence of enhancing-lesions) and Gd negative (absence of enhancing-lesions). We also recruited a healthy controls group underwent to the same neuropsychological assessment for two times with the same timing of MS patients.

Results: We included 84 relapsing-remitting patients and 40 healthy controls. Brain MRI results showed that 14/84 (16.7%) patients had asymptomatic Gd-enhancing-lesion. No significant variation in cognitive performance between baseline and follow-up was observed in patients with or without MRI-enhancing lesions. However, an increase between baseline and follow-up was observed in the mean scores of the Symbol Digit Modality Test (41.9 at baseline versus 46.7 at follow-up, p :< 0.001). This increase was significantly lower in Gd positive patients compared to Gd negative patients (mean increase 1.1 in Gd positive versus 4.9 in Gd negative, p: < 0.001) and to healthy controls groups (mean increase 7.2; p < 0.001) CONCLUSIONS: In our study, the absence of a practice effect in Gd positive compared to Gd negative patients and to healthy controls suggests a possible role of focal inflammation on cognitive function of MS patients.
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http://dx.doi.org/10.1016/j.msard.2018.05.012DOI Listing
July 2018

A cross-sectional and longitudinal study evaluating brain volumes, RNFL, and cognitive functions in MS patients and healthy controls.

BMC Neurol 2018 May 11;18(1):67. Epub 2018 May 11.

Multiple Sclerosis Center Binaghi Hospital, Department of Medical Sciences and Public Health, University of Cagliari, via Is Guadazzonis 2, 09126, Cagliari, Italy.

Background: The principal biomarker of neurodegeneration in multiple sclerosis (MS) is believed to be brain volume, which is associated with cognitive functions and retinal nerve fibre layer (RNFL). A cross-sectional and longitudinal assessment of the relationship between RNFL, cognitive functions and brain volume.

Methods: At baseline, relapsing patients and healthy controls underwent 1.5 T MRI to estimate the normalized volume of brain (NBV), grey (NGV), white (NWV) and peripheral grey (pNGV) matter. Cognitive functions were evaluated by BICAMS, RNFL by Spectral-Domain OCT. Patients were re-evaluated after 12 months.

Results: Cognitive functions, brain volume, and RNFL differed between the group of 66 patients and that of 16 healthy controls. In the MS group, at baseline, an association was found between: p-NGV and symbol-digit (SDMT) (p = 0.022); temporal-RNFL and NBV (p = 0.007), NWV (p = 0.012), NGV (p = 0.048), and p-NGV (p = 0.021); papillo-macular bundle-RNFL and NBV (p = 0.013), NWV (p = 0.02), NGV (p = 0.049), and p-NGV (p = 0.032). Over the observational period, we found a reduction of brain volume (p < 0.001), average-RNFL (p = 0.001), temporal-RNFL (p = 0.006), and papillo-macular bundle-RNFL (p = 0.009). No association was found between OCT, MRI, and cognitive changes.

Conclusions: Brain volume, cognitive functions, and RNFL are continuous measures of different neurodegenerative aspects. BICAMS and OCT have low costs and can be easily used in clinical practice to monitor neurodegeneration.
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http://dx.doi.org/10.1186/s12883-018-1065-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946463PMC
May 2018

New horizons for multiple sclerosis therapeutics: milestones in the development of ocrelizumab.

Neuropsychiatr Dis Treat 2018 23;14:1093-1099. Epub 2018 Apr 23.

Multiple Sclerosis Center Binaghi Hospital, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.

Multiple Sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system, and both T and B cells are involved in its pathogenesis. The vast majority of disease-modifying drugs used for MS act on the inflammatory component of the disease and are approved for use in relapsing-remitting (RR) patients. Ocrelizumab (OCR) is the only MS drug that has been approved by the US Food and Drug Administration (FDA) not only for patients with RRMS but also for patients with primary progressive (PP) MS. OCR is a humanized anti-CD20 monoclonal antibody that can deplete the targeted B cells through antibody-dependent cellular cytotoxicity. Treatment involves administration by intravenous infusion every 6 months. OCR can cause long-lasting B-cell depletion and change the pool of reconstituted B cells. Phase III clinical trials have confirmed the results of previous Phase II studies. In particular, OPERA I and II trials, which were performed in patients with RRMS, showed a reduction in the annualized relapse rate, the risk of disability progression, and the number of new/enlarging T2 lesions and enhancing lesions measured using brain magnetic resonance. The ORATORIO trial, performed in PP subjects, showed that OCR can reduce disability progression, improve performance on the timed 25-foot walk, and decrease the total volume of T2 lesions and the mean number of new or enlarging T2 lesions. The most frequent adverse events were the infusion-related reactions and infections. Infections were mostly nasopharyngitis, as well as upper respiratory and urinary tract infections. OCR gives no indication for severe or opportunistic infections. There is not a clear increased risk of malignancies. Nevertheless, it could not be excluded. Real-life registries will provide more information about the long-term safety, the risk of exposure during pregnancy, and the risk of rare adverse events. In this review, we analyze the evidence regarding the efficacy and the safety of OCR.
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http://dx.doi.org/10.2147/NDT.S147874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922247PMC
April 2018

The impact of climatic variations on the reproductive success of Gentiana lutea L. in a Mediterranean mountain area.

Int J Biometeorol 2018 Jul 30;62(7):1283-1295. Epub 2018 Mar 30.

Centro Conservazione Biodiversità, Dipartimento di Scienze della Vita e dell'Ambiente, Università degli Studi di Cagliari, Viale S. Ignazio da Laconi, 13, 09123, Cagliari, Italy.

Increases in temperature have been predicted and reported for the Mediterranean mountain ranges due to global warming and this phenomenon is expected to have profound consequences on biodiversity and ecosystem functioning. We hereby present the case of Gentiana lutea L. subsp. lutea, a rhizomatous long-lived plant living in Central-Southern Europe, which is at the edge of its ecological and distributional range in Sardinia. Concretely, we analysed the reproductive success experienced during three phenological cycles (2013/2014, 2014/2015 and 2015/2016) in four representative populations, with particular attention to the phenological cycle of 2014/2015, which has been recorded as one of the warmest periods of the last decades. The Smirnov-Grubbs test was used to evaluate differences in temperature and precipitation regimes among historical data and the analysed years, while the Kruskal-Wallis followed by the Wilcoxon test was used to measure differences between anthesis and reproductive performances among cycles and populations. In addition, generalised linear models were carried out to check relationships between climate variables and reproductive performance. Significant differences among climate variables and analysed cycles were highlighted, especially for maximum and mean temperatures. Such variations determined a non-flowering stage in two of the four analysed populations in 2014/2015 and significant differences of further five reproductive traits among cycles. These results confirmed that in current unstable climatic conditions, which are particularly evident in seasonal climates, reproductive success can be a sensitive and easily observable indicator of climatic anomalies. Considering the importance of this issue and the ease and cost-effectiveness of reproductive success monitoring, we argue that research in this sense can be a supporting tool for the enhancement of future crucial targets such as biodiversity conservation and the mitigation of global warming effects.
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http://dx.doi.org/10.1007/s00484-018-1533-3DOI Listing
July 2018

Fatigue, as measured using the Modified Fatigue Impact Scale, is a predictor of processing speed improvement induced by exercise in patients with multiple sclerosis: data from a randomized controlled trial.

J Neurol 2018 Jun 24;265(6):1328-1333. Epub 2018 Mar 24.

Department of Medical Sciences and Public Health, Multiple Sclerosis Center, University of Cagliari, Cagliari, Italy.

Background: Few studies have evaluated the impact of physical activity (PA) on cognition and fatigue, and none have considered the effects of PA on the relationship between cognition and fatigue.

Objectives: We evaluated the effect of PA in people with multiple sclerosis (pwMS) in a 6-month-long single-blind randomized controlled trial. We focused on the impact of exercise on cognition, fatigue, and the relationship between cognition and fatigue.

Methods: We recruited pwMS, who were then randomly assigned 1:1 to either a PA protocol group or a control group (CG). All patients underwent assessments using the Brief International Cognitive Assessment for Multiple Sclerosis including symbol digit modality test (SDMT), Berg Balance Scale (BBS), gait analysis, 6-Minute Walk Test, Timed Up and Go (TUG) test, and the Modified Fatigue Impact Scale (MFIS) at the beginning of the study (T0), at the end of the study (EOS) 24 weeks after T0, and at 24 weeks following the EOS (FU).

Results: A Wilcoxon test revealed a significant effect of exercise in the PA group, but not in the CG. Significant differences between T0 and EOS were found in the spatiotemporal parameters of gait, and performance on the SDMT, TUG, BBS, and MFIS. These differences were also present during the FU period. A regression model revealed that the baseline MFIS score predicted processing speed improvement (R = 0.65, p < 0.01), as the SDMT T score increased by 0.3 for each one-unit increase in the MFIS score at T0.

Conclusion: PA affects multiple aspects of the pathology in pwMS. Patients with greater fatigue must not be discouraged from exercise, as they may greatly benefit from PA. Specifically, PA was shown to improve information processing speed.
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http://dx.doi.org/10.1007/s00415-018-8836-5DOI Listing
June 2018

Autoimmune comorbidities in multiple sclerosis: what is the influence on brain volumes? A case-control MRI study.

J Neurol 2018 May 5;265(5):1096-1101. Epub 2018 Mar 5.

Department of Medical Sciences and Public Health, Multiple Sclerosis Center, Binaghi Hospital, ATS Sardegna, University of Cagliari, via Is Guadazzonis 2, 09126, Cagliari, Italy.

Background: Several studies indicated that multiple sclerosis (MS) is frequently associated with other autoimmune diseases. However, it is little known if the coexistence of these conditions may influence the radiologic features of MS, and in particular the brain volumes.

Objectives: To evaluate the effect of autoimmune comorbidities on brain atrophy in a large case-control MS population.

Methods: A group of MS patients affected by a second autoimmune disorder, and a control MS group without any comorbidity, were recruited. Patients underwent a brain MRI and volumes of whole brain (WB), white matter (WM), and gray matter (GM) with cortical GM were estimated by SIENAX.

Results: The sample included 286 MS patients, of which 30 (10.5%) subjects with type 1 diabetes (T1D), 53 (18.5%) with autoimmune thyroiditis (AT) and 4 (0.1%) with celiac disease. Multiple regression analysis found an association between T1D and lower GM (p = 0.038) and cortical GM (p = 0.036) volumes, independent from MS clinical features and related to T1D duration (p < 0.01), while no association was observed with AT and celiac disease.

Conclusions: Our data support the importance of considering T1D as possible factors influencing the brain atrophy in MS. Further studies are needed to confirm our data and to clarify the underlying mechanisms.
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http://dx.doi.org/10.1007/s00415-018-8811-1DOI Listing
May 2018

Exploring cognitive motor interference in multiple sclerosis by the visual Stroop test.

Mult Scler Relat Disord 2018 May 24;22:8-11. Epub 2018 Feb 24.

Department of Mechanical, Chemical and Materials Engineering, University of Cagliari, Cagliari, Italy. Electronic address:

Background: The dual task paradigm (the simultaneous performance of motor and cognitive task) is used in a laboratory setting to evaluate walking impairments that affect patients' daily lives. Although promising, it is poorly standardized and neither the cognitive task nor the motor task have been validated in a matched healthy control group (HC) for multiple sclerosis (MS).

Objective: Our aim was to set up a standardized instrument to evaluate cognitive motor interference in MS using the interference test par excellence: the stroop colour word test (SCWT).

Methods: Patients with MS and HC underwent 3D gait analysis with a dual task protocol, using the SCWT as a cognitive task. Gait performance impairment during the dual task was evaluated by dual task cost (DTC). A MANOVA was used to verify the effect of status (MS, HC) on DTC, calculated for the spatiotemporal parameter of the gait.

Results: In MS, the DTC was higher for the following gait parameters: speed (p = .013), cadence (p = .004), stride time (p = .005) stance phase (p < .001), and swing phase duration (p = .032).

Conclusion: DTC is present in MS and HC, but the motor cost in MS is higher. The present work provides a useful and validated basis for future studies about cognitive motor interference in MS.
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http://dx.doi.org/10.1016/j.msard.2018.02.026DOI Listing
May 2018

The impact of visible and invisible symptoms on employment status, work and social functioning in Multiple Sclerosis.

Work 2018 ;60(2):263-270

Department of Medical Sciences and Public Health, Multiple Sclerosis Centre, University of Cagliari, Sardinia, Italy.

Background: Frequently diagnosed in young adulthood, multiple sclerosis (MS) and several MS-related factors can influence patients' unemployment status and negatively affect work productivity and daily functioning.

Objective: We examined MS patients' employment status and evaluated clinical features influencing it. Furthermore, we investigated patients' burdens due to visible and invisible MS symptoms through their worsening daily functioning.

Methods: The study included outpatients affected by MS according to the 2010 McDonald criteria. The co-occurrence of invisible symptoms (fatigue, depression and apathy) was stated using validated, self-administered tools: Fatigue Severity Scale (FSS); Beck Depression Inventory-Second Edition (BDI-II); Apathy Evaluation Scale (AES). Impairment in daily functioning due to MS was assessed using the Work and Social Adjustment Scale (WSAS). Descriptive statistics, hierarchical regression analyses, Pearson's correlation, and the t-test were conducted.

Results: Of the 123 participants, 52 (42.3%) were unemployed. Results showed employment to be positively associated with higher education levels (p 0.01); female gender (p 0.03) and higher disability (p 0.02) showed negative associations with employment. No associations were found between employment and fatigue or clinically relevant depressive and apathetic symptoms. High correlations were found between WSAS score and Expanded Disability Status Scale score (r = 565, p < 0.001), BDI-II score (r = 588, p < 0.001), and FSS score (r = 545, p < 0.001).

Conclusion: Our study revealed physical disability's significance in determining MS patients' unemployment. Alternatively, invisible MS symptoms negatively affected principally patients' social lives. Therefore, programs should be designed to improve MS patients' work integration and daily activities.
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http://dx.doi.org/10.3233/WOR-182682DOI Listing
January 2019

Long-term follow-up of pediatric MS patients starting treatment with injectable first-line agents: A multicentre, Italian, retrospective, observational study.

Mult Scler 2019 03 24;25(3):399-407. Epub 2018 Jan 24.

Multiple Sclerosis Study Center, Gallarate Hospital, ASST Valle Olona, Via Eusebio Pastori 4, 21013 Gallarate, Italy.

Background: Few data are available on very long-term follow-up of pediatric multiple sclerosis (MS) patients treated with disease modifying treatments (DMTs).

Objectives: To present a long-term follow-up of a cohort of Pediatric-MS patients starting injectable first-line agents.

Methods: Data regarding treatments, annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS) score, and serious adverse event were collected. Baseline characteristics were tested in multivariate analysis to identify predictors of disease evolution.

Results: In total, 97 patients were followed for 12.5 ± 3.3 years. They started therapy at 13.9 ± 2.1 years, 88 with interferons and 9 with copaxone. During the whole follow-up, 82 patients changed therapy, switching to immunosuppressors/second-line treatment in 58% of cases. Compared to pre-treatment phase, the ARR was significantly reduced during the first treatment (from 3.2 ± 2.6 to 0.7 ± 1.5, p < 0.001), and it remained low during the whole follow-up (0.3 ± 0.2, p < 0.001). At last observation, 40% had disability worsening, but EDSS score remained <4 in 89%. One patient died at age of 23 years due to MS. One case of natalizumab-related progressive multifocal encephalopathy (PML) was recorded. Starting therapy before 12 years of age resulted in a better course of disease in multivariate analysis.

Conclusion: Pediatric-MS patients benefited from interferons/copaxone, but the majority had to switch to more powerful drugs. Starting therapy before 12 years of age could lead to a more favorable outcome.
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http://dx.doi.org/10.1177/1352458518754364DOI Listing
March 2019

Pulse steroid therapy in multiple sclerosis and mood changes: An exploratory prospective study.

Mult Scler Relat Disord 2018 Feb 31;20:104-108. Epub 2018 Jan 31.

Multiple Sclerosis Center, Binaghi Hospital, ATS Sardegna, Department of Medical Sciences and Public Health, University of Cagliari, via Is Guadazzonis, 2, 09126 Cagliari, Italy.

Background: Several reports suggest a higher risk of psychiatric disorders after high-dose corticosteroids (HDC), routinely used to treat clinical relapses in multiple sclerosis (MS). The present study aimed to examine the possible effect of HDC on mood in patients with MS and to determine the specific factors that influence mood changes.

Methods: The study included MS patients prior to receive HDC. The presence of depressive and bipolar symptoms was determined with the Beck Depression Inventory-Second Edition (BDI-II) and the Mood Disorder Questionnaire (MDQ). These assessments were made at three time points: prior to HDC initiation, after HDC completion, and 1 month after HDC.

Results: The study included 101 MS patients. At baseline, 32 (31.7%) patients had depressive symptoms (BDI-II scores ≥ 14) and 20 (19.8%) patients had bipolar symptoms (MDQ scores ≥ 7). While it was observed a reduction of BDI-II scores after HDC, an increase in MDQ score was found in patients with MDQ positivity at baseline, resulting associated with a higher number of HDC infusions (p 0.018).

Conclusions: Our results emphasize the importance of accurate screening for mood disorders in patients with MS prior to HDC initiation, and indicate that HDC should be used with caution in patients with MDQ positivity.
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http://dx.doi.org/10.1016/j.msard.2018.01.012DOI Listing
February 2018