Alessia Manni - Academia.edu (original) (raw)

Papers by Alessia Manni

Research paper thumbnail of Impact of depression on the perception of fatigue and information processing speed in a cohort of Multiple Sclerosis patients

Background:Information processing speed is commonly impaired in people with multiple sclerosis (P... more Background:Information processing speed is commonly impaired in people with multiple sclerosis (PwMS). However, depression and fatigue can affect the cognitive profile of patients: fatigue has a negative impact from the disease’s earliest stage and a reduced information processing speed is often associated with higher levels of depression. Therefore, the aim of this study was to investigate the correlations between information processing speed and physical fatigue in a cohort of Italian PwMS from a single center, considering the effect of depression. Methods: Two hundred (W=128; mean age=39.83 years; SD=11.86) PwMS, from the Bari University Hospital, underwent testing for processing speed (Symbol Digit Modalities Test [SDMT]), fatigue level (Fatigue Severity Scale [FSS]), and depression (Beck's Depression Inventory [BDI]). Results: Statistically significant correlations emerged between SDMT and FSS, SDMT and BDI, FSS and BDI. Mediation analyses revealed that while physical fatig...

Research paper thumbnail of Magnetoencephalography and High-Density Electroencephalography Study of Acoustic Event Related Potentials in Early Stage of Multiple Sclerosis: A Pilot Study on Cognitive Impairment and Fatigue

Brain Sciences, 2021

Cognitive impairment (CI) is a common and disabling symptom of Multiple Sclerosis (MS) with a neg... more Cognitive impairment (CI) is a common and disabling symptom of Multiple Sclerosis (MS) with a negative impact on daily living. In this pilot study, we applied magnetoencephalography (MEG) and high density (hd) electroencephalography (EEG) study to evaluate acoustic P300 features in a cohort of early MS. Sixteen MS patients (pwMS) and 19 healthy controls (HCs) matched for age and gender underwent an MEG-/(hd)-EEG-co-recording, using 306-channel Vectorview and 64 scalp electrodes. CI was assessed using Rao’s Brief Repeatable Battery (BRB). Moreover, we performed psychometric tests to assess depression and fatigue. In pwMS, we observed a slight latency prolongation of P300 peak compared to HCs, while P300 amplitude and scalp distribution were similar in the two groups. pwMS did not show an amplitude reduction and different scalp distribution of Event-Related Potentials (ERPs) and Event Related Fields (ERFs) related to an acoustic oddball paradigm. We found an inverse correlation betwee...

Research paper thumbnail of Long-term cardiac safety and tolerability of fingolimod in multiple sclerosis: A postmarketing study

The Journal of Clinical Pharmacology, 2015

Fingolimod is the first oral disease-modifying therapy (DMT) approved for Multiple Sclerosis (MS)... more Fingolimod is the first oral disease-modifying therapy (DMT) approved for Multiple Sclerosis (MS). The risks associated with the use of Fingolimod include cardiovascular adverse-events (AEs). First-dose observation (FDO) is required for all patients for at least 6 hours. We describe FDO data and long term cardiac tolerability in a cohort of Fingolimod-treated relapsing MS patients. Two hundred and twelve patients started Fingolimod 0.5 mg once daily. Before the first administration all subjects had an electrocardiogram (ECG) with cardiologist interpretation. Following administration they were monitored for 6 hours and underwent a cardiac monitoring every three months. In this cohort, there was a heart rate (HR) reduction at the VI hour of 9.6± 8 beats per minute (bpm) (p value <0.001). Fifty-four individuals (25.5 %) presented an abnormal ECG during the six hours. We experienced one case (0.22 %) of symptomatic 2nd degree atrioventricular block (AVB). The mean follow-up period was 1.5± 0.7 years. During this period, one patient showed atrial fibrillation that needed to be treated. We also observed five cases of persistent increase in blood pressure (BP). This post-marketing study shows that Fingolimod is well tolerated and cardiologic AEs are generally self limited in the long term.

Research paper thumbnail of Long-Term Data of Efficacy, Safety, and Tolerability in a Real-Life Setting of THC/CBD Oromucosal Spray-Treated Multiple Sclerosis Patients

The Journal of Clinical Pharmacology, 2015

Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray was approved as add-on ther... more Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray was approved as add-on therapy for spasticity in patients with multiple sclerosis (MS). We show our 40-week postmarketing experience regarding efficacy and safety of THC/CBD spray in an Italian cohort of 102 MS patients. Patients were evaluated using the Expanded Disability Status Scale (EDSS) score, the Numerical Rating Scale (NRS) for spasticity, the Ambulation Index (AI), and Timed 25-Foot Walk (T25-FW) at the beginning of treatment and then every 3 months. After 4 weeks, if a clinically significant improvement in spasticity (at least 20% of baseline NRS score) was not seen, administration of the drug was stopped. In our cohort, patients received an average of 6.5 ± 1.6 sprays each day. The mean reduction to the NRS spasticity score was 2.5 ± 1.2 points (P < .0001). Thirty-seven patients (36.2%) discontinued the treatment. The incidence of adverse events (AEs) was 40.2%. Fifty-eight patients (56.9%) were also assessed using the NRS for pain, and 46 patients (45.1%) with bladder dysfunction were assessed for the IPSS (International Prostatic Symptoms Score) score, showing a significant improvement in these scales (P = .011 and P = .001, respectively). In conclusion, treatment with THC/CBD spray appears to be a valid answer to some of the unmet needs in MS patients, such as spasticity and other refractory-to-treatment symptoms.

Research paper thumbnail of Real-Life Experience of the Effects of Cladribine Tablets on Lymphocyte Subsets and Serum Neurofilament Light Chain Levels in Relapsing Multiple Sclerosis Patients

Brain Sciences

Although cladribine induces sustained reductions in peripheral T and B lymphocytes, little is kno... more Although cladribine induces sustained reductions in peripheral T and B lymphocytes, little is known about its effect on axonal damage reduction in multiple sclerosis (MS), which could be demonstrated by assessing the serum neurofilament light chain (sNfL) levels. We investigated the reduction/reconstitution of different lymphocyte subsets (LS) by verifying the correlation with no evidence of disease activity (NEDA) and the variation in sNfL levels during cladribine treatment. We analysed 33 highly active relapsing MS patients and followed them up for 12 ± 3.3 months; blood samples were collected at treatment start (W0) and after 8, 24 and 48 weeks. Seventeen patients (60.7%) showed NEDA during the first treatment. At week 8, we observed a significant decrease in B memory cells, B regulatory 1 CD19+/CD38+ and B regulatory 2 CD19+/CD25+, a significant increase in T regulatory CD4+/CD25+, a slight increase in T cytotoxic CD3+/CD8+ and a non-significant decrease in T helper CD3+/CD4+. S...

Research paper thumbnail of Distribution of the EDSS score in NAb- and NAb+ patients in the NN-matched cohort

<p>Distribution of the EDSS score in NAb- and NAb+ patients in the NN-matched cohort.</p

Research paper thumbnail of The risk of COVID-19 in people with multiple sclerosis: A case-control study from the Italian MS Register

Multiple Sclerosis Journal, 2021

Research paper thumbnail of The role of neutralizing antibodies to interferon-β as a biomarker of persistent MRI activity in multiple sclerosis: a 7-year observational study

European Journal of Clinical Pharmacology

Purpose During interferon-β (IFN-β) therapy, up to 45 % of patients may develop neutralizing anti... more Purpose During interferon-β (IFN-β) therapy, up to 45 % of patients may develop neutralizing antibodies (NAbs), associated with a decreased efficacy of the drug. We investigated in a real-life setting the impact of NAbs on magnetic resonance imaging (MRI) outcomes in a population of 567 IFN-β-treated relapsing-remitting (RR) multiple sclerosis (MS) patients up to 7 years. We also evaluated NAbs' role as a biomarker of the persistence of MRI disease activity. Methods Patients' sera were tested for NAbs' presence by cytopathic effect (CPE) assay every 6-12 months. MRI scans were performed every 12 months. Generalized hierarchical linear models accounting for within-patient correlation were used to analyze T1 gadolinium-enhancing and new T2 lesions. Moreover, further tests were carried out to assess the overall outcome difference from year 1 to year 7 according to NAb status and the possible interaction between NAb status and time of follow-up. Results Seventy-five patients (13.2 %) became NAb positive (NAb+) during the follow-up. Considering T1 gadoliniumenhancing (GD+) lesions, we observed a significantly higher incidence in NAb+ patients (52 %, p = 0.0091). Also for new T2 lesions, we found a higher incidence in NAb+ patients (50 %, p = 0.0075). The negative impact of NAbs on the MRI outcomes considered did not change during the follow-up. Conclusions Our 7-year results show the negative effect of NAbs on MRI measures of disease activity and confirm their role as a surrogate marker of IFN-β treatment efficacy.

Research paper thumbnail of Macular ganglion cell-inner plexiform layer defect patterns in multiple sclerosis patients without optic neuritis: A Spectral-Domain-Optical Coherence Tomography Cross-Sectional, Case-Control, Pilot Study

European Journal of Ophthalmology

Purpose Spectral-domain optical coherence tomography (SD-OCT) was used to evaluate, in patients w... more Purpose Spectral-domain optical coherence tomography (SD-OCT) was used to evaluate, in patients with multiple sclerosis without a history of optic neuritis (MSNON), the proportion of the different macular ganglion cell-inner plexiform layer complex (mGCIP) defect patterns. The results were compared with those of healthy controls (HCs). Methods In this cross-sectional case-control study, 34 eyes of 34 individuals, 17 with MSNON and 17 HCs, were evaluated. All participants underwent mGCIP thickness measurement using SD-OCT (Zeiss Cirrus HD-OCT 4000, macular cube protocol). The mGCIP defect patterns were classified in nine types (minimal, inner, outer, diffuse mild, diffuse severe inferior confined, inferior dominant, superior confined, and superior dominant), according to the shape derived by the deviation map of the instrument, and the proportion of each type was assessed. Results A mGCIP defect pattern was detected in 70.5% of MSNON eyes, with an inner type as the most frequent patt...

Research paper thumbnail of Annual per patient costs to manage MS patients (DMDs excluded)

Research paper thumbnail of Risk of Getting COVID-19 in People With Multiple Sclerosis

Neurology - Neuroimmunology Neuroinflammation, 2022

Background and ObjectivesSeveral studies have assessed risk factors associated with the severity ... more Background and ObjectivesSeveral studies have assessed risk factors associated with the severity of COVID-19 outcomes in people with multiple sclerosis (PwMS). The potential role of disease-modifying therapies (DMTs) and demographic and clinical factors on the risk of acquiring SARS-CoV-2 infection has not been evaluated so far. The objective of this study was to assess risk factors of contracting SARS-CoV-2 infection in PwMS by using data collected in the Italian MS Register (IMSR).MethodsA case-control (1:2) study was set up. Cases included PwMS with a confirmed diagnosis of COVID-19, and controls included PwMS without a confirmed diagnosis of COVID-19. Both groups were propensity score–matched by the date of COVID-19 diagnosis, the date of last visit, and the region of residence. No healthy controls were included in this study. COVID-19 risk was estimated by multivariable logistic regression models including demographic and clinical covariates. The impact of DMTs was assessed in ...

Research paper thumbnail of Neutralizing Antibodies and Multiple Sclerosis in the Era of Disease Modifying Treatments

During an era of rapid changes in Multiple Sclerosis (MS), the early identification of nonrespond... more During an era of rapid changes in Multiple Sclerosis (MS), the early identification of nonresponder patients to therapies is crucial in order to provide them an alternative treatment strategy. The need to identify biomarkers of therapeutic response is a challenge in MS. Biopharmaceutical products approved for MS, such as interferon beta (IFNβ), glatiramer acetate (GA), and natalizumab (NTZ), can lead to the development of antidrug antibodies (ADA), with detrimental effects on their efficacy. In this chapter the evidences of the impact of neutralizing antibodies (NAbs) during IFNβ, GA, and NTZ treatment on clinical and MRI outcomes will be reported. The use of NAbs testing in clinical practice remains a powerful tool in the management of MS therapy.

Research paper thumbnail of Author response for "A case report of late‐onset atypical Hemolytic Uremic Syndrome during interferon beta in multiple sclerosis: Open issues in literature review

Research paper thumbnail of Serum neurofilament light chain in a cohort of multiple sclerosis, MOG-antibody diseases and neuromyelitis optica spectrum disorders patients

Journal of the Neurological Sciences, 2021

Research paper thumbnail of Durvalumab and multiple sclerosis: a causal link or simple unmasking?

European Journal of Clinical Pharmacology, 2020

Research paper thumbnail of Longitudinal Evaluation of Serum MOG-IgG and AQP4-IgG Antibodies in NMOSD by a Semiquantitative Ratiometric Method

Frontiers in Neurology, 2021

Background and purpose: Immunoadsorption (IA) is an antibody-depleting therapy used to treat neur... more Background and purpose: Immunoadsorption (IA) is an antibody-depleting therapy used to treat neuromyelitis optica spectrum disorder (NMOSD) associated to antiaquaporin 4 (anti-AQP4-IgG) and antimyelin oligodendrocyte glycoprotein (anti-MOG-IgG) serum autoantibodies. Our aim was to evaluate longitudinal changes of serum MOG-IgG and AQP4-IgG antibody titer and to correlate it with the clinical status.Methods: Autoantibody titer and clinical features of two MOG-IgG+/AQP4-IgG– and two AQP4-IgG+/MOG-IgG– patients with NMOSD were collected at baseline (T0), after 6 IA courses (T1), and then 2 weeks (T2) and 6 months after treatment (T3). A fluorescent ratiometric assay was used for a quantitative detection of MOG and AQP4 antibodies, based on HEK-293 cells transfected with the full-length hMOG fused to GFP or h-AQP4-M23 isoform fused to m-cherry, respectively. We defined the antibody titer as MOG quantitative ratio (MOGqr) and AQP4 quantitative ratio (AQP4qr).Results: In Case 1, the MOGqr...

Research paper thumbnail of A case report of late‐onset atypical Hemolytic Uremic Syndrome during interferon beta in multiple sclerosis: Open issues in literature review

Brain and Behavior, 2020

Interferon beta (IFNβ) is a well‐established first‐line therapy for relapsing–remitting multiple ... more Interferon beta (IFNβ) is a well‐established first‐line therapy for relapsing–remitting multiple sclerosis (RRMS) patients and remains the most widely prescribed agent. Atypical hemolytic uremic syndrome (aHUS) represents a rare but severe adverse effect (AE) that could occur even after many years from the beginning of IFNβ therapy. Eculizumab is currently approved for treatment of aHUS and recently for neuromyelitis optica spectrum disorder (NMOSD) with aquaporin‐4 antibodies (AQP4‐IgG). In this article, we report the case of the latest onset of IFNβ‐related aHUS experienced by an MS patient and we briefly review the literature on this topic.

Research paper thumbnail of Effect of Cladribine on Neuronal Apoptosis: New Insight of In Vitro Study in Multiple Sclerosis Therapy

Brain Sciences, 2020

Background: Cladribine (2-CdA) can cross the blood–brain barrier, resulting in inhibition of DNA ... more Background: Cladribine (2-CdA) can cross the blood–brain barrier, resulting in inhibition of DNA synthesis and repair and disruption of cellular proliferation in actively dividing lymphocytes. No data on effect on neurons are available. Aim: To study “in vitro” 2-CdA apoptotic effects on neurons in healthy donor and multiple sclerosis patient lymphocytes. Methods: Neuroblastoma cells were co-cultured with lymphocytes, with and without 2-CdA. Results: Apoptosis increased in lymphocytes with 2-CdA; increase was also observed when lymphocytes were cultured with neuronal cells. However, neurons were not affected by 2-CdA for apoptosis. Conclusions: 2-CdA causes peripheral and central lymphocyte death preserving neurons, with a reasonable impact on inflammation and neuroprotection.

Research paper thumbnail of Development and validation of the ID-EC - the ITALIAN version of the identify chronic migraine

The Journal of Headache and Pain, 2019

Background: Case-finding tools, such as the Identify Chronic Migraine (ID-CM) questionnaire, can ... more Background: Case-finding tools, such as the Identify Chronic Migraine (ID-CM) questionnaire, can improve detection of CM and alleviate its significant societal burden. We aimed to develop and validate the Italian version of the ID-CM (ID-EC) in paper and as a smart app version in a headache clinic-based setting. Methods: The study investigators translated and adapted to the Italian language the original ID-CM questionnaire (ID-EC) and further implemented it as a smart app. The ID-EC was tested in its paper and electronic version in consecutive patients referring to 9 Italian tertiary headache centers for their first in-person visit. The scoring algorithm of the ID-EC paper version was applied by the study investigators (case-finding) and by patients (selfdiagnosis), while the smart app provided to patients automatically the diagnosis. Diagnostic accuracy of the ID-EC was assessed by matching the questionnaire results with the interview-based diagnoses performed by the headache specialists during the visit according to the criteria of International Classification of Headache Disorders, III edition, beta version. Results: We enrolled 531 patients in the test of the paper version of ID-EC and 427 in the validation study of the smart app. According to the clinical diagnosis 209 patients had CM in the paper version study and 202 had CM in the smart app study. 79.5% of patients returned valid paper questionnaires, while 100% of patients returned valid and complete smart app questionnaires. The paper questionnaire had a 81.5% sensitivity and a 81.1% specificity for case-finding and a 30.7% sensitivity and 90.7% specificity for self-diagnosis, while the smart app had a 64.9% sensitivity and 90.2% specificity. Conclusions: Our data suggest that the ID-EC, developed and validated in tertiary headache centers, is a valid casefinding tool for CM, with sensitivity and specificity values above 80% in paper form, while the ID-EC smart app is more useful to exclude CM diagnosis in case of a negative result. Further studies are warranted to assess the diagnostic accuracy of the ID-EC in general practice and population-based settings.

Research paper thumbnail of Efficacy and Safety of Oral Therapies for Relapsing-Remitting Multiple Sclerosis

CNS Drugs, 2020

Disease-modifying therapies have now become standard treatment for multiple sclerosis. These incl... more Disease-modifying therapies have now become standard treatment for multiple sclerosis. These include five oral therapies for relapsing-remitting multiple sclerosis, namely fingolimod, dimethyl fumarate, teriflunomide, cladribine, and siponimod, although there is some discrepancy on the relative efficacy and safety of these agents. To gain further insight on these oral agents in relapsing-remitting multiple sclerosis, we performed a narrative review of fingolimod, dimethyl fumarate, teriflunomide, cladribine, and siponimod. We limited the analysis to randomized clinical studies in which a comparator was used (i.e., placebo or other disease-modifying therapy). As relapsing-remitting multiple sclerosis is a chronic disease and treatment is lifelong, long-term outcomes were an additional focus. A total of 37 studies met inclusion criteria: 15 for fingolimod, 8 for dimethyl fumarate, 7 for teriflunomide, 4 for cladribine, and 3 for siponimod. All drugs showed some functional and magnetic resonance imaging benefit in nearly all clinical studies. The reduction in annual relapse rate was similar for fingolimod, dimethyl fumarate, and cladribine, and somewhat greater than for teriflunomide; there is limited information on the annual relapse rate for siponimod. For all drugs, the benefits reported at short follow-up times are broadly consistent with those seen at longer follow-up times. For fingolimod and dimethyl fumarate, there was a definite trend towards a progressively lower annual relapse rate with continuing treatment. The safety profile of all five drugs was considered to be acceptable, even after extended treatment. While these results should be treated with caution, they highlight that future head-to-head studies are needed to better understand the long-term benefits of disease-modifying therapies. Such information will be of value when considering the risk-benefit profile of these oral therapies.

Research paper thumbnail of Impact of depression on the perception of fatigue and information processing speed in a cohort of Multiple Sclerosis patients

Background:Information processing speed is commonly impaired in people with multiple sclerosis (P... more Background:Information processing speed is commonly impaired in people with multiple sclerosis (PwMS). However, depression and fatigue can affect the cognitive profile of patients: fatigue has a negative impact from the disease’s earliest stage and a reduced information processing speed is often associated with higher levels of depression. Therefore, the aim of this study was to investigate the correlations between information processing speed and physical fatigue in a cohort of Italian PwMS from a single center, considering the effect of depression. Methods: Two hundred (W=128; mean age=39.83 years; SD=11.86) PwMS, from the Bari University Hospital, underwent testing for processing speed (Symbol Digit Modalities Test [SDMT]), fatigue level (Fatigue Severity Scale [FSS]), and depression (Beck's Depression Inventory [BDI]). Results: Statistically significant correlations emerged between SDMT and FSS, SDMT and BDI, FSS and BDI. Mediation analyses revealed that while physical fatig...

Research paper thumbnail of Magnetoencephalography and High-Density Electroencephalography Study of Acoustic Event Related Potentials in Early Stage of Multiple Sclerosis: A Pilot Study on Cognitive Impairment and Fatigue

Brain Sciences, 2021

Cognitive impairment (CI) is a common and disabling symptom of Multiple Sclerosis (MS) with a neg... more Cognitive impairment (CI) is a common and disabling symptom of Multiple Sclerosis (MS) with a negative impact on daily living. In this pilot study, we applied magnetoencephalography (MEG) and high density (hd) electroencephalography (EEG) study to evaluate acoustic P300 features in a cohort of early MS. Sixteen MS patients (pwMS) and 19 healthy controls (HCs) matched for age and gender underwent an MEG-/(hd)-EEG-co-recording, using 306-channel Vectorview and 64 scalp electrodes. CI was assessed using Rao’s Brief Repeatable Battery (BRB). Moreover, we performed psychometric tests to assess depression and fatigue. In pwMS, we observed a slight latency prolongation of P300 peak compared to HCs, while P300 amplitude and scalp distribution were similar in the two groups. pwMS did not show an amplitude reduction and different scalp distribution of Event-Related Potentials (ERPs) and Event Related Fields (ERFs) related to an acoustic oddball paradigm. We found an inverse correlation betwee...

Research paper thumbnail of Long-term cardiac safety and tolerability of fingolimod in multiple sclerosis: A postmarketing study

The Journal of Clinical Pharmacology, 2015

Fingolimod is the first oral disease-modifying therapy (DMT) approved for Multiple Sclerosis (MS)... more Fingolimod is the first oral disease-modifying therapy (DMT) approved for Multiple Sclerosis (MS). The risks associated with the use of Fingolimod include cardiovascular adverse-events (AEs). First-dose observation (FDO) is required for all patients for at least 6 hours. We describe FDO data and long term cardiac tolerability in a cohort of Fingolimod-treated relapsing MS patients. Two hundred and twelve patients started Fingolimod 0.5 mg once daily. Before the first administration all subjects had an electrocardiogram (ECG) with cardiologist interpretation. Following administration they were monitored for 6 hours and underwent a cardiac monitoring every three months. In this cohort, there was a heart rate (HR) reduction at the VI hour of 9.6± 8 beats per minute (bpm) (p value <0.001). Fifty-four individuals (25.5 %) presented an abnormal ECG during the six hours. We experienced one case (0.22 %) of symptomatic 2nd degree atrioventricular block (AVB). The mean follow-up period was 1.5± 0.7 years. During this period, one patient showed atrial fibrillation that needed to be treated. We also observed five cases of persistent increase in blood pressure (BP). This post-marketing study shows that Fingolimod is well tolerated and cardiologic AEs are generally self limited in the long term.

Research paper thumbnail of Long-Term Data of Efficacy, Safety, and Tolerability in a Real-Life Setting of THC/CBD Oromucosal Spray-Treated Multiple Sclerosis Patients

The Journal of Clinical Pharmacology, 2015

Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray was approved as add-on ther... more Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray was approved as add-on therapy for spasticity in patients with multiple sclerosis (MS). We show our 40-week postmarketing experience regarding efficacy and safety of THC/CBD spray in an Italian cohort of 102 MS patients. Patients were evaluated using the Expanded Disability Status Scale (EDSS) score, the Numerical Rating Scale (NRS) for spasticity, the Ambulation Index (AI), and Timed 25-Foot Walk (T25-FW) at the beginning of treatment and then every 3 months. After 4 weeks, if a clinically significant improvement in spasticity (at least 20% of baseline NRS score) was not seen, administration of the drug was stopped. In our cohort, patients received an average of 6.5 ± 1.6 sprays each day. The mean reduction to the NRS spasticity score was 2.5 ± 1.2 points (P < .0001). Thirty-seven patients (36.2%) discontinued the treatment. The incidence of adverse events (AEs) was 40.2%. Fifty-eight patients (56.9%) were also assessed using the NRS for pain, and 46 patients (45.1%) with bladder dysfunction were assessed for the IPSS (International Prostatic Symptoms Score) score, showing a significant improvement in these scales (P = .011 and P = .001, respectively). In conclusion, treatment with THC/CBD spray appears to be a valid answer to some of the unmet needs in MS patients, such as spasticity and other refractory-to-treatment symptoms.

Research paper thumbnail of Real-Life Experience of the Effects of Cladribine Tablets on Lymphocyte Subsets and Serum Neurofilament Light Chain Levels in Relapsing Multiple Sclerosis Patients

Brain Sciences

Although cladribine induces sustained reductions in peripheral T and B lymphocytes, little is kno... more Although cladribine induces sustained reductions in peripheral T and B lymphocytes, little is known about its effect on axonal damage reduction in multiple sclerosis (MS), which could be demonstrated by assessing the serum neurofilament light chain (sNfL) levels. We investigated the reduction/reconstitution of different lymphocyte subsets (LS) by verifying the correlation with no evidence of disease activity (NEDA) and the variation in sNfL levels during cladribine treatment. We analysed 33 highly active relapsing MS patients and followed them up for 12 ± 3.3 months; blood samples were collected at treatment start (W0) and after 8, 24 and 48 weeks. Seventeen patients (60.7%) showed NEDA during the first treatment. At week 8, we observed a significant decrease in B memory cells, B regulatory 1 CD19+/CD38+ and B regulatory 2 CD19+/CD25+, a significant increase in T regulatory CD4+/CD25+, a slight increase in T cytotoxic CD3+/CD8+ and a non-significant decrease in T helper CD3+/CD4+. S...

Research paper thumbnail of Distribution of the EDSS score in NAb- and NAb+ patients in the NN-matched cohort

<p>Distribution of the EDSS score in NAb- and NAb+ patients in the NN-matched cohort.</p

Research paper thumbnail of The risk of COVID-19 in people with multiple sclerosis: A case-control study from the Italian MS Register

Multiple Sclerosis Journal, 2021

Research paper thumbnail of The role of neutralizing antibodies to interferon-β as a biomarker of persistent MRI activity in multiple sclerosis: a 7-year observational study

European Journal of Clinical Pharmacology

Purpose During interferon-β (IFN-β) therapy, up to 45 % of patients may develop neutralizing anti... more Purpose During interferon-β (IFN-β) therapy, up to 45 % of patients may develop neutralizing antibodies (NAbs), associated with a decreased efficacy of the drug. We investigated in a real-life setting the impact of NAbs on magnetic resonance imaging (MRI) outcomes in a population of 567 IFN-β-treated relapsing-remitting (RR) multiple sclerosis (MS) patients up to 7 years. We also evaluated NAbs' role as a biomarker of the persistence of MRI disease activity. Methods Patients' sera were tested for NAbs' presence by cytopathic effect (CPE) assay every 6-12 months. MRI scans were performed every 12 months. Generalized hierarchical linear models accounting for within-patient correlation were used to analyze T1 gadolinium-enhancing and new T2 lesions. Moreover, further tests were carried out to assess the overall outcome difference from year 1 to year 7 according to NAb status and the possible interaction between NAb status and time of follow-up. Results Seventy-five patients (13.2 %) became NAb positive (NAb+) during the follow-up. Considering T1 gadoliniumenhancing (GD+) lesions, we observed a significantly higher incidence in NAb+ patients (52 %, p = 0.0091). Also for new T2 lesions, we found a higher incidence in NAb+ patients (50 %, p = 0.0075). The negative impact of NAbs on the MRI outcomes considered did not change during the follow-up. Conclusions Our 7-year results show the negative effect of NAbs on MRI measures of disease activity and confirm their role as a surrogate marker of IFN-β treatment efficacy.

Research paper thumbnail of Macular ganglion cell-inner plexiform layer defect patterns in multiple sclerosis patients without optic neuritis: A Spectral-Domain-Optical Coherence Tomography Cross-Sectional, Case-Control, Pilot Study

European Journal of Ophthalmology

Purpose Spectral-domain optical coherence tomography (SD-OCT) was used to evaluate, in patients w... more Purpose Spectral-domain optical coherence tomography (SD-OCT) was used to evaluate, in patients with multiple sclerosis without a history of optic neuritis (MSNON), the proportion of the different macular ganglion cell-inner plexiform layer complex (mGCIP) defect patterns. The results were compared with those of healthy controls (HCs). Methods In this cross-sectional case-control study, 34 eyes of 34 individuals, 17 with MSNON and 17 HCs, were evaluated. All participants underwent mGCIP thickness measurement using SD-OCT (Zeiss Cirrus HD-OCT 4000, macular cube protocol). The mGCIP defect patterns were classified in nine types (minimal, inner, outer, diffuse mild, diffuse severe inferior confined, inferior dominant, superior confined, and superior dominant), according to the shape derived by the deviation map of the instrument, and the proportion of each type was assessed. Results A mGCIP defect pattern was detected in 70.5% of MSNON eyes, with an inner type as the most frequent patt...

Research paper thumbnail of Annual per patient costs to manage MS patients (DMDs excluded)

Research paper thumbnail of Risk of Getting COVID-19 in People With Multiple Sclerosis

Neurology - Neuroimmunology Neuroinflammation, 2022

Background and ObjectivesSeveral studies have assessed risk factors associated with the severity ... more Background and ObjectivesSeveral studies have assessed risk factors associated with the severity of COVID-19 outcomes in people with multiple sclerosis (PwMS). The potential role of disease-modifying therapies (DMTs) and demographic and clinical factors on the risk of acquiring SARS-CoV-2 infection has not been evaluated so far. The objective of this study was to assess risk factors of contracting SARS-CoV-2 infection in PwMS by using data collected in the Italian MS Register (IMSR).MethodsA case-control (1:2) study was set up. Cases included PwMS with a confirmed diagnosis of COVID-19, and controls included PwMS without a confirmed diagnosis of COVID-19. Both groups were propensity score–matched by the date of COVID-19 diagnosis, the date of last visit, and the region of residence. No healthy controls were included in this study. COVID-19 risk was estimated by multivariable logistic regression models including demographic and clinical covariates. The impact of DMTs was assessed in ...

Research paper thumbnail of Neutralizing Antibodies and Multiple Sclerosis in the Era of Disease Modifying Treatments

During an era of rapid changes in Multiple Sclerosis (MS), the early identification of nonrespond... more During an era of rapid changes in Multiple Sclerosis (MS), the early identification of nonresponder patients to therapies is crucial in order to provide them an alternative treatment strategy. The need to identify biomarkers of therapeutic response is a challenge in MS. Biopharmaceutical products approved for MS, such as interferon beta (IFNβ), glatiramer acetate (GA), and natalizumab (NTZ), can lead to the development of antidrug antibodies (ADA), with detrimental effects on their efficacy. In this chapter the evidences of the impact of neutralizing antibodies (NAbs) during IFNβ, GA, and NTZ treatment on clinical and MRI outcomes will be reported. The use of NAbs testing in clinical practice remains a powerful tool in the management of MS therapy.

Research paper thumbnail of Author response for "A case report of late‐onset atypical Hemolytic Uremic Syndrome during interferon beta in multiple sclerosis: Open issues in literature review

Research paper thumbnail of Serum neurofilament light chain in a cohort of multiple sclerosis, MOG-antibody diseases and neuromyelitis optica spectrum disorders patients

Journal of the Neurological Sciences, 2021

Research paper thumbnail of Durvalumab and multiple sclerosis: a causal link or simple unmasking?

European Journal of Clinical Pharmacology, 2020

Research paper thumbnail of Longitudinal Evaluation of Serum MOG-IgG and AQP4-IgG Antibodies in NMOSD by a Semiquantitative Ratiometric Method

Frontiers in Neurology, 2021

Background and purpose: Immunoadsorption (IA) is an antibody-depleting therapy used to treat neur... more Background and purpose: Immunoadsorption (IA) is an antibody-depleting therapy used to treat neuromyelitis optica spectrum disorder (NMOSD) associated to antiaquaporin 4 (anti-AQP4-IgG) and antimyelin oligodendrocyte glycoprotein (anti-MOG-IgG) serum autoantibodies. Our aim was to evaluate longitudinal changes of serum MOG-IgG and AQP4-IgG antibody titer and to correlate it with the clinical status.Methods: Autoantibody titer and clinical features of two MOG-IgG+/AQP4-IgG– and two AQP4-IgG+/MOG-IgG– patients with NMOSD were collected at baseline (T0), after 6 IA courses (T1), and then 2 weeks (T2) and 6 months after treatment (T3). A fluorescent ratiometric assay was used for a quantitative detection of MOG and AQP4 antibodies, based on HEK-293 cells transfected with the full-length hMOG fused to GFP or h-AQP4-M23 isoform fused to m-cherry, respectively. We defined the antibody titer as MOG quantitative ratio (MOGqr) and AQP4 quantitative ratio (AQP4qr).Results: In Case 1, the MOGqr...

Research paper thumbnail of A case report of late‐onset atypical Hemolytic Uremic Syndrome during interferon beta in multiple sclerosis: Open issues in literature review

Brain and Behavior, 2020

Interferon beta (IFNβ) is a well‐established first‐line therapy for relapsing–remitting multiple ... more Interferon beta (IFNβ) is a well‐established first‐line therapy for relapsing–remitting multiple sclerosis (RRMS) patients and remains the most widely prescribed agent. Atypical hemolytic uremic syndrome (aHUS) represents a rare but severe adverse effect (AE) that could occur even after many years from the beginning of IFNβ therapy. Eculizumab is currently approved for treatment of aHUS and recently for neuromyelitis optica spectrum disorder (NMOSD) with aquaporin‐4 antibodies (AQP4‐IgG). In this article, we report the case of the latest onset of IFNβ‐related aHUS experienced by an MS patient and we briefly review the literature on this topic.

Research paper thumbnail of Effect of Cladribine on Neuronal Apoptosis: New Insight of In Vitro Study in Multiple Sclerosis Therapy

Brain Sciences, 2020

Background: Cladribine (2-CdA) can cross the blood–brain barrier, resulting in inhibition of DNA ... more Background: Cladribine (2-CdA) can cross the blood–brain barrier, resulting in inhibition of DNA synthesis and repair and disruption of cellular proliferation in actively dividing lymphocytes. No data on effect on neurons are available. Aim: To study “in vitro” 2-CdA apoptotic effects on neurons in healthy donor and multiple sclerosis patient lymphocytes. Methods: Neuroblastoma cells were co-cultured with lymphocytes, with and without 2-CdA. Results: Apoptosis increased in lymphocytes with 2-CdA; increase was also observed when lymphocytes were cultured with neuronal cells. However, neurons were not affected by 2-CdA for apoptosis. Conclusions: 2-CdA causes peripheral and central lymphocyte death preserving neurons, with a reasonable impact on inflammation and neuroprotection.

Research paper thumbnail of Development and validation of the ID-EC - the ITALIAN version of the identify chronic migraine

The Journal of Headache and Pain, 2019

Background: Case-finding tools, such as the Identify Chronic Migraine (ID-CM) questionnaire, can ... more Background: Case-finding tools, such as the Identify Chronic Migraine (ID-CM) questionnaire, can improve detection of CM and alleviate its significant societal burden. We aimed to develop and validate the Italian version of the ID-CM (ID-EC) in paper and as a smart app version in a headache clinic-based setting. Methods: The study investigators translated and adapted to the Italian language the original ID-CM questionnaire (ID-EC) and further implemented it as a smart app. The ID-EC was tested in its paper and electronic version in consecutive patients referring to 9 Italian tertiary headache centers for their first in-person visit. The scoring algorithm of the ID-EC paper version was applied by the study investigators (case-finding) and by patients (selfdiagnosis), while the smart app provided to patients automatically the diagnosis. Diagnostic accuracy of the ID-EC was assessed by matching the questionnaire results with the interview-based diagnoses performed by the headache specialists during the visit according to the criteria of International Classification of Headache Disorders, III edition, beta version. Results: We enrolled 531 patients in the test of the paper version of ID-EC and 427 in the validation study of the smart app. According to the clinical diagnosis 209 patients had CM in the paper version study and 202 had CM in the smart app study. 79.5% of patients returned valid paper questionnaires, while 100% of patients returned valid and complete smart app questionnaires. The paper questionnaire had a 81.5% sensitivity and a 81.1% specificity for case-finding and a 30.7% sensitivity and 90.7% specificity for self-diagnosis, while the smart app had a 64.9% sensitivity and 90.2% specificity. Conclusions: Our data suggest that the ID-EC, developed and validated in tertiary headache centers, is a valid casefinding tool for CM, with sensitivity and specificity values above 80% in paper form, while the ID-EC smart app is more useful to exclude CM diagnosis in case of a negative result. Further studies are warranted to assess the diagnostic accuracy of the ID-EC in general practice and population-based settings.

Research paper thumbnail of Efficacy and Safety of Oral Therapies for Relapsing-Remitting Multiple Sclerosis

CNS Drugs, 2020

Disease-modifying therapies have now become standard treatment for multiple sclerosis. These incl... more Disease-modifying therapies have now become standard treatment for multiple sclerosis. These include five oral therapies for relapsing-remitting multiple sclerosis, namely fingolimod, dimethyl fumarate, teriflunomide, cladribine, and siponimod, although there is some discrepancy on the relative efficacy and safety of these agents. To gain further insight on these oral agents in relapsing-remitting multiple sclerosis, we performed a narrative review of fingolimod, dimethyl fumarate, teriflunomide, cladribine, and siponimod. We limited the analysis to randomized clinical studies in which a comparator was used (i.e., placebo or other disease-modifying therapy). As relapsing-remitting multiple sclerosis is a chronic disease and treatment is lifelong, long-term outcomes were an additional focus. A total of 37 studies met inclusion criteria: 15 for fingolimod, 8 for dimethyl fumarate, 7 for teriflunomide, 4 for cladribine, and 3 for siponimod. All drugs showed some functional and magnetic resonance imaging benefit in nearly all clinical studies. The reduction in annual relapse rate was similar for fingolimod, dimethyl fumarate, and cladribine, and somewhat greater than for teriflunomide; there is limited information on the annual relapse rate for siponimod. For all drugs, the benefits reported at short follow-up times are broadly consistent with those seen at longer follow-up times. For fingolimod and dimethyl fumarate, there was a definite trend towards a progressively lower annual relapse rate with continuing treatment. The safety profile of all five drugs was considered to be acceptable, even after extended treatment. While these results should be treated with caution, they highlight that future head-to-head studies are needed to better understand the long-term benefits of disease-modifying therapies. Such information will be of value when considering the risk-benefit profile of these oral therapies.