Publications by authors named "Roberta Lanzillo"

108 Publications

Asymptomatic bradycardia after first fingolimod dose in a pediatric patient with multiple sclerosis - a case report.

Neurol Sci 2021 Feb 26. Epub 2021 Feb 26.

Federico II University of Naples, Naples, Italy.

Fingolimod is currently approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of pediatric patients with relapsing-remitting multiple sclerosis (RRMS). However, transient asymptomatic bradycardia with treatment initiation has been reported in a small population of predisposed patients, which may be a result of short-term activation and internalization/desensitization of the G-protein-gated potassium channel IKACh on the atrial myocyte membrane. Asymptomatic bradycardia, with or without atrioventricular block, is generally self-limiting and has been reported within the first 6 h of administration of the first oral dose of fingolimod. Therefore, patients initiating fingolimod treatment are monitored for this initial period to identify any changes in their electrocardiogram and heart rate that may require further treatment. Here, we report a case of a 17-year-old female with RRMS who received her first fingolimod dose and showed asymptomatic bradycardia that resolved without treatment.
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http://dx.doi.org/10.1007/s10072-021-05086-5DOI Listing
February 2021

Ocrelizumab depletes T-lymphocytes more than rituximab in multiple sclerosis.

Mult Scler Relat Disord 2021 Jan 28;49:102802. Epub 2021 Jan 28.

Multiple Sclerosis Clinical Care and Research Centre, Department of Neuroscience, Reproductive Sciences and Odontostomatology, University of Naples Federico II, Naples, Italy. Electronic address:

Background: We aim to directly compare changes in lymphocyte subpopulations between chimeric (rituximab) and humanised (ocrelizumab) anti-CD20 antibodies in multiple sclerosis (MS).

Methods: In this retrospective analysis of prospectively collected data, we included 88 patients with MS, treated with rituximab (n=50) or ocrelizumab (n=38). We used flow cytometry in the peripheral blood to count total lymphocytes and lymphocytes expressing different phenotypic markers (CD4, CD8, CD19, CD20, CD4/CD8 ratio), before treatment and after 1, 3 and 6 months.

Results: On linear mixed effect regression models, after 1, 3 and 6 months, patients treated with rituximab and with ocrelizumab were similar in total lymphocyte count, CD19 lymphocytes, CD20 lymphocytes and CD4/CD8 ratio. However, patients treated with ocrelizumab presented with lower CD4 T lymphocytes and CD8 T lymphocytes after 1, 3 and 6 months (all p<0.05). No between-treatment difference in EDSS progression was found.

Discussion: B-cell levels in the peripheral blood were equally decreased by rituximab and ocrelizumab. On the contrary, CD4 and CD8 T lymphocyte reduction was more pronounced in ocrelizumab, when compared with rituximab, suggesting a broader immunomodulatory effect for the humanised antibody to be confirmed and correlated with clinical efficacy in the long term.
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http://dx.doi.org/10.1016/j.msard.2021.102802DOI Listing
January 2021

Prevalence of SARS-CoV-2 Antibodies in Multiple Sclerosis: The Hidden Part of the Iceberg.

J Clin Med 2020 Dec 16;9(12). Epub 2020 Dec 16.

Multiple Sclerosis Clinical Care and Research Centre, Department of Neuroscience, Reproductive Sciences and Odontostomatology, University of Naples "Federico II", 80138 Naples, Italy.

Background: We compared the prevalence of SARS-CoV-2 IgG/IgM in multiple sclerosis (MS), low-risk, and high-risk populations and explored possible clinical correlates.

Methods: In this cross-sectional study, we recruited MS patients, low-risk (university staff from non-clinical departments), and high-risk individuals (healthcare staff from COVID-19 wards) from 11 May to 15 June 2020. We used lateral flow immunoassay to detect SARS-CoV-2 IgG and IgM. We used t-test, Fisher's exact test, chi square test, or McNemar's test, as appropriate, to evaluate between-group differences.

Results: We recruited 310 MS patients (42.3 ± 12.4 years; females 67.1%), 862 low-risk individuals (42.9 ± 13.3 years; females 47.8%), and 235 high-risk individuals (39.4 ± 10.9 years; females 54.5%). The prevalence of SARS-CoV-2 IgG/IgM in MS patients (n = 9, 2.9%) was significantly lower than in the high-risk population (n = 25, 10.6%) ( < 0.001), and similar to the low-risk population (n = 11, 1.3%) ( = 0.057); these results were also confirmed after random matching by age and sex (1:1:1). No significant differences were found in demographic, clinical, treatment, and laboratory features. Among MS patients positive to SARS-CoV-2 IgG/IgM (n = 9), only two patients retrospectively reported mild and short-lasting COVID-19 symptoms.

Conclusions: MS patients have similar risk of SARS-CoV-2 infection to the general population, and can be asymptomatic from COVID-19, also if using treatments with systemic immunosuppression.
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http://dx.doi.org/10.3390/jcm9124066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766741PMC
December 2020

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

Eur J Neurol 2020 Dec 10. Epub 2020 Dec 10.

Clinica Neurologica, Dipartimento di Medicina e Chirurgia, Università degli Studi di Perugia, Perugia, Italy.

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
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

The Framingham cardiovascular risk score and 5-year progression of multiple sclerosis.

Eur J Neurol 2021 Mar 21;28(3):893-900. Epub 2020 Nov 21.

Department of Neuroscience, Reproductive Science and Odontostomatology, Multiple Sclerosis Clinical Care and Research Centre, Federico II University, Naples, Italy.

Background And Purpose: Cardiovascular risk factors and comorbidities can affect the prognosis of multiple sclerosis (MS). The Framingham risk score is an algorithm that can estimate the 10-year risk of developing macrovascular disease. Our objectives were to evaluate the possible association between the Framingham risk score at baseline and MS relapses, disability, and disease-modifying therapy (DMT) choices over a 5-year follow-up.

Methods: This is a retrospective cohort study including 251 MS subjects. At baseline, we calculated the Framingham risk score considering the following variables: age, sex, diabetes, smoking, systolic blood pressure, and body mass index. MS outcomes including relapses, disability, and treatments were collected over 5 years. Cox proportional regression models were employed to estimate hazard ratios (HRs).

Results: A one-point increase in the Framingham risk score was associated with 31% higher risk of relapse (HR = 1.31; 95% confidence interval [CI] = 1.03, 1.68), 19% higher risk of reaching of EDSS 6.0 (HR = 1.19; 95% CI = 1.05, 3.01), and 62% higher risk of DMT escalation (HR = 1.62; 95% CI = 1.22, 3.01).

Conclusions: Higher cardiovascular risk was associated with higher risk of relapses, disability, and DMT escalation in MS. Early identification, correction, and treatment of cardiovascular comorbidities should be carefully considered within MS management.
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http://dx.doi.org/10.1111/ene.14608DOI Listing
March 2021

Persistence, adherence, healthcare resource utilisation and costs for interferon Beta in multiple sclerosis: a population-based study in the Campania region (southern Italy).

BMC Health Serv Res 2020 Aug 26;20(1):797. Epub 2020 Aug 26.

Department of Public Health, Federico II University, Naples, Italy.

Background: To differentiate five formulations of Interferon Beta for the treatment of multiple sclerosis (MS) in clinical practice, by analysing persistence, adherence, healthcare resource utilisation and costs at population level.

Methods: In this population-based study, we included individuals with MS living in the Campania Region of Italy from 2015 to 2017, on treatment with intramuscular Interferon Beta-1a (Avonex® = 618), subcutaneous pegylated Interferon Beta-1a (Plegridy® = 259), subcutaneous Interferon Beta-1a (Rebif® = 1220), and subcutaneous Interferon Beta-1b (Betaferon® = 348; and Extavia® = 69). We recorded healthcare resource utilisation from administrative databases (hospital discharges, drug prescriptions, MS-related outpatients), and derived costs from the Regional formulary. We classified hospital admissions into MS-related and non-MS-related. Persistence (time to switch to other disease modifying treatments (DMTs)), and adherence (medication possession ratio (MPR) = medication supply obtained/medication supply expected during follow-up period) were calculated.

Results: Patients treated with Rebif® were younger, when compared with other Interferon Beta formulations (p < 0.01). The probability of switching to other DMTs was 60% higher for Betaferon®, 90% higher for Extavia®, and 110% higher for Plegridy®, when compared with Rebif® (p < 0.01). Plegridy® presented with 7% higher adherence (p < 0.01), and Betaferon® with 3% lower adherence (p = 0.03), when compared with Rebif®. The probability of MS-related hospital admissions was 40% higher in Avonex® (p = 0.03), 400% higher in Betaferon® (p < 0.01), and 60% higher in Plegridy® (p = 0.04), resulting into higher non-DMT-related costs, when compared with Rebif®.

Discussion: Interferon Beta formulations presented with different prescription patterns, persistence, adherence, healthcare resource utilisation and costs, with Rebif® being used in younger patients and with less MS-related hospital admissions.
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http://dx.doi.org/10.1186/s12913-020-05664-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448448PMC
August 2020

Mild or no COVID-19 symptoms in cladribine-treated multiple sclerosis: Two cases and implications for clinical practice.

Mult Scler Relat Disord 2020 Oct 16;45:102452. Epub 2020 Aug 16.

Multiple Sclerosis Clinical Care and Research Centre, Department of Neuroscience, Reproductive Science and Odontostomatology, Federico II University of Naples, Via Sergio Pansini 5, 80131 Naples, Italy. Electronic address:

Background: The use of disease-modifying therapies (DMTs) in multiple sclerosis (MS) could affect COVID-19 outcomes by modulating the immune response, which, in turn, might favor viral replication and/or confer protection from COVID-19 induced inflammatory response CASE REPORT: We report on two MS patients treated with cladribine, with heterogeneous demographics and clinical features, who developed mild or no symptoms from COVID-19 and produced anti-SARS-CoV-2 antibodies, notwithstanding low lymphocyte levels.

Implications: Benign COVID-19 clinical course and anti-SARS-CoV-2 antibody production can occur in MS patients with lymphopenia, suggesting the possibility to respond to COVID-19 vaccination, once available, in this vulnerable population.
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http://dx.doi.org/10.1016/j.msard.2020.102452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428688PMC
October 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

Surface-enhanced Raman spectroscopy of tears: toward a diagnostic tool for neurodegenerative disease identification.

J Biomed Opt 2020 08;25(8):1-12

Universitá della Campania "L. Vanvitelli," Dipartimento di Medicina Sperimentale, Napoli, Italy.

Significance: A noninvasive method based on surface-enhanced Raman spectroscopy (SERS) of tears was proposed as a support for diagnosing neurodegenerative pathologies, including different forms of dementia and Alzheimer's disease (AD). In this field, timely and reliable discrimination and diagnosis are critical aspects for choosing a valid medical therapy, and new methods are highly required.

Aim: The aim is to evince spectral differences in SERS response of human tears from AD affected, mild cognitive impaired (MCI), and healthy control (Ctr) subjects.

Approach: Human tears were characterized by SERS coupled with multivariate data analysis. Thirty-one informed subjects (Ctr, MCI, and AD) were considered.

Results: Average SERS spectra from Ctr, MCI, and AD subjects evidenced differences related to lactoferrin and lysozyme protein components. Quantitative changes were also observed by determining the intensity ratio between selected bands. We also constructed a classification model that discriminated among AD, MCI, and Ctr subjects. The model was built using the scores obtained by performing principal component analysis on specific spectral regions (i-PCA).

Conclusions: The results are very encouraging with interesting perspectives for medical applications as support of clinical diagnosis and discrimination of AD from other forms of dementia.
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http://dx.doi.org/10.1117/1.JBO.25.8.087002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406892PMC
August 2020

Harmonization of real-world studies in multiple sclerosis: Retrospective analysis from the rirems group.

Mult Scler Relat Disord 2020 Oct 12;45:102394. Epub 2020 Jul 12.

Rehabilitation Department, Mons. L. Novarese, Moncrivello, Vercelli, Italy.

Background: Worldwide multiple sclerosis (MS) centers have coordinated their efforts to use data acquired in clinical practice for real-world observational studies. In this retrospective study, we aim to harmonize outcome measures, and to evaluate their heterogeneity within the Rising Italian Researchers in MS (RIReMS) study group.

Methods: RIReMS members filled in a structured questionnaire evaluating the use of different outcome measures in clinical practice. Thereafter, thirty-four already-published papers from RIReMS centers were used for heterogeneity analyses, using the DerSimonian and Laird random-effects method to compute the between-study variance (τ).

Results: Based on questionnaire results, we defined basic modules for diagnosis and follow-up, consisting of outcome measures recorded by all participating centers at the time of diagnosis, and, then, at least annually; we also defined more detailed/optional modules, with outcome measures recorded less frequently and/or in the presence of specific clinical indications. Looking at heterogeneity, we found 5-year variance in age at onset (ES=27.34; 95%CI=26.18, 28.49; p<0.01; τ=4.76), and 7% in female percent (ES=66.42; 95%CI=63.08, 69.76; p<0.01; τ=7.15). EDSS variance was 0.2 in studies including patients with average age <36.1 years (ES=1.96; 95%CI=1.69, 2.24; p<0.01; τ=0.19), or from 36.8 to 41.1 years (ES=2.70; 95%CI=2.39, 3.01; p<0.01; τ=0.18), but increased to 3 in studies including patients aged >41.4 years (ES=4.37; 95%CI=3.40, 5.35; p<0.01; τ=2.96). The lowest variance of relapse rate was found in studies with follow-up duration ≤2 years (ES=9.07; 95%CI=5.21, 12.93; p = 0.02; τ=5.53), whilst the lowest variance in EDSS progression was found in studies with follow-up duration >2 years (ES=5.41; 95%CI=3.22, 7.60; p = 0.02; τ=1.00).

Discussion: We suggest common sets of biomarkers to be acquired in clinical practice, that can be used for research purposes. Also, we provide researchers with specific indications for improving inclusion criteria and data analysis, ultimately allowing data harmonization and high-quality collaborative studies.
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http://dx.doi.org/10.1016/j.msard.2020.102394DOI Listing
October 2020

A Multiple -Glucosylated Peptide Epitope Efficiently Detecting Antibodies in Multiple Sclerosis.

Brain Sci 2020 Jul 15;10(7). Epub 2020 Jul 15.

Interdepartmental Research Unit of Peptide and Protein Chemistry and Biology, Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy.

Diagnostics of Multiple Sclerosis (MS) are essentially based on the gold standard magnetic resonance imaging. Few alternative simple assays are available to follow up disease activity. Considering that the disease can remain elusive for years, identification of antibodies fluctuating in biological fluids as relevant biomarkers of immune response is a challenge. In previous studies, we reported that anti--glucosylated (-Glc) peptide antibodies that can be easily detected in Solid-Phase Enzyme-Linked ImmunoSorbent Assays (SP-ELISA) on MS patients' sera preferentially recognize hyperglucosylated adhesin of non-typeable . Since multivalency can be useful for diagnostic purposes to allow an efficient coating in ELISA, we report herein the development of a collection of Multiple -glucosylated Peptide Epitopes (-Glc MEPs) to detect anti--Glc antibodies in MS. To this aim, a series of -Glc peptide antigens to be represented in the -GlcMEPs were tested in competitive ELISA. We confirmed that the epitope recognized by antibodies shall contain at least 5-mer sequences including the fundamental -Glc moiety. Using a 4-branched dendrimeric lysine scaffold, we selected the -Glc MEP , carrying the minimal epitope Asn(Glc) anchored to a polyethylene glycol-based spacer (PEG) containing a 19-atoms chain, as an efficient multivalent probe to reveal specific and high affinity anti--Glc antibodies in MS.
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http://dx.doi.org/10.3390/brainsci10070453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408607PMC
July 2020

Nabiximols discontinuation rate in a large population of patients with multiple sclerosis: a 18-month multicentre study.

J Neurol Neurosurg Psychiatry 2020 09 13;91(9):914-920. Epub 2020 Jul 13.

Department of Medical, Surgical Science and Advanced Technology "GF Ingrassia", section of neurosciences, Università degli Studi di Catania, Catania, Sicilia, Italy

Introduction: Delta-δ-tetrahydrocannabinol and cannabidiol (THC:CBD) oromucosal spray is used as an add-on therapy option for moderate to severe multiple sclerosis (MS) spasticity resistant to other medications. Aims of this study were to provide real-life data on long-term clinical outcomes in a large population of Italian patients treated with THC:CBD and to evaluate predictors of THC:CBD therapy continuation.

Materials And Methods: This prospective observational multicentre Italian study screened all patients with MS consecutively included in the Agenzia Italiana del Farmaco e-registry at the start of THC:CBD treatment (baseline), after 4 weeks (T1), 12±3 weeks (T2), 24±3 weeks (T3), 48±3 weeks (T4) and 72±3 weeks (T5) from baseline.

Results: A total of 1845 patients were recruited from 32 MS Italian centres. At T1, 1502 (81.4%) of patients reached a Numerical Rating Scale (NRS) improvement of ≥20%, with an NRS reduction of 26.9% at T1 and of 34.4% at T5. At T5, 725 patients (48.3% of 1502) discontinued treatment with highest discontinuation rate at T2 and T3. Daily number of puffs was generally stable through the observation period. The multivariate analysis showed that higher NRS scores at baseline (OR 2.28, 95% CI 1.15 to 6.36, p<0.01) and higher differences of NRS between T0 and T1 (OR 2.11, 95% CI 1.08 to 8.26, p<0.05) were associated with an increased probability to continue therapy after 18 months.

Discussion: THC:CBD effects were sustained for 18 months with a relatively stable number of puffs per day. About 50% of patients abandoned THC:CBD therapy for loss of efficacy or adverse events.
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http://dx.doi.org/10.1136/jnnp-2019-322480DOI Listing
September 2020

Peripapillary Vessel Density as Early Biomarker in Multiple Sclerosis.

Front Neurol 2020 17;11:542. Epub 2020 Jun 17.

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

To evaluate retinal vessel density (VD) in macular and in peripapillary regions in patients with recent onset of multiple sclerosis, at initial demyelinating event (IDE) and in matched relapsing-remitting multiple sclerosis (RRMS) patients. We evaluated VD in superficial capillary plexus, deep capillary plexus, choriocapillaris and radial peripapillary capillary plexus in IDE, RRMS patients and in matched healthy controls (HCs) through Optical Coherence Tomography Angiography (OCT-A). Clinical history, including history of optic neuritis, Expanded Disability Status scale and disease duration of patients were collected. Thirty patients (20 with IDE and 10 with RRMS) and 15 HCs were enrolled. IDE patients showed a lower VD in radial peripapillary capillary plexus compared with controls (coeff. β = -3.578; = 0.002). RRMS patients displayed a lower VD in both superficial capillary plexus and radial peripapillary capillary plexus compared with HCs (coeff. β = -4.955; = 0.002, and coeff. β = -7.446; < 0.001, respectively). Furthermore, RRMS patients showed a decreased VD in radial peripapillary capillary plexus compared with IDE patients (coeff. β = -3.868; = 0.003). Peripapillary region vessel density reduction, revealed through OCT-A, might be considered as an early event in MS, and might be relevant as a biomarker of disease pathology.
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http://dx.doi.org/10.3389/fneur.2020.00542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311750PMC
June 2020

Single-Center 8-Years Clinical Follow-Up of Cladribine-Treated Patients From Phase 2 and 3 Trials.

Front Neurol 2020 17;11:489. Epub 2020 Jun 17.

Department of Neuroscience, Reproductive Science and Odontostomatology, Multiple Sclerosis Clinical Care and Research Center, Federico II University, Naples, Italy.

Cladribine is approved for the treatment of highly-active relapsing multiple sclerosis (MS), where it is also effective on disability progression. In the present single-center study, we aim to report on the 8-years clinical follow-up of 27 patients included in phase 2 and 3 clinical trials for cladribine. We included patients exposed to cladribine ( = 13) or placebo ( = 14) in ONWARD, CLARITY, and ORACLE-MS trials, and followed-up at the same center after trial termination. Outcomes of long-term disease progression were recorded. During 8-year follow-up, patients treated with cladribine presented with reduced risk of EDSS progression (HR = 0.148; 95%CI = 0.031, 0.709; = 0.017), of reaching EDSS 6.0 (HR = 0.115; 95%CI = 0.015, 0.872; = 0.036), and of SP conversion (HR = 0.010; 95%CI = 0.001, 0.329; = 0.010), when compared with placebo. Our exploratory study provides additional evidence that cladribine may be useful to prevent or, at least, mitigate the risk of disability progression after 8 years.
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http://dx.doi.org/10.3389/fneur.2020.00489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311570PMC
June 2020

The Use of Social Media and Digital Devices Among Italian Neurologists.

Front Neurol 2020 16;11:583. Epub 2020 Jun 16.

Second Division of Neurology, Department of Advanced Medical and Surgical Sciences, MRI Research Center SUN-FISM, AOU - University of Campania "Luigi Vanvitelli", Naples, Italy.

Digital devices and online social networks are changing clinical practice. In this study, we explored attitudes, awareness, opinions, and experiences of neurologists toward social media and digital devices. Each member of the Italian Society of Neurology (SIN) participated in an online survey (January to May 2018) to collect information on their attitude toward digital health. Four hundred and five neurologists participated in the study. At work, 95% of responders use the personal computer, 87% the smartphone, and 43.5% the tablet. These devices are used to obtain health information (91%), maintain contact with colleagues (71%), provide clinical information (59%), and receive updates (67%). Most participants (56%) use social media to communicate with patients, although 65% are against a friendship with them on social media. Most participants interact with patients on social media outside working hours (65.2%) and think that social media have improved (38.0%) or greatly improved (25.4%) the relationship with patients. Most responders (66.7%) have no wearable devices available in clinical practice. Italian neurologists have different practices and views regarding the doctor-patient relationship in social media. The availability of digital devices in daily practice is limited. The use of social networks and digital devices will increasingly permeate into everyday life, bringing a new dimension to health care. The danger is that advancement will not go hand in hand with a legal and cultural adaptation, thus creating ambiguity and risks for clinicians and patients. Neurologists will need to be able to face the opportunities and challenges of this new scenario.
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http://dx.doi.org/10.3389/fneur.2020.00583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308485PMC
June 2020

COVID-19 prevention and multiple sclerosis management: The SAFE pathway for the post-peak.

Mult Scler Relat Disord 2020 Sep 10;44:102282. Epub 2020 Jun 10.

Multiple Sclerosis Clinical Care and Research Centre, Department of Neuroscience, Reproductive Science and Odontostomatology, Federico II University of Naples, Italy.

Background: We hereby report on our experience from Naples (South Italy), where the peak of coronavirus disease 2019 (COVID-19) has already passed.

Methods: Assuming that COVID-19 will be circulating until vaccination and/or herd immunity is achieved (possibly not earlier than 2021), we have developed a protocol for the long-term management of multiple sclerosis (MS).

Results: We have defined a pathway for the access to the MS Centre with logistic, preventative and clinical recommendations, and have also included 14-day self-isolation and COVID-19 testing before some disease modifying treatments.

Discussion: Overall, we believe our experience could be helpful for MS management in the upcoming months.
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http://dx.doi.org/10.1016/j.msard.2020.102282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283048PMC
September 2020

Dimethyl fumarate vs Teriflunomide: an Italian time-to-event data analysis.

J Neurol 2020 Oct 6;267(10):3008-3020. Epub 2020 Jun 6.

Department "G.F. Ingrassia", MS Center University of Catania, Policlinico G. Rodolico, V. Santa Sofia 78, 95123, Catania, Italy.

Background: The introduction of oral disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) changed algorithms of RRMS treatment.

Objectives: To compare the effectiveness of treatment with dimethyl fumarate (DMF) and teriflunomide (TRF) in a large multicentre Italian cohort of RRMS patients.

Materials And Methods: Patients with RRMS who received treatment with DMF and TRF between January 1st, 2012 and December 31st, 2018 from twelve MS centers were identified. The events investigated were "time-to-first-relapse", "time-to-Magnetic-Resonance-Imaging (MRI)-activity" and "time-to-disability-progression".

Results: 1445 patients were enrolled (1039 on DMF, 406 on TRF) and followed for a median of 34 months. Patients on TRF were older (43.5 ± 8.6 vs 38.8 ± 9.2 years), with a predominance of men and higher level of disability (p < 0.001 for all). Patients on DMF had a higher number of relapses and radiological activity (p < .05) at baseline. Time-varying Cox-model for the event "time-to-first relapse" revealed that no differences were found between the two groups in the first 38 months of treatment (HR = 0.73, CI = 0.52 to 1.03, p = 0.079). When the time-on-therapy exceeds 38 months patients on DMF had an approximately 0.3 times lower relapse hazard risk than those who took TRF (HR = 3.83, CI = 1.11 to 13.23, p = 0.033). Both DMTs controlled similarly MRI activity and disability progression.

Conclusions: Patients on DMF had higher relapse-free survival time than TRF group after the first 38 months on therapy.
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http://dx.doi.org/10.1007/s00415-020-09959-1DOI Listing
October 2020

Assessment of retinal vascular network in amnestic mild cognitive impairment by optical coherence tomography angiography.

PLoS One 2020 3;15(6):e0233975. Epub 2020 Jun 3.

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

Objective: To assess the presence of retinal vascular network abnormalities in amnestic mild cognitive impairment (aMCI) patients and healthy subjects (HS) through optical coherence tomography angiography (OCTA).

Methods: OCTA and SD-OCT were performed in aMCI patients and cognitive normal HS. A complete neuropsychological evaluation was performed. Differences in vessel density (VD) in each retinal vascular plexus and in foveal avascular zone (FAZ) were evaluated with linear mixed model after correction for age, sex and disease duration.

Results: Twenty-seven aMCI patients (10 Single domain aMCI, 17 Multidomain aMCI) and 29 HS were enrolled. aMCI patients showed a statistically significant reduced VD in superficial capillary plexus (SCP), deep capillary plexus (DCP) and an increased FAZ compared to controls. When aMCI patients were divided in single domain (SD) and multiple domains (MD) aMCI, SD aMCI showed no VD differences in SCP, DCP and Radial Peripapillary Capillary, while the FAZ area was significantly larger compared to controls. In MD aMCI, VD values were lower and FAZ was increased compared to controls. Comparing both aMCI groups, MD aMCI showed a significant reduction in VD values of SCP. No correlation was found between mini mental state examination (MMSE) scores and OCTA parameters.

Conclusions: OCTA is able to detect changes in retinal microvascular network in early cognitive deficits and, the most sensitive alteration seems to be the enlargement of the FAZ. This non-invasive tool provides useful information on retinal involvement patterns in MCI diagnosis and follow up. Vascular network impairment seems to be related to the number of domains affected and not to MMSE.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233975PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269252PMC
August 2020

Unraveling diagnostic uncertainty in transition phase from relapsing-remitting to secondary progressive multiple sclerosis.

Mult Scler Relat Disord 2020 Aug 24;43:102211. Epub 2020 May 24.

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

Background: Clinicians struggle to timely diagnose secondary-progressive multiple sclerosis (SP-MS), with a 'transition phase' period of diagnostic uncertainty. We aimed at defining clinical markers predicting evolution to SP-MS.

Methods: We reviewed 210 newly diagnosed MS patients experiencing at least one confirmed disability worsening (CDW). CDWs were classified as disability worsening either due to incomplete recovery following relapse (r-CDW), or independent of relapse activity (nr-CDW). Logistic regression and Cox regression models were used to evaluate variables at CDW associated with SP-MS diagnosis.

Results: On CDW, higher EDSS (OR: 2.73, p=0.002) and nr-CDW (OR: 2.63, p=0.03) were associated with conversion to SP-MS over the follow-up. In addition, the risk of SP-MS was higher in patients with EDSS>3.0 at CDW (HR: 2.26, p<0.001), and with time to second CDW <24 months (HR: 0.98, p<0.001), compared with patients that experienced a CDW but did not receive SP-MS diagnosis (AUC: 0.95, Sensitivity: 0.83, Specificity: 0.96).

Conclusion: At their first CDW, patients with higher EDSS, experiencing CDW without relapse and developing a further CDW within 2 years are at higher risk of SP-MS conversion. This provides proxies for conversion to SP-MS since first episode of CDW.
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http://dx.doi.org/10.1016/j.msard.2020.102211DOI Listing
August 2020

Assessing disability and relapses in multiple sclerosis on tele-neurology.

Neurol Sci 2020 Jun 21;41(6):1369-1371. Epub 2020 May 21.

Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy.

Background: As a consequence of the coronavirus disease 2019 (COVID-19) pandemic, a large amount of consultations will be delivered through tele-medicine, especially for diseases causing chronic disability and requiring immunomodulatory treatments, such as multiple sclerosis (MS).

Methods: We have hereby reviewed available tools for tele-neurology examination in MS, including components of neurological examination that can be assessed through video, patient-reported outcome measures (PROMs), and digital technology.

Results: Overall, we have suggested a battery for assessing MS disability and relapses on tele-medicine, which brings together conventional examination, PROMs (e.g., Patient Determined Disease Steps, MS Impact Scale), and cognitive tests (Symbol Digit Modalities Test) that can be delivered remotely and in multiple languages.

Discussion: The use of common tools for neurological examination could improve tele-neurology practice for both general neurologists and MS specialists, and quality of care for people with MS.
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http://dx.doi.org/10.1007/s10072-020-04470-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241064PMC
June 2020

Multiple Sclerosis in the Campania Region (South Italy): Algorithm Validation and 2015-2017 Prevalence.

Int J Environ Res Public Health 2020 05 13;17(10). Epub 2020 May 13.

Department of Public Health, Federico II University, 80131 Naples, Italy.

We aim to validate a case-finding algorithm to detect individuals with multiple sclerosis (MS) using routinely collected healthcare data, and to assess the prevalence of MS in the Campania Region (South Italy). To identify individuals with MS living in the Campania Region, we employed an algorithm using different routinely collected healthcare administrative databases (hospital discharges, drug prescriptions, outpatient consultations with payment exemptions), from 1 January 2015 to 31 December 2017. The algorithm was validated towards the clinical registry from the largest regional MS centre (n = 1460). We used the direct method to standardise the prevalence rate and the capture-recapture method to estimate the proportion of undetected cases. The case-finding algorithm including individuals with at least one MS record during the study period captured 5362 MS patients (females = 64.4%; age = 44.6 ± 12.9 years), with 99.0% sensitivity (95% CI = 98.3%, 99.4%). Standardised prevalence rate per 100,000 people was 89.8 (95% CI = 87.4, 92.2) (111.8 for females [95% CI = 108.1, 115.6] and 66.2 for males [95% CI = 63.2, 69.2]). The number of expected MS cases was 2.7% higher than cases we detected. We developed a case-finding algorithm for MS using routinely collected healthcare data from the Campania Region, which was validated towards a clinical dataset, with high sensitivity and low proportion of undetected cases. Our prevalence estimates are in line with those reported by international studies conducted using similar methods. In the future, this cohort could be used for studies with high granularity of clinical, environmental, healthcare resource utilisation, and pharmacoeconomic variables.
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http://dx.doi.org/10.3390/ijerph17103388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277756PMC
May 2020

Effects of THC/CBD oromucosal spray on spasticity-related symptoms in people with multiple sclerosis: results from a retrospective multicenter study.

Neurol Sci 2020 Oct 25;41(10):2905-2913. Epub 2020 Apr 25.

Department "G.F. Ingrassia", section of Neurosciences, University of Catania, Catania, Italy.

Introduction: The approval of 9-δ-tetrahydocannabinol (THC)+cannabidiol (CBD) oromucosal spray (Sativex®) in Italy as an add-on medication for the management of moderate to severe spasticity in multiple sclerosis (MS) has provided a new opportunity for MS patients with drug-resistant spasticity. We aimed to investigate the improvement of MS spasticity-related symptoms in a large cohort of patients with moderate to severe spasticity in daily clinical practice.

Materials And Methods: MS patients with drug-resistant spasticity were recruited from 30 Italian MS centers. All patients were eligible for THC:CBD treatment according to the approved label: ≥ 18 years of age, at least moderate spasticity (MS spasticity numerical rating scale [NRS] score ≥ 4) and not responding to the common antispastic drugs. Patients were evaluated at baseline (T0) and after 4 weeks of treatment (T1) with the spasticity NRS scale and were also asked about meaningful improvements in 6 key spasticity-related symptoms.

Results: Out of 1615 enrolled patients, 1432 reached the end of the first month trial period (T1). Of these, 1010 patients (70.5%) reached a ≥ 20% NRS score reduction compared with baseline (initial responders; IR). We found that 627 (43.8% of 1432) patients showed an improvement in at least one spasticity-related symptom (SRSr group), 543 (86.6%) of them belonging to the IR group and 84 (13.4%) to the spasticity NRS non-responders group.

Conclusion: Our study confirmed that the therapeutic benefit of cannabinoids may extend beyond spasticity, improving spasticity-related symptoms even in non-NRS responder patients.
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http://dx.doi.org/10.1007/s10072-020-04413-6DOI Listing
October 2020

Prevalence of GLA gene mutations and polymorphisms in patients with multiple sclerosis: A cross-sectional study.

J Neurol Sci 2020 May 19;412:116782. Epub 2020 Mar 19.

Department of Public Health, Nephrology Unit, University of Naples "Federico II", Naples, Italy.

Purpose: Fabry Disease (FD) has been frequently proposed as possible underestimated differential diagnosis of Multiple Sclerosis (MS), but no study has been performed to test prevalence of GLA gene mutations in a population fulfilling diagnostic criteria of MS. Aim of this study is to determine the prevalence of GLA gene mutations in a large and representative population diagnosed with MS, simultaneously providing a critical revision of current literature reports of coexistence or misdiagnosis between these two conditions.

Methods: In this mono-centric cross-sectional study, 927 patients fulfilling McDonald diagnostic criteria and encompassing all MS phenotypes were enrolled. Patients underwent evaluation of α-GalA activity and genotyping. Both genetic variants annotated as pathogenic and GVUS were considered. Estimated alleles frequencies were then compared to the ones reported in the gnomAD database.

Results: GLA gene variants were found in seven individuals. Five patients carried variants previously described having controversial impact on FD phenotype, and the analysis of exome database revealed that they are not rare among healthy individuals. One patient showed a new variant never described before, and another one carried a late-onset FD cardiac variant.

Conclusions: The overall prevalence of GLA gene variants in MS patients is comparable to the one estimated in healthy population. This result is further supported by critical revision of current literature evidences of misdiagnosis between MS and FD, arguing in favour of independence between these disorders.
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http://dx.doi.org/10.1016/j.jns.2020.116782DOI Listing
May 2020

First therapy choice in newly diagnosed Multiple Sclerosis patients: A multicenter Italian study.

Mult Scler Relat Disord 2020 Jul 16;42:102059. Epub 2020 Mar 16.

Department of Health Sciences Section of Biostatistics, University of Genova, Italy. Electronic address:

Background: The approval of an increasing number of disease modifying drugs for the treatment of Multiple Sclerosis (MS) creates new challenges for patients and clinicians on the first treatment choice. The main aim of this study was to assess factors impacting first therapy choice in a large Italian MS cohort.

Methods: Newly diagnosed relapsing-remitting (RR) MS patients (2010-2018) followed in 24 Italian MS centres were included in the study. We evaluated the association of baseline demographics, clinical and MRI characteristics to the first treatment choice by logistic regression models applied to pre-defined binary alternatives: dimethyl fumarate vs injectables (interferon and glatiramer acetate), teriflunomide vs injectables, fingolimod vs dimethyl fumarate and fingolimod vs natalizumab.

Results: We enrolled 3025 patients in the period between January 2010 and June 2018. Relapses in the previous year (OR = 2.75; p = 0.001), presence of spinal cord lesions (OR = 1.80; p = 0.002) and higher number (>9) of T2 lesions on the baseline brain MRI scan (OR = 1.65; p = 0.022) were the factors associated to dimethyl fumarate choice as first therapy vs an injectable drug. Older age (OR = 1.06; p < 0.001), male sex (OR = 2.29; p = 0.001) and higher EDSS (OR = 1.36; p < 0.001) were the factors associated with the choice of teriflunomide vs injectables. In more recent years, dimethyl fumarate (OR = 3.23; p < 0.001) and teriflunomide (OR = 2.53; p < 0.001) were chosen more frequently than injectables therapies. The main determinant for the choice of fingolimod as compared with dimethyl fumarate was a higher EDSS (OR = 1.56; p = 0.001), while there was a weak association with a longer disease duration (p = 0.068) and a longer time from onset to diagnosis (p = 0.085). Compared to fingolimod, natalizumab was preferred in patients with a younger age (OR = 0.95; p = 0.003) and higher EDSS (OR = 1.45; p = 0.007) and a shorter disease duration (OR = 0.52; p = 0.076).

Conclusion: Many factors guided therapeutic decision for our Italian cohort of MS patients; they are mainly related to MS disease activity, baseline EDSS, disease duration and age.
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http://dx.doi.org/10.1016/j.msard.2020.102059DOI Listing
July 2020

Predictors of Nabiximols (Sativex) discontinuation over long-term follow-up: a real-life study.

J Neurol 2020 Jun 2;267(6):1737-1743. Epub 2020 Mar 2.

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

Nabiximols is an effective treatment for spasticity in MS. However, treatment discontinuation over-time might occur and predictors of sustained treatment persistence over long-term follow-up in real-world settings are highly needed. We aim at evaluating baseline predictors of treatment persistence on Nabiximols. This is a retrospective real-world study including MS patients treated with Nabiximols. At baseline (Nabiximols prescription), we evaluated disability using the EDSS, and cognitive function using the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS). Nabiximols discontinuation was evaluated after 4 weeks of treatment ("titration phase''), and over the follow-up ("treatment phase"). We included 396 MS patients (228 females and 168 males). After 4 weeks (titration phase), 266 MS patients (67.2%) were considered persistent on treatment, while 130 patients dropped out. After 19 ± 21 months (treatment phase), 136 out of 266 MS patients (51.1%) were still on treatment, whereas 130 patients dropped at follow-up. Higher EDSS and cognitive impairment predicted treatment discontinuation at follow-up (p = 0.04 and p = 0.005, respectively). In conclusion, higher physical and cognitive disability predicted Nabiximols treatment discontinuation over 2 years in MS patients suffering from spasticity. Nabiximols should be started earlier to decrease the likelihood of treatment discontinuation over time.
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http://dx.doi.org/10.1007/s00415-020-09739-xDOI Listing
June 2020

2D linear measures of ventricular enlargement may be relevant markers of brain atrophy and long-term disability progression in multiple sclerosis.

Eur Radiol 2020 Jul 25;30(7):3813-3822. Epub 2020 Feb 25.

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

Objectives: Aim of this study was to investigate the reliability and validity of 2D linear measures of ventricular enlargement as indirect markers of brain atrophy and possible predictors of clinical disability.

Methods: In this retrospective longitudinal analysis of relapsing-remitting MS patients, brain volumes were computed at baseline and after 2 years. Frontal horn width (FHW), intercaudate distance (ICD), third ventricle width (TVW), and 4th ventricle width were obtained. Two-dimensional measures associated with brain volume at correlation analyses were entered in linear and logistic regression models testing the relationship with baseline clinical disability and 10-year confirmed disability progression (CDP), respectively. Possible cutoff values for clinically relevant atrophy were estimated via receiver operating characteristic (ROC) analyses and probed as 10-year CDP predictors using hierarchical logistic regression.

Results: Eighty-seven patients were available (61/26 = F/M; 34.1 ± 8.5 years). Moderate negative correlations emerged between ICD and TVW and normalized brain volume (NBV; p < 0.001) and percentage brain volume change per year (PBVC/y) and FHW, ICD, and TVW annual changes (p ≤ 0.005). Baseline disability was moderately associated with NBV, ICD, and TVW (p < 0.001), while PBVC/y predicted 10-year CDP (p = 0.01). A cutoff percentage ICD change per year (PICDC/y) value of 4.38%, corresponding to - 0.91% PBVC/y, correlated with 10-year CDP (p = 0.04). These estimated cutoff values provided extra value for predicting 10-year CDP (PBVC/y: p = 0.001; PICDC/y: p = 0.03).

Conclusions: Two-dimensional measures of ventricular enlargement are reproducible and clinically relevant markers of brain atrophy, with ICD and its increase over time showing the best association with clinical disability. Specifically, a cutoff PICDC/y value of 4.38% could serve as a potential surrogate marker of long-term disability progression.

Key Points: • Assessment of ventricular enlargement as a rapidly accessible indirect marker of brain atrophy may prove useful in cases in which brain volume quantification is not practicable. • Two-dimensional linear measures of ventricular enlargement represent reliable, valid, and clinically relevant markers of brain atrophy. • A cutoff annualized percentage brain volume change of - 0.91% and the corresponding annualized percentage increase of 4.38% for intercaudate distance are able to discriminate patients who will develop long-term disability progression.
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http://dx.doi.org/10.1007/s00330-020-06738-4DOI Listing
July 2020

Voxel-based analysis of gray matter relaxation rates shows different correlation patterns for cognitive impairment and physical disability in relapsing-remitting multiple sclerosis.

Neuroimage Clin 2020 30;26:102201. Epub 2020 Jan 30.

Department of Advanced Biomedical Sciences, University "Federico II", Via Pansini, 5, 80131 Naples, Italy.

Background: Regional analyses of markers of microstructural gray matter (GM) changes, including relaxation rates, have shown inconsistent correlations with physical and cognitive impairment in MS.

Objective: To assess voxelwise the correlation of the R1 and R2 relaxation rates with the physical and cognitive impairment in MS.

Methods: GM R1 and R2 relaxation rate maps were obtained in 241 relapsing-remitting MS patients by relaxometric segmentation of MRI studies. Correlations with the Expanded Disability Status Scale (EDSS) and the percentage of impaired cognitive test (Brief Repeatable Battery and Stroop Test, available in 186 patients) were assessed voxelwise, including voxel GM content as nuisance covariate to remove the effect of atrophy on the correlations.

Results: Extensive clusters of inverse correlation between EDSS and R2 were detected throughout the brain, while inverse correlations with R1 were mostly limited to perirolandic and supramarginal cortices. Cognitive impairment correlated negatively with R1, and to a lesser extent with R2, in the middle frontal, mesial temporal, midcingulate and medial parieto-occipital cortices.

Conclusion: In relapsing-remitting MS patients, GM microstructural changes correlate diffusely with physical disability, independent of atrophy, with a preferential role of the sensorimotor cortices. Neuronal damage in the limbic system and dorsolateral prefrontal cortices correlates with cognitive dysfunction.
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http://dx.doi.org/10.1016/j.nicl.2020.102201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025083PMC
January 2020

Associations between cognitive impairment at onset and disability accrual in young people with multiple sclerosis.

Sci Rep 2019 12 2;9(1):18074. Epub 2019 Dec 2.

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

Differently from the adult multiple sclerosis (MS) population, the predictive value of cognitive impairment in early-onset MS is still unknown. We aim to evaluate whether cognitive performances at disease onset predict disease progression in young people with MS. This is a retrospective study on early onset (<25 years) MS patients, who had a baseline cognitive evaluation at disease onset. Demographic and longitudinal clinical data were collected up to 7 years follow up. Cognitive abilities were assessed at baseline through the Brief Repeatable Battery. Associations between cognitive abilities and clinical outcomes (occurrence of a relapse, and 1-point EDSS progression) were evaluated with stepwise logistic and Cox regression models. We included 51 patients (26 females), with a mean age at MS onset of 17.2 ± 3.9 years, and an EDSS of 2.5 (1.0-6.0). Over the follow-up, twenty-five patients had at least one relapse, and 7 patients had 1-point EDSS progression. Relapse occurrence was associated with lower 10/36 SPART scores (HR = 0.92; p = 0.002) and higher WLG scores (HR = 1.05; p = 0.01). EDSS progression was associated with lower SDMT score (OR: 0.70; p = 0.04). Worse visual memory and attention/information processing were associated with relapses and with increased motor disability after up to 7-years follow-up. Therefor, specific cognitive subdomains might better predict clinical outcomes than the overall cognitive impairment in early-onset MS.
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http://dx.doi.org/10.1038/s41598-019-54153-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889418PMC
December 2019

The impact of diagnostic criteria and treatments on the 20-year costs for treating relapsing-remitting multiple sclerosis.

Mult Scler Relat Disord 2020 Feb 9;38:101514. Epub 2019 Nov 9.

Multiple Sclerosis Clinical Care and Research Centre, Department of Neuroscience, Reproductive Science and Odontostomatology, Federico II University, Naples, Italy. Electronic address:

Objective: To assess whether the introduction of the new diagnostic criteria and disease modifying therapies (DMTs) is associated with higher cost for treating multiple sclerosis (MS).

Methods: This is a regression-based quasi-experimental study employing interrupted time series analysis, including data from 2229 patients (age 42.1 ± 11.2 years; female 63.34%), with incident diagnosis of relapsing remitting MS (RRMS) and followed up from 1997 to 2017, extracted from the database of the MS Clinical Care and Research Centre of the Federico II University Hospital of Naples (Italy). Annual healthcare costs for DMT (e.g., prescription, staff involved in DMT administration) and management (e.g., neurological consultations, other consultations related to DMT safety, MRI, laboratory exams), were calculated and inflated to the most recent value.

Results: Annual costs per patient for DMT prescription and management were not affected by the introduction of 2001 and 2005 criteria, but decreased by 0.4% after the introduction of 2011 criteria (PD= -0.4%; 95% C.I. -0.7%/-0.0%; p = 0.023). Annual costs per patient increased by 11.2% after the introduction of Natalizumab in 2007 (PD= 11.2%; 95% C.I.= 9.4%/13.0%; p <0.001), by 10.9% after the introduction of tablets in 2011 (Fingolimod, Teriflunomide and Dimethyl Fumarate) (PD= 10.9%; 95% C.I. 9.2%/12.7%; p<0.001), and by 10.7% after the introduction of Alemtuzumab in 2015 (PD= 10.7%; 95% C.I. 9.0%/12.4%; p< 0.001).

Discussion: DMTs remain the main responsible for increased medical direct costs in MS, whilst improved diagnostic skills and subsequent patient profiling can at least in part mitigate costs for MS treatment and management.
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http://dx.doi.org/10.1016/j.msard.2019.101514DOI Listing
February 2020