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1. A comparison of natalizumab and ocrelizumab on disease progression in multiple sclerosis

Author: Pietro Iaffaldano, Giuseppe Lucisano, Tommaso Guerra, Damiano Paolicelli, Emilio Portaccio, Matilde Inglese, Matteo Foschi, Francesco Patti, Franco Granella, Silvia Romano, Paola Cavalla, Giovanna De Luca, Paolo Gallo, Paolo Bellantonio, Antonio Gallo, Sara Montepietra, Alessia Di Sapio, Marika Vianello, Rocco Quatrale, Daniele Spitaleri, Raffaella Clerici, Valentina Torri Clerici, Eleonora Cocco, Vincenzo Brescia Morra, Girolama Alessandra Marfia, Vincenzo Daniele Boccia, Massimo Filippi, Maria Pia Amato, Maria Trojano, and the Italian MS Register
Subjects: Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Objective No direct comparisons of the effect of natalizumab and ocrelizumab on progression independent of relapse activity (PIRA) and relapse‐associated worsening (RAW) events are currently available. We aimed to compare the risk of achieving first 6 months confirmed PIRA and RAW events and irreversible Expanded Disability Status Scale (EDSS) 4.0 and 6.0 in a cohort of naïve patients treated with natalizumab or ocrelizumab from the Italian Multiple Sclerosis Register. Methods Patients with a first visit within 1 year from onset, treated with natalizumab or ocrelizumab, and ≥3 visits were extracted. Pairwise propensity score‐matched analyses were performed. Risk of reaching the first PIRA, RAW, and EDSS 4.0 and 6.0 events were estimated using multivariable Cox proportional hazards models. Kaplan–Meier curves were used to show cumulative probabilities of reaching outcomes. Results In total, 770 subjects were included (natalizumab = 568; ocrelizumab = 212) and the propensity score‐matching retrieved 195 pairs. No RAW events were found in natalizumab group and only 1 was reported in ocrelizumab group. A first PIRA event was reached by 23 natalizumab and 25 ocrelizumab exposed patients; 7 natalizumab‐ and 10 ocrelizumab‐treated patients obtained an irreversible EDSS 4.0, while 13 natalizumab‐ and 15 ocrelizumab‐treated patients reached an irreversible EDSS 6.0. No differences between the two groups were found in the risk (HR, 95%CI) of reaching a first PIRA (1.04, 0.59–1.84; p = 0.88) event, an irreversible EDSS 4.0 (1.23, 0.57–2.66; p = 0.60) and 6.0 (0.93, 0.32–2.68; p = 0.89). Interpretation Both medications strongly suppress RAW events and, in the short term, the risk of achieving PIRA events, EDSS 4.0 and 6.0 milestones is not significantly different.
Published: 2024
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2. 3018 A multi-centre longitudinal study analysing disease modifying therapy prescribing patterns during the COVID-19 pandemic

Author: Nevin John, Steve Vucic, Riadh Gouider, Tomas Kalincik, Guillermo Izquierdo, Alexandre Prat, Marc Girard, Pierre Duquette, Pierre Grammond, Serkan Ozakbas, Jeannette Lechner-Scott, Cavit Boz, Julie Prevost, Recai Turkoglu, Vincent Van Pesch, Cristina Ramo-Tello, Mark Slee, Raed Alroughani, Vahid Shaygannejad, Daniele Spitaleri, José Luis Sánchez-Menoyo, Suzanne Hodgkinson, Rana Karabudak, Tim Spelman, Helmut Butzkueven, Noriko Isobe, Paul G Sanfilippo, Michael Barnett, Orla Gray, Maria José Sá, Allan Kermode, Guy Laureys, Richard Macdonell, Anneke Van Der Walt, Ayse Altintas, Mario Habek, Pamela McCombe, Seyed Mohammad Baghbanian, Yi Chao Foong, Riki Matsumoto, Abdullah Al-Asmi, Bruce Taylor, Samia J Khoury, Todd Hardy, Katherine Buzzard, Marzena Fabis-Pedrini, Louise Rath, Olga Skibina, Jiwon Oh, William M Carroll, Katrin Gross-Paju, Jan Schepel, Sara Eichau, Elisabetta Cartechini, Aysun Soysal, Davide Maimone, Anoushka Lal, Masoud Etemadifar, Oliver Gerlach, Saloua Mrabet, Emanuele D'Amico, Yolanda Blanco, Matteo Foschi, Melissa Cambron, Andrea Surcinelli, David Levitz, Liesbeth Van Hijfte, Mehmet Fatih Yetkin, Simón Cárdenas-Robledo, Emmanuelle Lapointe, Abdorreza Naser Moghadasi, Gregor Brecl Jakob, and Talal Al-Harbi
Subjects: Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Published: 2024
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3. Long-term effectiveness of natalizumab in secondary progressive multiple sclerosis: A propensity-matched study

Author: Clara G. Chisari, Umberto Aguglia, Maria Pia Amato, Roberto Bergamaschi, Antonio Bertolotto, Simona Bonavita, Vincenzo Brescia Morra, Paola Cavalla, Eleonora Cocco, Antonella Conte, Salvatore Cottone, Giovanna De Luca, Alessia Di Sapio, Massimo Filippi, Antonio Gallo, Claudio Gasperini, Franco Granella, Giacomo Lus, Davide Maimone, Giorgia Teresa Maniscalco, Girolama Marfia, Lucia Moiola, Damiano Paolicelli, Ilaria Pesci, Paolo Ragonese, Marco Rovaris, Giuseppe Salemi, Claudio Solaro, Rocco Totaro, Maria Trojano, Marika Vianello, Mauro Zaffaroni, Vito Lepore, Francesco Patti, Carlo Avolio, Roberto Balgera, Paola Banfi, Paolo Bellantonio, Placido Bramanti, Lorenzo Capone, Guido Cavalletti, Luca Chiveri, Raffaella Clerici, Marinella Clerico, Francesco Corea, Vincenzo Dattola, Francesca De Robertis, Giancarlo Di Battista, Simonetta Galgani, Maurizia Gatto, Maria Grazia Grasso, Matilde Inglese, Lorenzo Lo Russo, Francesco Ottavio Logullo, Renato Mantegazza, Alessandra Protti, Monica Rezzonico, Mariarosa Rottoli, Marco Salvetti, Elio Scarpini, Leonardo Sinisi, Maddalena Sparaco, Daniele Spitaleri, Tiziana Tassinari, Simone Tonietti, Paola Valentino, Franco Valzania, and Simonetta Venturi
Subjects: Natalizumab, Interferon beta 1b, Secondary progressive multiple sclerosis, Disability progression, Neurology. Diseases of the nervous system, RC346-429
Abstract: Treatment options for secondary progressive MS (SPMS) are limited, especially considering that the new drugs recently approved are licensed for actively relapsing patients. We aimed to compare the disability progression in a real-world cohort of SPMS patients treated with natalizumab (NTZ) or interferon beta-1b (IFNb-1b). This multicenter retrospective enrolled patients with a diagnosis of SPMS according to 2014 Lublin criteria, who received NTZ or IFNb-1b for at least 48 months between the 1st June 2012 and the 15th May 2018 at 33 Italian MS centers contributing to the Italian MS Registry NTZ or IFNb-1b. Confirmed Expanded Disability Status Scale worsening (CEW) and progression independent of relapse (PIRA) were evaluated. In order to correct for non-randomization, a propensity score matching of the groups was performed. Out of 5206 MS patients identified at the time of data extraction, 421 SPMS patients treated with NTZ (224 [53.2%] females, mean age 45.3 ± 25.4 years) and 353 with IFNb-1b (133 [37.8%] females, mean age 48.5 ± 19.8 years) were enrolled. After applying the matching procedure, 102 patients were retained in the NTZ group and 98 in the IFNb-2b group. The proportion of patients who reached the 48-month 1-point CEW was significantly higher in IFNb-1b compared to NTZ group (58.2% versus 30.4%, p = 0.01). The proportion of patients who developed PIRA at 48 months were significantly higher in IFNb-1b compared to NTZ (72.4% versus 40.2%, p = 0.01). EDSS before treatment initiation and SPMS duration were risk factors for disability progression in terms of PIRA (HR 2.54, 25%CI 1.67–5.7; p = 0.006 and HR 2.04, 25%CI 1.22–3.35; p = 0.01, respectively). Patients treated with IFNb-1b were 1.64 times more to likely to develop PIRA (HR 1.64, 25%CI 1.04–4.87; p = 0.001). Treatment with NTZ in SPMS patients showed more favorable disability outcomes compared to IFNb-1b with beneficial effects over 48 months.
Published: 2024
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4. Machine-learning-based prediction of disability progression in multiple sclerosis: An observational, international, multi-center study.

Author: Edward De Brouwer, Thijs Becker, Lorin Werthen-Brabants, Pieter Dewulf, Dimitrios Iliadis, Cathérine Dekeyser, Guy Laureys, Bart Van Wijmeersch, Veronica Popescu, Tom Dhaene, Dirk Deschrijver, Willem Waegeman, Bernard De Baets, Michiel Stock, Dana Horakova, Francesco Patti, Guillermo Izquierdo, Sara Eichau, Marc Girard, Alexandre Prat, Alessandra Lugaresi, Pierre Grammond, Tomas Kalincik, Raed Alroughani, Francois Grand'Maison, Olga Skibina, Murat Terzi, Jeannette Lechner-Scott, Oliver Gerlach, Samia J Khoury, Elisabetta Cartechini, Vincent Van Pesch, Maria José Sà, Bianca Weinstock-Guttman, Yolanda Blanco, Radek Ampapa, Daniele Spitaleri, Claudio Solaro, Davide Maimone, Aysun Soysal, Gerardo Iuliano, Riadh Gouider, Tamara Castillo-Triviño, José Luis Sánchez-Menoyo, Anneke van der Walt, Jiwon Oh, Eduardo Aguera-Morales, Ayse Altintas, Abdullah Al-Asmi, Koen de Gans, Yara Fragoso, Tunde Csepany, Suzanne Hodgkinson, Norma Deri, Talal Al-Harbi, Bruce Taylor, Orla Gray, Patrice Lalive, Csilla Rozsa, Chris McGuigan, Allan Kermode, Angel Pérez Sempere, Simu Mihaela, Magdolna Simo, Todd Hardy, Danny Decoo, Stella Hughes, Nikolaos Grigoriadis, Attila Sas, Norbert Vella, Yves Moreau, and Liesbet Peeters
Subjects: Computer applications to medicine. Medical informatics, R858-859.7
Abstract: BackgroundDisability progression is a key milestone in the disease evolution of people with multiple sclerosis (PwMS). Prediction models of the probability of disability progression have not yet reached the level of trust needed to be adopted in the clinic. A common benchmark to assess model development in multiple sclerosis is also currently lacking.MethodsData of adult PwMS with a follow-up of at least three years from 146 MS centers, spread over 40 countries and collected by the MSBase consortium was used. With basic inclusion criteria for quality requirements, it represents a total of 15, 240 PwMS. External validation was performed and repeated five times to assess the significance of the results. Transparent Reporting for Individual Prognosis Or Diagnosis (TRIPOD) guidelines were followed. Confirmed disability progression after two years was predicted, with a confirmation window of six months. Only routinely collected variables were used such as the expanded disability status scale, treatment, relapse information, and MS course. To learn the probability of disability progression, state-of-the-art machine learning models were investigated. The discrimination performance of the models is evaluated with the area under the receiver operator curve (ROC-AUC) and under the precision recall curve (AUC-PR), and their calibration via the Brier score and the expected calibration error. All our preprocessing and model code are available at https://gitlab.com/edebrouwer/ms_benchmark, making this task an ideal benchmark for predicting disability progression in MS.FindingsMachine learning models achieved a ROC-AUC of 0⋅71 ± 0⋅01, an AUC-PR of 0⋅26 ± 0⋅02, a Brier score of 0⋅1 ± 0⋅01 and an expected calibration error of 0⋅07 ± 0⋅04. The history of disability progression was identified as being more predictive for future disability progression than the treatment or relapses history.ConclusionsGood discrimination and calibration performance on an external validation set is achieved, using only routinely collected variables. This suggests machine-learning models can reliably inform clinicians about the future occurrence of progression and are mature for a clinical impact study.
Published: 2024
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5. Distinct Neuropsychological Correlates of Apathy Sub-Domains in Multiple Sclerosis

Author: Simona Raimo, Mariachiara Gaita, Antonio Costanzo, Daniele Spitaleri, and Gabriella Santangelo
Subjects: multiple sclerosis, apathy, behavioral disorders, cognitive dysfunctions, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Background: Apathy is relatively frequent and significantly associated with clinical and cognitive outcomes in Multiple Sclerosis (MS), even if previous research has produced mixed results. This varied picture could be due to most studies treating apathy as a unitary construct, despite the evidence showing that apathy is a multifaceted syndrome including three different sub-domains (i.e., cognitive, affective, and behavioral). This study aims to investigate the neuropsychological correlates of apathy fractionated into its three sub-domains in participants with MS. Methods: Eighty-five participants with MS underwent a comprehensive neuropsychological battery. The severity of apathy symptoms was assessed by the self-report version of the Apathy Evaluation Scale. Results: Correlational analysis showed that cognitive apathy sub-domain scores had a high correlation with the performances obtained at cognitive tests tapping into inhibitory control (i.e., IML and Strop test-interference task), whereas the affective apathy sub-domain scores had a high correlation with the performances obtained at cognitive test tapping into the use of executive functions in visuospatial abilities (i.e., Clock Drawing Test). Moreover, linear regression analysis results showed that the cognitive apathy sub-domain scores predicted executive functioning domain scores and that the cognitive and affective apathy sub-domains scores predicted visuospatial abilities domain scores. Conclusion: These results confirm that apathy is a multidimensional concept with important neuropsychological correlates, visible only when it is fractionated into its sub-domains.
Published: 2023
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6. Hypercalcemia and Nephrogenic Diabetes Insipidus: Rare and Life-Threatening Effects of Lithium Intoxication

Author: Arturo de Falco, Maria Lieto, Valentina Scarano, Daniele Spitaleri, and Vincenzo Palma
Subjects: lithium toxicity, hypercalcemia, nephrogenic diabetes insipidus, hypernatremia, Medicine (General), R5-920
Abstract: Lithium is the most effective therapy for bipolar and schizoaffective disorders. Despite its efficacy, lithium has a narrow therapeutic index and adverse effects are frequent. Lithium intoxication (LI) generally affects brain, but less frequently can affect kidneys, thyroid, and parathyroid. Here, we report the case of a patient with lithium neurotoxic effects complicated by parathyroid and renal adverse effects. The patient was a 52-year-old woman treated with lithium, who was recently diagnosed with hypercalcemia and hyperparathyroidism. She was admitted for severe agitation, confusion, and diffuse tremor. Despite serum lithium and calcium normalization, laboratory tests revealed a life-threatening hypernatremia caused by nephrogenic diabetes insipidus (NDI). Hemodialysis was started, but after the first treatment the patient died for cardiac arrest. Neurological symptoms of LI may occur even if the dosage is close to the normal therapeutic range. Hypercalcemia and NDI are rare, but should be promptly diagnosed and treated. In case of poor clinical outcome, hemodialysis should be performed independently of lithium serum level.
Published: 2020
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7. The Association of Olfactory Dysfunction, Frailty, and Mortality Is Mediated by Inflammation: Results from the InCHIANTI Study

Author: Alice Laudisio, Luca Navarini, Domenico Paolo Emanuele Margiotta, Davide Onofrio Fontana, Irene Chiarella, Daniele Spitaleri, Stefania Bandinelli, Antonella Gemma, Luigi Ferrucci, and Raffaele Antonelli Incalzi
Subjects: Immunologic diseases. Allergy, RC581-607
Abstract: Background. Olfactory dysfunction might unveil the association between ageing and frailty, as it is associated with declining cognitive function, depression, reduced physical performance, reduced dietary intake, and mortality; all these conditions are characterized by increased levels of inflammatory parameters. The present study is aimed at evaluating the association between olfactory dysfunction, frailty, and mortality and whether such association might be mediated by inflammation. Methods. We analysed data of 1035 participants aged 65+ enrolled in the “InCHIANTI” study. Olfactory function was tested by the recognition of the smells of coffee, mint, and air. Olfactory dysfunction was defined as lack of recognition of at least two smells. Considering the items “shrinking,” “exhaustion,” “sedentariness,” “slowness,” and “weakness” included in the Fried definition, frailty was defined as the presence of at least three criteria, prefrailty of one or two, and robustness of none. Serum interleukin-6 (IL-6) was measured in duplicate by high-sensitivity enzyme-linked immunosorbent assays. Logistic regression was adopted to assess the association of frailty with olfactory function, as well as with the increasing number of olfactory deficits. Cox regression was used to test the association between olfactory dysfunction and 9-year survival. Results. Olfactory dysfunction was associated with frailty, after adjusting (OR 1.94, 95% CI=1.07-3.51; P=.028); analysis of the interaction term indicated that the association varied according to interleukin-6 levels (P for interaction=.005). Increasing levels of olfactory dysfunction were associated with increasing probability of being frail. Also, olfactory dysfunction was associated with reduced survival (HR 1.52, 95% CI=1.16-1.98; P=.002); this association varied according to the presence of frailty (P for interaction=.017) and prefrailty status (P for interaction=.046), as well as increased interleukin-6 levels (P for interaction = .011). Conclusions. Impairment of olfactory function might represent a marker of frailty, prefrailty, and consequently reduced survival in an advanced age. Inflammation might represent the possible link between these conditions.
Published: 2019
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8. Sativex in resistant multiple sclerosis spasticity: Discontinuation study in a large population of Italian patients (SA.FE. study).

Author: Silvia Messina, Claudio Solaro, Isabella Righini, Roberto Bergamaschi, Simona Bonavita, Roberto Bruno Bossio, Vincenzo Brescia Morra, Gianfranco Costantino, Paola Cavalla, Diego Centonze, Giancarlo Comi, Salvatore Cottone, Maura Chiara Danni, Ada Francia, Alberto Gajofatto, Claudio Gasperini, Mauro Zaffaroni, Loredana Petrucci, Elisabetta Signoriello, Giorgia Teresa Maniscalco, Gabriella Spinicci, Manuela Matta, Massimiliano Mirabella, Graziella Pedà, Letizia Castelli, Marco Rovaris, Edoardo Sessa, Daniele Spitaleri, Damiano Paolicelli, Alfredo Granata, Mario Zappia, Francesco Patti, and SA.FE. study group
Subjects: Medicine, Science
Abstract: The approval of Sativex for the management of multiple sclerosis (MS) spasticity opened a new opportunity to many patients. In Italy, the healthcare payer can be fully reimbursed by the involved pharma company with the cost of treatment for patients not responding after a 4 week (28 days) trial period (Payment by Results, PbR), and 50% reimbursed with the cost of 6 weeks (42 days) treatment for other patients discontinuing (Cost Sharing, CS). The aim of our study was to describe the Sativex discontinuation profile from a large population of spasticity treated Italian MS patients.We collected data of patients from 30 MS centres across the country starting Sativex between January 2014 and February 2015. Data were collected from the mandatory Italian Medicines Agency (AIFA) web-registry. Predictors of treatment discontinuation were assessed using a multivariate Cox proportional regression analysis.During the observation period 631 out of 1597 (39.5%) patients discontinued Sativex. The Kaplan-Meier estimates curve showed that 333 patients (20.8%) discontinued treatment at 4 weeks while 422 patients (26.4%) discontinued at 6 weeks. We found after adjusted modeling that a higher NRS score at T1 (adjHR 2.23, 95% 2.07-2.41, p
Published: 2017
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9. Prevalence and predictors of bowel dysfunction in a large multiple sclerosis outpatient population: an Italian multicenter study

Author: Alvino, Bisecco, Arianna, Fornasiero, Assunta, Bianco, Antonio, Cortese, Emanuele, d’Amico, Giorgia, Mataluni, Leonardo, Sinisi, Daniele, Spitaleri, Renato, Docimo, Buscarinu, Maria Chiara, Massimiliano, Mirabella, Crisafulli, Sebastiano Giuseppe, Aurora, Zanghì, Gabri Nicoletti, Carolina, Marco, Salvetti, Viola, Baione, Francesco, Patti, Marfia, Alessandra Girolama, Grazia, Sibilia, Valentina, Scarano, Davide, Orlando, Giovanni, Stabile, Gioacchino, Tedeschi, and Gallo, Antonio
Published: 2022
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10. Longitudinal modeling of MS patient trajectories improves predictions of disability progression.

Author: Edward De Brouwer, Thijs Becker, Yves Moreau, Eva Kubala Havrdova, Maria Trojano, Sara Eichau, Serkan Ozakbas, Marco Onofrj, Pierre Grammond, Jens Kuhle, Ludwig Kappos, Patrizia Sola, Elisabetta Cartechini, Jeannette Lechner-Scott, Raed Alroughani, Oliver Gerlach, Tomas Kalincik, Franco Granella, Francois Grand'Maison, Roberto Bergamaschi, Maria Jose Sa, Bart Van Wijmeersch, Aysun Soysal, Jose Luis Sanchez-Menoyo, Claudio Solaro, Cavit Boz, Gerardo Iuliano, Katherine Buzzard, Eduardo Aguera-Morales, Murat Terzi, Tamara Castillo Trivio, Daniele Spitaleri, Vincent Van Pesch, Vahid Shaygannej, Fraser Moore, Celia Oreja Guevara, Davide Maimone, Riadh Gouider, Tunde Csepany, Cristina Ramo-Tello, and Liesbet M. Peeters
Published: 2020

11. Corrigendum to Longitudinal machine learning modeling of MS patient trajectories improves predictions of disability progression: [Computer Methods and Programs in Biomedicine, Volume 208, (September 2021) 106180].

Author: Edward De Brouwer, Thijs Becker, Yves Moreau, Eva Kubala Havrdova, Maria Trojano, Sara Eichau, Serkan Ozakbas, Marco Onofrj, Pierre Grammond, Jens Kuhle, Ludwig Kappos, Patrizia Sola, Elisabetta Cartechini, Jeannette Lechner-Scott, Raed Alroughani, Oliver Gerlach, Tomas Kalincik, Franco Granella, Francois Grand'Maison, Roberto Bergamaschi, Maria Jose Sa, Bart Van Wijmeersch, Aysun Soysal, Jose Luis Sanchez-Menoyo, Claudio Solaro, Cavit Boz, Gerardo Iuliano, Katherine Buzzard, Eduardo Aguera-Morales, Murat Terzi, Tamara Castillo Trivio, Daniele Spitaleri, Vincent Van Pesch, Vahid Shaygannejad, Fraser Moore, Celia Oreja Guevara, Davide Maimone, Riadh Gouider, Tunde Csepany, Cristina Ramo-Tello, and Liesbet M. Peeters
Published: 2022
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12. Comparative effectiveness in multiple sclerosis: A methodological comparison

Author: Izanne Roos, Ibrahima Diouf, Sifat Sharmin, Dana Horakova, Eva Kubala Havrdova, Francesco Patti, Vahid Shaygannejad, Serkan Ozakbas, Guillermo Izquierdo, Sara Eichau, Marco Onofrj, Alessandra Lugaresi, Raed Alroughani, Alexandre Prat, Marc Girard, Pierre Duquette, Murat Terzi, Cavit Boz, Francois Grand’Maison, Patrizia Sola, Diana Ferraro, Pierre Grammond, Recai Turkoglu, Katherine Buzzard, Olga Skibina, Bassem Yamou, Ayse Altintas, Oliver Gerlach, Vincent van Pesch, Yolanda Blanco, Davide Maimone, Jeannette Lechner-Scott, Roberto Bergamaschi, Rana Karabudak, Chris McGuigan, Elisabetta Cartechini, Michael Barnett, Stella Hughes, Maria José Sa, Claudio Solaro, Cristina Ramo-Tello, Suzanne Hodgkinson, Daniele Spitaleri, Aysun Soysal, Thor Petersen, Franco Granella, Koen de Gans, Pamela McCombe, Radek Ampapa, Bart Van Wijmeersch, Anneke van der Walt, Helmut Butzkueven, Julie Prevost, Jose Luis Sanchez-Menoyo, Guy Laureys, Riadh Gouider, Tamara Castillo-Triviño, Orla Gray, Eduardo Aguera-Morales, Abdullah Al-Asmi, Cameron Shaw, Norma Deri, Talal Al-Harbi, Yara Fragoso, Tunde Csepany, Angel Perez Sempere, Irene Trevino-Frenk, Jan Schepel, Fraser Moore, Charles Malpas, Tomas Kalincik, and UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire
Subjects: Multiple Sclerosis, Fingolimod Hydrochloride, Natalizumab, Multiple Sclerosis, Relapsing-Remitting, Treatment Outcome, Neurology, Recurrence, Humans, Immunologic Factors, Neurology (clinical), causal inference, Propensity Score, Observational, Immunosuppressive Agents
Abstract: Background: In the absence of evidence from randomised controlled trials, observational data can be used to emulate clinical trials and guide clinical decisions. Observational studies are, however, susceptible to confounding and bias. Among the used techniques to reduce indication bias are propensity score matching and marginal structural models. Objective: To use the comparative effectiveness of fingolimod vs natalizumab to compare the results obtained with propensity score matching and marginal structural models. Methods: Patients with clinically isolated syndrome or relapsing remitting MS who were treated with either fingolimod or natalizumab were identified in the MSBase registry. Patients were propensity score matched, and inverse probability of treatment weighted at six monthly intervals, using the following variables: age, sex, disability, MS duration, MS course, prior relapses, and prior therapies. Studied outcomes were cumulative hazard of relapse, disability accumulation, and disability improvement. Results: 4608 patients (1659 natalizumab, 2949 fingolimod) fulfilled inclusion criteria, and were propensity score matched or repeatedly reweighed with marginal structural models. Natalizumab treatment was associated with a lower probability of relapse (PS matching: HR 0.67 [95% CI 0.62-0.80]; marginal structural model: 0.71 [0.62-0.80]), and higher probability of disability improvement (PS matching: 1.21 [1.02 -1.43]; marginal structural model 1.43 1.19 -1.72]). There was no evidence of a difference in the magnitude of effect between the two methods. Conclusions: The relative effectiveness of two therapies can be efficiently compared by either marginal structural models or propensity score matching when applied in clearly defined clinical contexts and in sufficiently powered cohorts.
Published: 2023
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13. Longitudinal machine learning modeling of MS patient trajectories improves predictions of disability progression.

Author: Edward De Brouwer, Thijs Becker, Yves Moreau, Eva Kubala Havrdova, Maria Trojano, Sara Eichau, Serkan Ozakbas, Marco Onofrj, Pierre Grammond, Jens Kuhle, Ludwig Kappos, Patrizia Sola, Elisabetta Cartechini, Jeannette Lechner-Scott, Raed Alroughani, Oliver Gerlach, Tomas Kalincik, Franco Granella, Francois Grand'Maison, Roberto Bergamaschi, Maria Jose Sa, Bart Van Wijmeersch, Aysun Soysal, Jose Luis Sanchez-Menoyo, Claudio Solaro, Cavit Boz, Gerardo Iuliano, Katherine Buzzard, Eduardo Aguera-Morales, Murat Terzi, Tamara Castillo Trivio, Daniele Spitaleri, Vincent Van Pesch, Vahid Shaygannejad, Fraser Moore, Celia Oreja Guevara, Davide Maimone, Riadh Gouider, Tunde Csepany, Cristina Ramo-Tello, and Liesbet M. Peeters
Published: 2021
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14. Variability of the response to immunotherapy among subgroups of patients with multiple sclerosis

Author: Ibrahima Diouf, Charles B. Malpas, Sifat Sharmin, Izanne Roos, Dana Horakova, Eva Kubala Havrdova, Francesco Patti, Vahid Shaygannejad, Serkan Ozakbas, Guillermo Izquierdo, Sara Eichau, Marco Onofrj, Alessandra Lugaresi, Raed Alroughani, Alexandre Prat, Marc Girard, Pierre Duquette, Murat Terzi, Cavit Boz, Francois Grand'Maison, Sherif Hamdy, Patrizia Sola, Diana Ferraro, Pierre Grammond, Recai Turkoglu, Katherine Buzzard, Olga Skibina, Bassem Yamout, Ayse Altintas, Oliver Gerlach, Vincent van Pesch, Yolanda Blanco, Davide Maimone, Jeannette Lechner‐Scott, Roberto Bergamaschi, Rana Karabudak, Gerardo Iuliano, Chris McGuigan, Elisabetta Cartechini, Michael Barnett, Stella Hughes, Maria José Sa, Claudio Solaro, Ludwig Kappos, Cristina Ramo‐Tello, Edgardo Cristiano, Suzanne Hodgkinson, Daniele Spitaleri, Aysun Soysal, Thor Petersen, Mark Slee, Ernest Butler, Franco Granella, Koen de Gans, Pamela McCombe, Radek Ampapa, Bart Van Wijmeersch, Anneke van der Walt, Helmut Butzkueven, Julie Prevost, L. G. F. Sinnige, Jose Luis Sanchez‐Menoyo, Steve Vucic, Guy Laureys, Liesbeth Van Hijfte, Dheeraj Khurana, Richard Macdonell, Riadh Gouider, Tamara Castillo‐Triviño, Orla Gray, Eduardo Aguera‐Morales, Abdullah Al‐Asmi, Cameron Shaw, Norma Deri, Talal Al‐Harbi, Yara Fragoso, Tunde Csepany, Angel Perez Sempere, Irene Trevino‐Frenk, Jan Schepel, Fraser Moore, Tomas Kalincik, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, Laureys, Guy/0000-0002-1708-4373, Lugaresi, Alessandra/0000-0003-2902-5589, Aguera-Morales, Eduardo/0000-0002-8604-2054, Petersen, Thor/0000-0001-5633-2600, Roos, Izanne/0000-0003-0371-3666, Slee, Mark/0000-0003-4323-2453, patti, francesco/0000-0002-6923-0846, Diouf, Ibrahima, Malpas, Charles B., Sharmin , Sifat, Roos, Izanne, Horakova, Dana, Havrdova, Eva Kubala, Patti, Francesco, Shaygannejad, Vahid, Ozakbas, Serkan, Izquierdo, Guillermo, Eichau, Sara, Onofrj, Marco, Lugaresi, Alessandra, Alroughani, Raed, Prat, Alexandre, Girard, Marc, Duquette, Pierre, Terzi, Murat, Boz, Cavit, Grand'Maison, Francois, Hamdy, Sherif, Sola, Patrizia, Ferraro, Diana, Grammond, Pierre, Turkoglu, Recai, Buzzard, Katherine, Skibina, Olga, Yamout, Bassem, Altintas, Ayse, Gerlach, Oliver, van Pesch, Vincent, Blanco, Yolanda, Maimone, Davide, Lechner-Scott, Jeannette, Bergamaschi, Roberto, Karabudak, Rana, Iuliano, Gerardo, McGuigan, Chris, Cartechini, Elisabetta, Barnett, Michael, Hughes, Stella, Sa, Maria Jose, Solaro, Claudio, Kappos, Ludwig, Ramo-Tello, Cristina, Cristiano, Edgardo, Hodgkinson, Suzanne, Spitaleri, Daniele, Soysal, Aysun, Petersen, Thor, Slee, Mark, Butler, Ernest, Granella, Franco, de Gans, Koen, McCombe, Pamela, Ampapa, Radek, VAN WIJMEERSCH, Bart, van der Walt, Anneke, Butzkueven, Helmut, Prevost, Julie, Sinnige, L. G. F., Sanchez-Menoyo, Jose Luis, Vucic, Steve, Laureys, Guy, Van Hijfte, Liesbeth, Khurana, Dheeraj, Macdonell, Richard, Gouider, Riadh, Castillo-Trivino, Tamara, Gray, Orla, Aguera-Morales, Eduardo, Al-Asmi, Abdullah, Shaw, Cameron, Deri, Norma, Al-Harbi, Talal, Fragoso, Yara, Csepany, Tunde, Sempere, Angel Perez, Trevino-Frenk, Irene, Schepel, Jan, Moore, Fraser, and Kalincik, Tomas
Subjects: marginal structural model, relapse, Multiple Sclerosis, Multiple Sclerosis, Chronic Progressive, multiple sclerosis, Multiple Sclerosis, Relapsing-Remitting, Neurology, Recurrence, Medicine and Health Sciences, Humans, Neurology (clinical), EDSS, immunotherapy, Proportional Hazards Models
Abstract: Background and purpose: This study assessed the effect of patient characteristics on the response to disease-modifying therapy (DMT) in multiple sclerosis (MS).Methods: We extracted data from 61,810 patients from 135 centers across 35 countries from the MSBase registry. The selection criteria were: clinically isolated syndrome or definite MS, follow -up >= 1 year, and Expanded Disability Status Scale (EDSS) score >= 3, with >= 1 score recorded per year. Marginal structural models with interaction terms were used to compare the hazards of 12 -month confirmed worsening and improvement of disability, and the incidence of relapses between treated and untreated patients stratified by their characteristics.Results: Among 24,344 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence (hazard ratio [HR] = 0.52, 95% confidence interval [CI] = 0.45- 0.60), 46% lower risk of disability worsening (HR = 0.54, 95% CI = 0.41- 0.71), and 32% greater chance of disability improvement (HR = 1.32, 95% CI = 1.09- 1.59). The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The magnitude of the effect of DMT on suppressing relapses declined with higher prior relapse rate and prior cerebral magnetic resonance imaging activity. We did not find any evidence for the effect of age on the effectiveness of DMT. After inclusion of 1985 participants with progressive MS, the effect of DMT on disability mostly depended on MS phenotype, whereas its effect on relapses was driven mainly by prior relapse activity.Conclusions: DMT is generally most effective among patients with lower disability and in relapsing MS phenotypes. There is no evidence of attenuation of the effect of DMT with age. This study was financially supported by the National Health and Medical Research Council of Australia (1129189, 1140766, 1080518) We thank the patients and their carers who have agreed to participate in the global MSBase cohort study. The MSBase Foundation is a not-for-profit organization that receives support from Roche, Merck, Biogen, Novartis, Bayer-Schering, Sanofi-Genzyme, and Teva. The study was conducted separately and apart from the guidance of the sponsors. Open access publishing facilitated by The University of Melbourne, as part of the Wiley - The University of Melbourne agreement via the Council of Australian University Librarians.
Published: 2023
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15. Sensitivity of conventional cognitive tests in multiple sclerosis: Application of item response theory

Author: Simona Raimo, Roberto Giorgini, Mariachiara Gaita, Antonio Costanzo, Daniele Spitaleri, Liana Palermo, Marco Tullio Liuzza, Gabriella Santangelo, Raimo, Simona, Giorgini, Roberto, Gaita, Mariachiara, Costanzo, Antonio, Spitaleri, Daniele, Palermo, Liana, Liuzza, Marco Tullio, and Santangelo, Gabriella
Subjects: Multiple sclerosis, MACFIMS, Cognitive deficit, Neurology, Neurology (clinical), General Medicine, BRN-B, Item response theory, BICAMS
Abstract: Background: Cognitive impairment (CI) is common in Multiple Sclerosis (MS), and its prevalence rate ranges between 22% and 70%. Because CI significantly impacts vocational status, caregiver burden, and quality of life, an accurate neuropsychological assessment is required. Three widely used and validated batteries for MS-associated CI are the Brief Repeatable Neuropsychological Battery (BRN-B), the Minimal Assessment of Cognitive Function (MACFIMS), and the Brief International Cognitive Assessment (BICAMS). Although similar, these batteries differ in time-consuming and in specific tests employed. This study aims to assess the sensitivity of cognitive tests included in these batteries through an Item Response Theory approach. Methods: Ninety-seven patients with MS and 91 demographically matched controls (HC) were consecutively assessed using the three neuropsychological batteries (i.e., BRN-B, MACFIMS, and BICAMS). Continuous Response Model (CRM) was used to identify the cognitive test(s) that best discriminate patients with MS from HC. Receiver Operating Characteristic (ROC) curve analysis was used to determine the accuracy of the CRM results. Results: Cognitive tests loaded on two different latent variables: the 'higher-order executive functioning,' consisting of tests assessing concept formation, problem-solving, and inhibitory control, and the 'memory and information processing speed,' comprising tests assessing long-term, working memory, and information processing speed. The Delis Kaplan Executive Functioning System-Sorting Test and the Stroop Test were the most sensitive tests in differentiating cognitive functioning between MS and HC. Conclusions: This study confirms the importance of including a more extensive executive assessment in MS clinical practice since higher-order executive functions (e.g., abstraction and inhibitory control) significantly impact patients' quality of life and functional autonomy. Clinical implications of careful dissection of executive functioning in MS neuropsychological assessment are discussed.
Published: 2022

16. Machine-learning-based prediction of disability progression in multiple sclerosis: an observational, international, multi-center study

Author: Edward De Brouwer, Thijs Becker, Lorin Werthen-Brabants, Pieter Dewulf, Dimitrios Iliadis, Cathérine Dekeyser, Guy Laureys, Bart Van Wijmeersch, Veronica Popescu, Tom Dhaene, Dirk Deschrijver, Willem Waegeman, Bernard De Baets, Michiel Stock, Dana Horakova, Francesco Patti, Guillermo Izquierdo, Sara Eichau, Marc Girard, Alexandre Prat, Alessandra Lugaresi, Pierre Grammond, Tomas Kalincik, Raed Alroughani, Francois Grand’Maison, Olga Skibina, Murat Terzi, Jeannette Lechner-Scott, Oliver Gerlach, Samia J. Khoury, Elisabetta Cartechini, Vincent Van Pesch, Maria Jose Sa, Bianca Weinstock-Guttman, Yolanda Blanco, Radek Ampapa, Daniele Spitaleri, Claudio Solaro, Davide Maimone, Aysun Soysal, Gerardo Iuliano, Riadh Gouider, Tamara Castillo-Triviño, Jose Luis Sanchez-Menoyo, Anneke van der Walt, Jiwon Oh, Eduardo Aguera-Morales, Ayse Altintas, Abdullah Al-Asmi, Koen de Gans, Yara Fragoso, Tunde Csepany, Suzanne Hodgkinson, Norma Deri, Talal Al-Harbi, Bruce Taylor, Orla Gray, Patrice Lalive, Csilla Rozsa, Chris McGuigan, Allan Kermode, Angel Perez sempere, Simu Mihaela, Magdolna Simo, Todd Hardy, Danny Decoo, Stella Hughes, Nikolaos Grigoriadis, Attila Sas, Norbert Vella, Yves Moreau, and Liesbet Peeters
Abstract: BackgroundDisability progression is a key milestone in the disease evolution of people with multiple sclerosis (PwMS). Prediction models of disability progression have not yet reached the level of trust needed to be adopted in the clinic. A common benchmark to assess model development in multiple sclerosis is also currently lacking.MethodsData of adult PwMS with a follow-up of at least three years from 146 MS centers, spread over 40 countries and collected by the MSBase consortium was used. With basic inclusion criteria for quality requirements, it represents a total of 15, 240 PwMS. External validation was performed and repeated five times to assess the significance of the results. TRIPOD guidelines were followed.Confirmed disability progression after two years was predicted, with a confirmation window of six months. Only routinely collected variables were used such as the expended disability status scale, treatment, relapse information, and MS course.To learn the probability of disability progression, state-of-the-art machine learning models were investigated. The discrimination performance of the models is evaluated on their area under the receiver operator curve (ROC-AUC) and under the precision recall curve (AUC-PR), and their calibration via the Brier score and the expected calibration error.FindingsA temporal attention model was the best model. It achieved a ROC-AUC of 0·71 ± 0·01, an AUC-PR of 0·26 ± 0·02, a Brier score of 0·1 ± 0·01 and an expected calibration error of 0·07 ± 0·04. The history of disability progression is more predictive for future disability progression than the treatment or relapses.InterpretationGood discrimination and calibration performance on an external validation set is achieved, using only routinely collected variables. This makes these models ready for a clinical impact study. All our preprocessing and model code is available at https://gitlab.com/edebrouwer/ms_benchmark, making this task an ideal benchmark for predicting disability progression in MS.
Published: 2022
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17. Progression is independent of relapse activity in early multiple sclerosis: a real-life cohort study

Author: Emilio Portaccio, Angelo Bellinvia, Mattia Fonderico, Luisa Pastò, Lorenzo Razzolini, Rocco Totaro, Daniele Spitaleri, Alessandra Lugaresi, Eleonora Cocco, Marco Onofrj, Franco Di Palma, Francesco Patti, Davide Maimone, Paola Valentino, Paolo Confalonieri, Alessandra Protti, Patrizia Sola, Giacomo Lus, Giorgia Teresa Maniscalco, Vincenzo Brescia Morra, Giuseppe Salemi, Franco Granella, Ilaria Pesci, Roberto Bergamaschi, Umberto Aguglia, Marika Vianello, Marta Simone, Vito Lepore, Pietro Iaffaldano, Massimo Filippi, Maria Trojano, Maria Pia Amato, Portaccio, Emilio, Bellinvia, Angelo, Fonderico, Mattia, Pastò, Luisa, Razzolini, Lorenzo, Totaro, Rocco, Spitaleri, Daniele, Lugaresi, Alessandra, Cocco, Eleonora, Onofrj, Marco, Di Palma, Franco, Patti, Francesco, Maimone, Davide, Valentino, Paola, Confalonieri, Paolo, Protti, Alessandra, Sola, Patrizia, Lus, Giacomo, Maniscalco, Giorgia Teresa, Brescia Morra, Vincenzo, Salemi, Giuseppe, Granella, Franco, Pesci, Ilaria, Bergamaschi, Roberto, Aguglia, Umberto, Vianello, Marika, Simone, Marta, Lepore, Vito, Iaffaldano, Pietro, Filippi, Massimo, Trojano, Maria, and Amato, Maria Pia
Subjects: Multiple Sclerosis, relapse-associated worsening, progression independent of relapse activity, relapsing multiple sclerosis, Cohort Studies, Multiple Sclerosis, Relapsing-Remitting, relapse associated worsening, Recurrence, Chronic Disease, Disease Progression, Humans, Settore MED/26 - Neurologia, Neurology (clinical), Retrospective Studies
Abstract: Portaccio et al. report that in early relapsing-onset multiple sclerosis, progression independent of relapse activity is an important contributor to disability accumulation. Insidious progression occurs even in the earliest disease phases, suggesting that inflammation and degeneration may represent a single disease continuum.Disability accrual in multiple sclerosis may occur as relapse-associated worsening or progression independent of relapse activity. The role of progression independent of relapse activity in early multiple sclerosis is yet to be established. The objective of this multicentre, observational, retrospective cohort study was to investigate the contribution of relapse-associated worsening and progression independent of relapse activity to confirmed disability accumulation in patients with clinically isolated syndrome and early relapsing-remitting multiple sclerosis, assessed within one year from onset and with follow-up >= 5 years (n = 5169). Data were extracted from the Italian Multiple Sclerosis Register. Confirmed disability accumulation was defined by an increase in Expanded Disability Status Scale score confirmed at 6 months, and classified per temporal association with relapses. Factors associated with progression independent of relapse activity and relapse-associated worsening were assessed using multivariable Cox regression models. Over a follow-up period of 11.5 +/- 5.5 years, progression independent of relapse activity occurred in 1427 (27.6%) and relapse-associated worsening in 922 (17.8%) patients. Progression independent of relapse activity was associated with older age at baseline [hazard ratio (HR) = 1.19; 95% confidence interval (CI) 1.13-1.25, P < 0.001], having a relapsing-remitting course at baseline (HR = 1.44; 95% CI 1.28-1.61, P < 0.001), longer disease duration at baseline (HR = 1.56; 95% CI 1.28-1.90, P < 0.001), lower Expanded Disability Status Scale at baseline (HR = 0.92; 95% CI 0.88-0.96, P < 0.001) and lower number of relapses before the event (HR = 0.76; 95% CI 0.73-0.80, P < 0.001). Relapse-associated worsening was associated with younger age at baseline (HR = 0.87; 95% CI 0.81-0.93, P < 0.001), having a relapsing-remitting course at baseline (HR = 1.55; 95% CI 1.35-1.79, P < 0.001), lower Expanded Disability Status Scale at baseline (HR = 0.94; 95% CI 0.89-0.99, P = 0.017) and a higher number of relapses before the event (HR = 1.04; 95% CI 1.01-1.07, P < 0.001). Longer exposure to disease-modifying drugs was associated with a lower risk of both progression independent of relapse activity and relapse-associated worsening (P < 0.001). This study provides evidence that in an early relapsing-onset multiple sclerosis cohort, progression independent of relapse activity was an important contributor to confirmed disability accumulation. Our findings indicate that insidious progression appears even in the earliest phases of the disease, suggesting that inflammation and neurodegeneration can represent a single disease continuum, in which age is one of the main determinants of disease phenomenology.
Published: 2022

18. Confirmed disability progression as a marker of permanent disability in multiple sclerosis

Author: Sifat Sharmin, Francesca Bovis, Charles Malpas, Dana Horakova, Eva Kubala Havrdova, Guillermo Izquierdo, Sara Eichau, Maria Trojano, Alexandre Prat, Marc Girard, Pierre Duquette, Marco Onofrj, Alessandra Lugaresi, Francois Grand'Maison, Pierre Grammond, Patrizia Sola, Diana Ferraro, Murat Terzi, Oliver Gerlach, Raed Alroughani, Cavit Boz, Vahid Shaygannejad, Vincent van Pesch, Elisabetta Cartechini, Ludwig Kappos, Jeannette Lechner‐Scott, Roberto Bergamaschi, Recai Turkoglu, Claudio Solaro, Gerardo Iuliano, Franco Granella, Bart Van Wijmeersch, Daniele Spitaleri, Mark Slee, Pamela McCombe, Julie Prevost, Radek Ampapa, Serkan Ozakbas, Jose Luis Sanchez‐Menoyo, Aysun Soysal, Steve Vucic, Thor Petersen, Koen de Gans, Ernest Butler, Suzanne Hodgkinson, Youssef Sidhom, Riadh Gouider, Edgardo Cristiano, Tamara Castillo‐Triviño, Maria Laura Saladino, Michael Barnett, Fraser Moore, Csilla Rozsa, Bassem Yamout, Olga Skibina, Anneke van der Walt, Katherine Buzzard, Orla Gray, Stella Hughes, Angel Perez Sempere, Bhim Singhal, Yara Fragoso, Cameron Shaw, Allan Kermode, Bruce Taylor, Magdolna Simo, Neil Shuey, Talal Al‐Harbi, Richard Macdonell, Jose Andres Dominguez, Tunde Csepany, Carmen Adella Sirbu, Maria Pia Sormani, Helmut Butzkueven, Tomas Kalincik, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, UCL - (SLuc) Service de biochimie médicale, UCL - (SLuc) Service de neurologie, Sirbu, Carmen Adella/0000-0002-1982-1066, Malpas, Charles/0000-0003-0534-3718, Sharmin, Sifat, Bovis, Francesca, Malpas, Charle, Horakova, Dana, Havrdova, Eva Kubala, Izquierdo, Guillermo, Eichau, Sara, Trojano, Maria, Prat, Alexandre, Girard, Marc, Duquette, Pierre, Onofrj, Marco, Lugaresi, Alessandra, Grand'Maison, Francoi, Grammond, Pierre, Sola, Patrizia, Ferraro, Diana, Terzi, Murat, Gerlach, Oliver, Alroughani, Raed, Boz, Cavit, Shaygannejad, Vahid, van Pesch, Vincent, Cartechini, Elisabetta, Kappos, Ludwig, Lechner-Scott, Jeannette, Bergamaschi, Roberto, Turkoglu, Recai, Solaro, Claudio, Iuliano, Gerardo, Granella, Franco, Van Wijmeersch, Bart, Spitaleri, Daniele, Slee, Mark, McCombe, Pamela, Prevost, Julie, Ampapa, Radek, Ozakbas, Serkan, Sanchez-Menoyo, Jose Lui, Soysal, Aysun, Vucic, Steve, Petersen, Thor, de Gans, Koen, Butler, Ernest, Hodgkinson, Suzanne, Sidhom, Youssef, Gouider, Riadh, Cristiano, Edgardo, Castillo-Triviño, Tamara, Saladino, Maria Laura, Barnett, Michael, Moore, Fraser, Rozsa, Csilla, Yamout, Bassem, Skibina, Olga, van der Walt, Anneke, Buzzard, Katherine, Gray, Orla, Hughes, Stella, Sempere, Angel Perez, Singhal, Bhim, Fragoso, Yara, Shaw, Cameron, Kermode, Allan, Taylor, Bruce, Simo, Magdolna, Shuey, Neil, Al-Harbi, Talal, Macdonell, Richard, Dominguez, Jose Andre, Csepany, Tunde, Sirbu, Carmen Adella, Sormani, Maria Pia, Butzkueven, Helmut, and Kalincik, Tomas
Subjects: Male, risk scoring, sustained disability progression, Multiple Sclerosis, CLARITY, clinical trial, functional system impairment, Cohort Studies, Disability Evaluation, Multiple Sclerosis, Relapsing-Remitting, Neurology, Disease Progression, Cladribine, Humans, Female, Neurology (clinical), Randomized Controlled Trials as Topic
Abstract: Background and purpose The prevention of disability over the long term is the main treatment goal in multiple sclerosis (MS); however, randomized clinical trials evaluate only short-term treatment effects on disability. This study aimed to define criteria for 6-month confirmed disability progression events of MS with a high probability of resulting in sustained long-term disability worsening. Methods In total, 14,802 6-month confirmed disability progression events were identified in 8741 patients from the global MSBase registry. For each 6-month confirmed progression event (13,321 in the development and 1481 in the validation cohort), a sustained progression score was calculated based on the demographic and clinical characteristics at the time of progression that were predictive of long-term disability worsening. The score was externally validated in the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) trial. Results The score was based on age, sex, MS phenotype, relapse activity, disability score and its change from baseline, number of affected functional system domains and worsening in six of the domains. In the internal validation cohort, a 61% lower chance of improvement was estimated with each unit increase in the score (hazard ratio 0.39, 95% confidence interval 0.29-0.52; discriminatory index 0.89). The proportions of progression events sustained at 5 years stratified by the score were 1: 72%; 2: 88%; 3: 94%; 4: 100%. The results of the CLARITY trial were confirmed for reduction of disability progression that was >88% likely to be sustained (events with score >1.5). Conclusions Clinicodemographic characteristics of 6-month confirmed disability progression events identify those at high risk of sustained long-term disability. This knowledge will allow future trials to better assess the effect of therapy on long-term disability accrual. NHMRC [1129189, 1157717, 1140766]; Merck; Biogen; Novartis; Roche; Bayer; Schering; Sanofi Genzyme; Teva Pharmaceutical Industries
Published: 2022
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19. Perfusion-weighted MRI in cerebral amyloid angiopathy-related transient focal neurological episodes

Author: Marta Simone, Florindo d’Onofrio, Daniele Spitaleri, Fabrizio A. de Falco, and Arturo de Falco
Subjects: Pathology, medicine.medical_specialty, Siderosis, Subarachnoid hemorrhage, Neurology, Dermatology, 03 medical and health sciences, 0302 clinical medicine, Cortex (anatomy), mental disorders, medicine, Humans, cardiovascular diseases, 030212 general & internal medicine, Cerebral Hemorrhage, Intracerebral hemorrhage, business.industry, nutritional and metabolic diseases, General Medicine, medicine.disease, Magnetic Resonance Imaging, Superficial siderosis, Perfusion, Cerebral Amyloid Angiopathy, Psychiatry and Mental health, medicine.anatomical_structure, Cerebral cortex, Neurology (clinical), Cerebral amyloid angiopathy, business, 030217 neurology & neurosurgery
Abstract: Sporadic cerebral amyloid angiopathy (CAA) is a common age-related cerebral small vessel disease characterized by progressive s-amyloid deposition in the walls of small cortical arteries, arterioles, and capillaries in the cerebral cortex and overlying leptomeninges. CAA-related transient focal neurological episodes (CAA-TFNEs) represent a challenging clinical feature interesting from a pathophysiological point of view. Here we present two cases of CAA-TFNEs in which we performed functional imaging with perfusion-weighted imaging MR and brain 18 F-FDG PET. In both cases, we found a topographic relationship between the involved cortical areas and the clinical expression of CAA-TFNEs. Cortical superficial siderosis in the first case and a convexity subarachnoid hemorrhage in the second case were found in the contralateral rolandic area corresponding to the clinical symptoms. The same areas showed a reduction of rCBV and rCBF on perfusion-weighted MR and were also associated in one case with hypometabolism on 18 F-FDG PET. These new findings strengthen the hypothesis that CAA involves the superficial leptomeningeal arteries but also the short penetrating arterioles reaching different depths in the cortex generating hypoperfusion and altered vascular reactivity and consequently reduced neuronal activity. Understanding CAA-TFNEs is pivotal because they carry a very high risk of subsequent lobar intracerebral hemorrhage but are frequently misdiagnosed as TIAs and treated with antithrombotics enhancing the bleeding risk associated with CAA.
Published: 2021
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20. Effects of THC/CBD oromucosal spray on spasticity-related symptoms in people with multiple sclerosis: results from a retrospective multicenter study

Author: Domenico Ippolito, Giorgia Teresa Maniscalco, Damiano Paolicelli, Daniele Spitaleri, Francesco Patti, Gianfranco Costantino, Margherita Russo, Clara Grazia Chisari, Letizia Castelli, Giovanna Salamone, Roberto Bruno Bossio, Maria Trotta, Claudio Solaro, Eliana Berra, Roberta Lanzillo, Elisabetta Signoriello, Raffaella Cerqua, Isabella Righini, Fabio Buttari, Gabriella Spinicci, Loredana Petrucci, Angelica Guareschi, Manuela Matta, Mario Zappia, Simona Pontecorvo, Maria Donata Benedetti, Paola Cavalla, Assunta Bianco, Claudio Gasperini, Eleonora Tavazzi, Francesco Saccà, Mauro Zaffaroni, Patti, F., Chisari, C. G., Solaro, C., Benedetti, M. D., Berra, E., Bianco, A., Bruno Bossio, R., Buttari, F., Castelli, L., Cavalla, P., Cerqua, R., Costantino, G., Gasperini, C., Guareschi, A., Ippolito, D., Lanzillo, R., Maniscalco, G. T., Matta, M., Paolicelli, D., Petrucci, L., Pontecorvo, S., Righini, I., Russo, M., Saccà, Francesco, Salamone, G., Signoriello, E., Spinicci, G., Spitaleri, D., Tavazzi, E., Trotta, M., Zaffaroni, M., Zappia, M., Patti, Francesco, Grazia Chisari, Clara, Solaro, Claudio, Donata Benedetti, Maria, Berra, Eliana, Bianco, Assunta, Bruno Bossio, Roberto, Buttari, Fabio, Castelli, Letizia, Cavalla, Paola, Cerqua, Raffaella, Costantino, Gianfranco, Gasperini, Claudio, Guareschi, Angelica, Ippolito, Domenico, Lanzillo, Roberta, Teresa Maniscalco, Giorgia, Matta, Manuela, Paolicelli, Damiano, Petrucci, Loredana, Pontecorvo, Simona, Righini, Isabella, Russo, Margherita, Salamone, Giovanna, Signoriello, Elisabetta, Spinicci, Gabriella, Spitaleri, Daniele, Tavazzi, Eleonora, Trotta, Maria, Zaffaroni, Mauro, and Zappia, Mario
Subjects: medicine.medical_specialty, Multiple Sclerosis, THC, Neurology, Dermatology, Clinical practice, Spasticity-related symptom, CBD, Multiple sclerosis, Spasticity-related symptoms, 03 medical and health sciences, 0302 clinical medicine, Rating scale, Internal medicine, medicine, Cannabidiol, Humans, Multiple sclerosi, Dronabinol, 030212 general & internal medicine, Spasticity, Oromucosal spray, Retrospective Studies, Plant Extracts, business.industry, General Medicine, medicine.disease, nervous system diseases, Clinical Practice, Drug Combinations, Psychiatry and Mental health, Italy, Muscle Spasticity, Neurology (clinical), Neurosurgery, medicine.symptom, business, 030217 neurology & neurosurgery, medicine.drug
Abstract: 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. © 2020, Fondazione Società Italiana di Neurologia.
Published: 2020
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21. Trends of recanalization therapies and state of art for ischemic stroke treatment in Campania region, Italy

Author: Emanuele Spina, Paolo Candelaresi, Giampiero Volpe, Florindo D’Onofrio, Daniele Spitaleri, Gioacchino Martusciello, Giovanni Piccirillo, Francesco Briganti, Mario Muto, Michele Feleppa, Marco Sparaco, Andrea Manto, Teresa Cuomo, Salvatore Ascione, Patrizia Ripa, Daniele Giuseppe Romano, Vincenzo Andreone, Fiore Manganelli, Rosa Napoletano, Spina, Emanuele, Candelaresi, Paolo, Volpe, Giampiero, D'Onofrio, Florindo, Spitaleri, Daniele, Martusciello, Gioacchino, Piccirillo, Giovanni, Briganti, Francesco, Muto, Mario, Feleppa, Michele, Sparaco, Marco, Manto, Andrea, Cuomo, Teresa, Ascione, Salvatore, Ripa, Patrizia, Romano, Daniele Giuseppe, Andreone, Vincenzo, Manganelli, Fiore, and Napoletano, Rosa
Subjects: Epidemiology, Dermatology, General Medicine, Brain Ischemia, Stroke, Psychiatry and Mental health, Treatment Outcome, Fibrinolytic Agents, Trend, Humans, Thrombolytic Therapy, Neurology (clinical), Campania, Recanalization therapie, Thrombectomy, Ischemic Stroke
Abstract: Background According to the last Italian report by the Ministry of Health in 2018, the estimated number of acute ischemic strokes (AIS) in Campania is 10,000/year, with an expected number of 1390 intravenous thrombolysis (IVT) and 694 mechanical thrombectomies (MT). In 2017, only 1.5% of expected patients received IVT and 0.2% MT. This study analyzed the trend of IVT and MT in 2019–2020 and depicted the state of art of Stroke Care in Campania. Methods From the regional health task force, we obtained the hospital discharge forms from all private and public hospitals in Campania; we selected patients with a principal diagnosis of AIS and measured the rate of patients admitted to neurology units and the rate of IVT, MT, and IVT + MT for both 2019 and 2020. Results In 2019, we observed 4817 admissions for AIS; 2858/4817 (59.3%) patients were admitted to neurology units. Out of 4817 patients, 192 received IVT, 165 MT, and 131 IVT + MT (488 treated patients; 10.1%). In 2020, we observed 4129 admissions for AIS; 2502/4129 (62.7%) patients were admitted to neurology units. Out of 4129 patients, 198 received IVT, 250 MT, and 180 IVT + MT (628 treated patients; 15.2%). These results showed that despite a reduction of AIS admissions in 2020, the relative and absolute rate of recanalization treatments increased. However, the number of patients who were not admitted to neurology units nor received acute treatments remained dramatically high. Conclusion Despite the development of acute treatments, the Campania Stroke Network still needs significative efforts to improve.
Published: 2022

22. Relationship between apathy and cognitive dysfunctions in multiple sclerosis: A 4-year prospective longitudinal study

Author: Simona Raimo, Luigi Trojano, Mariachiara Gaita, Florindo d'Onofrio, Daniele Spitaleri, Gabriella Santangelo, Raimo, Simona, Trojano, Luigi, Gaita, Mariachiara, D'Onofrio, Florindo, Spitaleri, Daniele, and Santangelo, Gabriella
Subjects: Multiple Sclerosis, Cognitive deficit, Depression, Apathy, Longitudinal Studie, General Medicine, Neuropsychological Tests, Prospective Studie, Neurology, Behavioural disorder, Humans, Multiple sclerosi, Neuropsychological Test, Cognitive Dysfunction, Neurology (clinical), Longitudinal Studies, Prospective Studies, Human
Abstract: Cognitive dysfunctions are highly prevalent in multiple sclerosis (MS) and negatively impact occupational and social functioning.In the present longitudinal study, we aimed at modeling cognitive changes and at assessing whether apathy could be a predictor of cognitive decline in MS.We assessed 67 people with MS at two-time points (baseline, T0; 4-year follow-up, T1), by means of several clinical, behavioural, and cognitive measures. We used a delta approach to measure cognitive decline during the follow-up period. We applied a mixed factorial design and a linear regression model to explore factors associated with cognitive changes over time.A higher level of apathy at baseline predicted the progressive cognitive decline at follow-up, whereas a higher level of depression did not. Among demographic and clinical characteristics, only low education level was significantly associated with cognitive decline over time. Interestingly, participants with persistent apathy (diagnosis of apathy at T0 and T1, A+A+) and those who developed apathy (A-A+) showed poorer inhibitory control and a larger decline in executive functioning during the 4-year follow-up than participants who had never received the diagnosis of apathy (A-A-).Apathy represents an early marker of cognitive decline in MS. These findings have important clinical and prognostic implications.
Published: 2022

23. Disease-Modifying Treatments and Time to Loss of Ambulatory Function in Patients with Primary Progressive Multiple Sclerosis

Author: Emilio, Portaccio, Mattia, Fonderico, Pietro, Iaffaldano, Luisa, Pastò, Lorenzo, Razzolini, Angelo, Bellinvia, Giovanna, De Luca, Paolo, Ragonese, Francesco, Patti, Vincenzo, Brescia Morra, Eleonora, Cocco, Patrizia, Sola, Matilde, Inglese, Giacomo, Lus, Carlo, Pozzilli, Davide, Maimone, Alessandra, Lugaresi, Paola, Gazzola, Giancarlo, Comi, Ilaria, Pesci, Daniele, Spitaleri, Marta, Rezzonico, Marika, Vianello, Carlo, Avolio, Francesco O, Logullo, Franco, Granella, Marco, Salvetti, Mauro, Zaffaroni, Giuseppe, Lucisano, Massimo, Filippi, Maria, Trojano, Maria Pia, Amato, Alessandra, Protti, Portaccio, E, Fonderico, M, Iaffaldano, P, Pasto, L, Razzolini, L, Bellinvia, A, De Luca, G, Ragonese, P, Patti, F, Brescia Morra, V, Cocco, E, Sola, P, Inglese, M, Lus, G, Pozzilli, C, Maimone, D, Lugaresi, A, Gazzola, P, Comi, G, Pesci, I, Spitaleri, D, Rezzonico, M, Vianello, M, Avolio, C, Logullo, F, Granella, F, Salvetti, M, Zaffaroni, M, Lucisano, G, Filippi, M, Trojano, M, Amato, M, Cavaletti, G, Portaccio, Emilio, Fonderico, Mattia, Iaffaldano, Pietro, Pastò, Luisa, Razzolini, Lorenzo, Bellinvia, Angelo, De Luca, Giovanna, Ragonese, Paolo, Patti, Francesco, Brescia Morra, Vincenzo, Cocco, Eleonora, Sola, Patrizia, Inglese, Matilde, Lus, Giacomo, Pozzilli, Carlo, Maimone, Davide, Lugaresi, Alessandra, Gazzola, Paola, Comi, Giancarlo, Pesci, Ilaria, Spitaleri, Daniele, Rezzonico, Marta, Vianello, Marika, Avolio, Carlo, Logullo, Francesco O, Granella, Franco, Salvetti, Marco, Zaffaroni, Mauro, Lucisano, Giuseppe, Filippi, Massimo, Trojano, Maria, and Amato, Maria Pia
Subjects: Adult, Multiple Sclerosis, Multiple Sclerosis, Relapsing-Remitting, Recurrence, Retrospective Studie, Multiple Sclerosi, Disease Progression, Humans, Female, Neurology (clinical), Multiple Sclerosis, Chronic Progressive, Retrospective Studies, Human
Abstract: Importance: Except for ocrelizumab, treatment options in primary progressive multiple sclerosis (PPMS) are lacking. Objective: To investigate the effectiveness of DMTs on the risk of becoming wheelchair dependent in a real-world population of patients with PPMS. Design, Setting, and Participants: This was a multicenter, observational, retrospective, comparative effectiveness research study. Data were extracted on November 28, 2018, from the Italian multiple sclerosis register and analyzed from June to December 2021. Mean study follow-up was 11 years. Included in the study cohort were patients with a diagnosis of PPMS and at least 3 years of Expanded Disability Status Scale (EDSS) evaluations and 3 years of follow-up. Main Outcomes and Measures: The risk of reaching an EDSS score of 7.0 was assessed through multivariable Cox regression models. Exposures: Patients who received DMT before the outcome were considered treated. DMT was assessed as a time-dependent variable and by class of DMT (moderately and highly effective). Results: From a total of 3298 patients with PPMS, 2633 were excluded because they did not meet the entry criteria for the phase 3, multicenter, randomized, parallel-group, double-blind, placebo-controlled study to evaluate the efficacy and safety of ocrelizumab in adults with PPMS (ORATORIO) trial. Among the remaining 665 patients (mean [SD] age, 43.0 [10.7] years; 366 female patients [55.0%]), 409 were further selected for propensity score matching (288 treated and 121 untreated patients). In the matched cohort, during the study follow-up, 37% of patients (152 of 409) reached an EDSS score of 7.0 after a mean (SD) follow-up of 10.6 (5.6) years. A higher EDSS score at baseline (adjusted hazard ratio [aHR], 1.32; 95% CI, 1.13-1.55; P
Published: 2022

24. Correction to: Prevalence and predictors of bowel dysfunction in a large multiple sclerosis outpatient population: an Italian multicenter study

Author: Alvino Bisecco, Arianna Fornasiero, Assunta Bianco, Antonio Cortese, Emanuele D’Amico, Giorgia Mataluni, Leonardo Sinisi, Daniele Spitaleri, Renato Docimo, Maria Chiara Buscarinu, Massimiliano Mirabella, Sebastiano Giuseppe Crisafulli, Aurora Zanghì, Carolina Gabri Nicoletti, Marco Salvetti, Viola Baione, Francesco Patti, Alessandra Girolama Marfia, Grazia Sibilia, Valentina Scarano, Davide Orlando, Giovanni Stabile, Gioacchino Tedeschi, and Antonio Gallo
Subjects: Neurology, Neurology (clinical)
Abstract: The original version of this article unfortunately contained a mistake. The given and family names of authors were Interchanged except the following author Maria Chiara Buscarinu, Carolina Gabri Nicoletti, Alessandra Girolama Marfia and Antonio Gallo.
Published: 2022

25. 004 Pregnancy-related relapse in natalizumab, fingolimod and dimethyl fumarate-treated women with multiple sclerosis

Author: Karolina Vodehnalova, Tomas Uher, Patrizia Sola, Murat Terzi, Raed Alroughani, Daniele Spitaleri, MSBase Registry, Melissa Gresle, Michael Barnett, Maria Pia Amato, Dana Horakova, Franco Granella, Richard A L Macdonell, Ayse Altintas, Francois Grand'Maison, Radek Ampapa, Recai Turkoglu, Jeannette Lechner-Scott, Helmut Butzkueven, Vilija Jokubaitis, Vincent Van Pesch, Pierre Grammond, Putu Ayu Widyastuti, Serkan Ozakbas, Pamela A. McCombe, Francesco Patti, Celia Oreja-Guevara, Raymond Hupperts, Tamara Castillo-Triviño, Tomas Kalincik, Olga Skibina, Cavit Boz, Elisabetta Cartechini, Sara Eichau, Marco Onofrj, Roberto Bergamaschi, Aysun Soysal, Jim Stankovich, Albert Saiz, Pierre Duquette, Suzanne Hodgkinson, Maria José Sá, Wei Z Yeh, Anneke van der Walt, Eva Havrdova, Davide Maimone, and Bassem Yamout
Subjects: Pregnancy, medicine.medical_specialty, Dimethyl fumarate, Proportional hazards model, business.industry, Obstetrics, Multiple sclerosis, Neurosciences. Biological psychiatry. Neuropsychiatry, medicine.disease, Fingolimod, chemistry.chemical_compound, Natalizumab, chemistry, Cohort, medicine, Gestation, business, RC321-571, medicine.drug
Abstract: Objective To investigate pregnancy-related disease activity in a contemporary multiple sclerosis (MS) cohort. Methods Data were obtained from the MSBase Registry. Term/preterm pregnancies conceived from 2011-2019 were included (modern cohort). Annualised relapse rates (ARR) were calculated before, during and after pregnancy. Predictors of intrapartum and early postpartum (1st3 months) relapse were determined by clustered logistic and Cox regression analyses, respectively. Results We included 1640 pregnancies from 1452 women. Disease-modifying therapy (DMT) used in the one-year preconception included natalizumab (n=219), fingolimod (n=147), dimethyl fumarate (DMF; n=57) and low-efficacy therapies (n=845). Preconception ARR by DMT class used before conception were: natalizumab, 0.29 (95% CI 0.22-0.37); fingolimod, 0.37 (0.28-0.49); DMF, 0.24 (0.13-0.41); low-efficacy, 0.29 (0.25-0.33); and none, 0.24 (0.19-0.31). Among women who used fingolimod or natalizumab, ARR increased during pregnancy. Intrapartum ARR decreased in preconception DMF, low-efficacy or no DMT groups. ARR spiked after delivery across all DMT groups. Natalizumab continuation into pregnancy reduced the odds of relapse during pregnancy (OR 0.76 per month [0.60-0.95], p=0.017). DMT re-initiation with natalizumab protected against postpartum relapse (HR 0.11 [0.04-0.32], p Conclusion Women with MS prescribed natalizumab or fingolimod preconception had higher rates of intrapartum and postpartum relapse. In women considered to be at high relapse risk, use of natalizumab before pregnancy and continued up to 32-34 weeks gestation, with early re-initiation after delivery is an effective option to minimise relapse risks. Strategies of DMT use have to be balanced against potential foetal/neonatal complications.
Published: 2021
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26. The Association of Olfactory Dysfunction, Frailty, and Mortality Is Mediated by Inflammation: Results from the InCHIANTI Study

Author: Domenico Paolo Emanuele Margiotta, Davide Fontana, Luigi Ferrucci, Daniele Spitaleri, Irene Chiarella, Raffaele Antonelli Incalzi, Luca Navarini, Stefania Bandinelli, Antonella Gemma, and Alice Laudisio
Subjects: lcsh:Immunologic diseases. Allergy, Male, Oncology, Olfactory system, Aging, medicine.medical_specialty, Weakness, Article Subject, Immunology, Logistic regression, Olfaction Disorders, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Immunology and Allergy, Prospective Studies, 030212 general & internal medicine, Prospective cohort study, Depression (differential diagnoses), Aged, Aged, 80 and over, Inflammation, Frailty, Interleukin-6, business.industry, Proportional hazards model, Cognition, General Medicine, Italy, Ageing, Female, medicine.symptom, lcsh:RC581-607, business, Biomarkers, 030217 neurology & neurosurgery, Research Article
Abstract: Background. Olfactory dysfunction might unveil the association between ageing and frailty, as it is associated with declining cognitive function, depression, reduced physical performance, reduced dietary intake, and mortality; all these conditions are characterized by increased levels of inflammatory parameters. The present study is aimed at evaluating the association between olfactory dysfunction, frailty, and mortality and whether such association might be mediated by inflammation. Methods. We analysed data of 1035 participants aged 65+ enrolled in the “InCHIANTI” study. Olfactory function was tested by the recognition of the smells of coffee, mint, and air. Olfactory dysfunction was defined as lack of recognition of at least two smells. Considering the items “shrinking,” “exhaustion,” “sedentariness,” “slowness,” and “weakness” included in the Fried definition, frailty was defined as the presence of at least three criteria, prefrailty of one or two, and robustness of none. Serum interleukin-6 (IL-6) was measured in duplicate by high-sensitivity enzyme-linked immunosorbent assays. Logistic regression was adopted to assess the association of frailty with olfactory function, as well as with the increasing number of olfactory deficits. Cox regression was used to test the association between olfactory dysfunction and 9-year survival. Results. Olfactory dysfunction was associated with frailty, after adjusting (OR 1.94, 95% CI=1.07-3.51; P=.028); analysis of the interaction term indicated that the association varied according to interleukin-6 levels (P for interaction=.005). Increasing levels of olfactory dysfunction were associated with increasing probability of being frail. Also, olfactory dysfunction was associated with reduced survival (HR 1.52, 95% CI=1.16-1.98; P=.002); this association varied according to the presence of frailty (P for interaction=.017) and prefrailty status (P for interaction=.046), as well as increased interleukin-6 levels (P for interaction = .011). Conclusions. Impairment of olfactory function might represent a marker of frailty, prefrailty, and consequently reduced survival in an advanced age. Inflammation might represent the possible link between these conditions.
Published: 2019
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27. Apathy as a herald of cognitive changes in multiple sclerosis: A 2-year follow-up study

Author: Simona Raimo, Luigi Trojano, Daniele Spitaleri, Gabriella Santangelo, Raimo, Simona, Spitaleri, Daniele, Trojano, Luigi, and Santangelo, Gabriella
Subjects: Adult, Male, Multiple Sclerosis, Apathy, Neuropsychological Tests, Behavioural disorders, 050105 experimental psychology, cognitive deficit, Executive Function, 03 medical and health sciences, 0302 clinical medicine, Cognitive Changes, Humans, Medicine, Multiple sclerosi, Attention, Cognitive Dysfunction, 0501 psychology and cognitive sciences, Depression (differential diagnoses), Depression, business.industry, Multiple sclerosis, 05 social sciences, Follow up studies, Cognition, Middle Aged, medicine.disease, behavioural disorder, Inhibition, Psychological, Neurology, Female, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, Follow-Up Studies, Clinical psychology
Abstract: Background: Behavioral symptoms, such as apathy and depression, are common in multiple sclerosis (MS) but their relationship with cognitive and clinical characteristics often remains underinvestigated and not monitored over time. Objective: The aim of this study was to assess the evolution of cognitive profile of patients affected by MS in relation to apathy and depression using a 2-year follow-up study. Methods: Two years after the first assessment, 100 of 125 MS patients were re-evaluated on a comprehensive neuropsychological battery, and on specific scales for assessment of apathy (Apathy Evaluation Scale—Self-reported) and depression (Hamilton Depression Rating Scale). Results: After 2 years (T1), we found a relatively consistent prevalence of apathy (about 40%) and a reduction in prevalence of depression (from 44% to 30%). Higher level of apathy at baseline predicted the progressive cognitive changes at follow-up; and patients with apathy without depression (“pure” apathy) than patients without apathy had poorer performance on the interference task of the Stroop test assessing inhibitory control. Conclusion: The present results suggested that apathy in MS was associated with more severe executive dysfunctions (in particular cognitive control). Apathy rather than depression predicted cognitive impairment in MS over time.
Published: 2019
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28. Prevalence and predictors of bowel dysfunction in a large multiple sclerosis outpatient population: an Italian multicenter study

Author: Alvino, Bisecco, primary, Arianna, Fornasiero, additional, Assunta, Bianco, additional, Antonio, Cortese, additional, Emanuele, d’Amico, additional, Giorgia, Mataluni, additional, Leonardo, Sinisi, additional, Daniele, Spitaleri, additional, Renato, Docimo, additional, Buscarinu, Maria Chiara, additional, Massimiliano, Mirabella, additional, Crisafulli, Sebastiano Giuseppe, additional, Aurora, Zanghì, additional, Gabri Nicoletti, Carolina, additional, Marco, Salvetti, additional, Viola, Baione, additional, Francesco, Patti, additional, Marfia, Alessandra Girolama, additional, Grazia, Sibilia, additional, Valentina, Scarano, additional, Davide, Orlando, additional, Giovanni, Stabile, additional, Gioacchino, Tedeschi, additional, and Gallo, Antonio, additional
Published: 2021
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29. Social vulnerability is associated with increased mortality in older patients with cancer

Author: Fiammetta Monacelli, Irene Chiarella, Chiara Giannotti, Alberto Ballestrero, Alice Laudisio, Alessio Nencioni, Patrizio Odetti, Raffaele Antonelli Incalzi, and Daniele Spitaleri
Subjects: Gerontology, Frailty, Older adults with cancer, One year mortality, Social vulnerability, Aged, Geriatric Assessment, Humans, Frail Elderly, Neoplasms, business.industry, Cancer, Geriatric assessment, medicine.disease, Oncology, Older patients, Medicine, Frail elderly, Geriatrics and Gerontology, business
Published: 2021

30. The effectiveness of natalizumab vs fingolimod–A comparison of international registry studies

Author: Alexis Montcuquet, Henrik Kahr Mathiesen, Tomas Kalincik, Marc Girard, Karolina Hankiewicz, Marco Onofrj, Francois Grand Maison, Raed Alroughani, Mathilde Lefort, Olivier Gout, Jeannette Lechner-Scott, Marc Debouverie, Julie Prevost, Eva Havrdova, Olivier Casez, Per Soelberg Sørensen, Pierre Duquette, Jean Pelletier, Claudio Solaro, Alessandra Lugaresi, Francesco Patti, Emmanuelle Leray, Johanna Balslev Andersen, Bassem Yamout, Céline Labeyrie, Karen Schreiber, Eric Thouvenot, Nils Koch-Henriksen, Michael Broksgaard Jensen, Elisabeth Maillart, Chantal Nifle, Stephan Bramow, Pierre Clavelou, Bruno Stankoff, Olivier Heinzlef, Finn Sellebjerg, Abir Wahab, Mark Slee, Gilles Defer, Pierre Labauge, Melinda Magyari, Steve Vucic, Guillermo Izquierdo, Helmut Butzkueven, Peter Vestergaard Rasmussen, Bertrand Bourre, Maria Trojano, Franco Granella, Corinne Pottier, Jette L. Frederiksen, Olga Skibina, Recai Turkoglu, Ivania Patry, Pierre Grammond, Bart Van Wijmeersch, Eric Berger, Aurélie Ruet, Serkan Ozakbas, Jonathan Ciron, Tünde Csépány, Jean Philippe Camdessanche, Sandra Vukusic, Nicolas Maubeuge, David Laplaud, Cavit Boz, Christine Lebrun, Claudia C. Hilt Christensen, Patrizia Sola, Vahid Shaygannejad, Romain Casey, Murat Terzi, Philippe Cabre, Jérôme De Seze, Abdullatif Al-Khedr, Dana Horakova, Pamela A. McCombe, Daniele Spitaleri, Alexandre Prat, Gilles Edan, Hélène Zéphir, Aude Marousset, Sifat Sharmin, Diana Ferraro, Sara Eichau, Rana Karabudak, Thibault Moreau, Sellebjerg, Finn/0000-0002-1333-9623, Lugaresi, Alessandra/0000-0003-2902-5589, frederiksen, jette/0000-0003-1661-7438, Ciron, Jonathan/0000-0002-3386-6308, University of Copenhagen = Københavns Universitet (KU), University of Melbourne, Recherche en Pharmaco-épidémiologie et Recours aux Soins (REPERES), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Aarhus University Hospital, Rigshospitalet [Copenhagen], Copenhagen University Hospital, Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre hospitalier universitaire de Nantes (CHU Nantes), The MSBase Foundation is a not-for-profit organization that receives support from Biogen, Novartis, Merck, Roche, Teva and Sanofi Genzyme. The study was conducted separately and apart from the guidance of the sponsors. CORe received funding from NHMRC [1140766, 1129789, 1157717] to support studies of comparative effectiveness of MS therapies.OFSEP was supported by a grant provided by the French State and handled by the 'Agence Nationale de la Recherche,' within the framework of the 'Investments for the Future' program, under the reference ANR-10-COHO-002, by the Eugène Devic EDMUS Foundation against multiple sclerosis and by the ARSEP Foundation.DMSR did not receive any funding to collaborate in this study., ANR-10-COHO-0002,OFSEP,Observatoire Français de la Sclérose en Plaques(2010), Andersen J.B., Sharmin S., Lefort M., Koch-Henriksen N., Sellebjerg F., Sorensen P.S., Hilt Christensen C.C., Rasmussen P.V., Jensen M.B., Frederiksen J.L., Bramow S., Mathiesen H.K., Schreiber K.I., Horakova D., Havrdova E.K., Alroughani R., Izquierdo G., Eichau S., Ozakbas S., Patti F., Onofrj M., Lugaresi A., Terzi M., Grammond P., Grand Maison F., Yamout B., Prat A., Girard M., Duquette P., Boz C., Trojano M., McCombe P., Slee M., Lechner-Scott J., Turkoglu R., Sola P., Ferraro D., Granella F., Shaygannejad V., Prevost J., Skibina O., Solaro C., Karabudak R., Wijmeersch B.V., Csepany T., Spitaleri D., Vucic S., Casey R., Debouverie M., Edan G., Ciron J., Ruet A., Seze J.D., Maillart E., Zephir H., Labauge P., Defer G., Lebrun C., Moreau T., Berger E., Clavelou P., Pelletier J., Stankoff B., Gout O., Thouvenot E., Heinzlef O., Al-Khedr A., Bourre B., Casez O., Cabre P., Montcuquet A., Wahab A., Camdessanche J.-P., Marousset A., Patry I., Hankiewicz K., Pottier C., Maubeuge N., Labeyrie C., Nifle C., Leray E., Laplaud D.A., Butzkueven H., Kalincik T., Vukusic S., Magyari M., University of Copenhagen = Københavns Universitet (UCPH), Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Bordeaux [Bordeaux], CHU Strasbourg, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Universitaire de Nice (CHU Nice), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHU Clermont-Ferrand, Hôpital de la Timone [CHU - APHM] (TIMONE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital de la Fondation Ophtalmologique Adolphe de Rothschild [AP-HP], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy], CHU Amiens-Picardie, CHU Rouen, Normandie Université (NU), Centre Hospitalier Universitaire [Grenoble] (CHU), CHU de la Martinique [Fort de France], CHU Limoges, Hôpital Henri Mondor, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier de Saint-Denis [Ile-de-France], Centre hospitalier universitaire de Poitiers (CHU Poitiers), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), and Centre Hospitalier de Versailles André Mignot (CHV)
Subjects: medicine.medical_specialty, Fingolimod, Head-to-head comparison, Multiple sclerosis, Natalizumab, Treatment effectiveness, [SDV]Life Sciences [q-bio], Relapse rate, 03 medical and health sciences, Multiple Sclerosis, Relapsing-Remitting, 0302 clinical medicine, Internal medicine, Fingolimod Hydrochloride, Epidemiology, Humans, Medicine, Multiple sclerosi, Registries, 030212 general & internal medicine, business.industry, Hazard ratio, General Medicine, medicine.disease, 3. Good health, First relapse, Treatment Outcome, Neurology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), business, Immunosuppressive Agents, 030217 neurology & neurosurgery, medicine.drug
Abstract: Background: Natalizumab and fingolimod were the first preparations recommended for disease breakthrough in priorly treated relapsing-remitting multiple sclerosis. Of three published head-to-head studies two showed that natalizumab is the more effective to prevent relapses and EDSS worsening. Methods: By re-analyzing original published results from MSBase, France, and Denmark using uniform meth-odologies, we aimed at identifying the effects of differences in methodology, in the MS-populations, and at re-evaluating the differences in effectiveness between the two drugs. We gained access to copies of the individual amended databases and pooled all data. We used uniform inclusion/ exclusion criteria and statistical methods with Inverse Probability Treatment Weighting. Results: The pooled analyses comprised 968 natalizumab-and 1479 fingolimod treated patients. The on-treatment natalizumab/fingolimod relapse rate ratio was 0.77 (p=0.004). The hazard ratio (HR) for a first relapse was 0.82 (p=0.030), and the HR for sustained EDSS improvement was 1.4 (p=0.009). There were modest differences between each of the original published studies and the replication study, but the conclusions of the three original studies remained unchanged: in two of them natalizumab was more effective, but in the third there was no difference between natalizumab and fingolimod. Conclusion: The results were largely invariant to the epidemiological and statistical methods but differed between the MS populations. Generally, the advantage of natalizumab was confirmed. BiogenBiogen; NovartisNovartis; MerckMerck & Company; RocheRoche Holding; Teva; Sanofi GenzymeSanofi-AventisGenzyme Corporation; NHMRCNational Health and Medical Research Council of Australia [1140766,1129789, 1157717]; French State; Agence Nationale de la Recherche-French National Research Agency (ANR)European Commission [ANR-10-COHO-002]; Eugene Devic EDMUS Foundation; ARSEP Foundation
Published: 2021
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31. Determinants of therapeutic lag in multiple sclerosis

Author: Tomas Kalincik, Marc Girard, Corinne Pottier, Murat Terzi, Jean Pelletier, Oliver Gerlach, Julie Prevost, Dana Horakova, Francois Grand'Maison, Raed Alroughani, Guillermo Izquierdo, Francesco Patti, Federico Frascoli, Maria Trojano, Franco Granella, Pamela A. McCombe, Charles B Malpas, Recai Turkoglu, Aurélie Ruet, Jonathan Ciron, Tünde Csépány, Nicolas Maubeuge, Helmut Butzkueven, Pierre Clavelou, Tamara Castillo Trivino, Marco Onofrj, Jean Philippe Camdessanche, Pierre Labauge, Vincent Van Pesch, Pierre Grammond, Abir Wahab, Roberto Bergamaschi, Aysun Soysal, Diana Ferraro, Bertrand Bourre, Olivier Gout, Jeannette Lechner-Scott, Sara Eichau, Emmanuelle Leray, Alexis Montcuquet, Pierre Duquette, Olivier Casez, Youssef Sidhom, Patrizia Sola, Bart Van Wijmeersch, Izanne Roos, Gilles Edan, Serkan Ozakbas, David Laplaud, Sandra Vukusic, Abdullatif Al Khedr, Céline Labeyrie, Philippe Cabre, Eric Thouvenot, Céline Louapre, Romain Casey, Alessandra Lugaresi, Riadh Gouider, Alasdair Coles, Eric Berger, Ivania Patry, Gerardo Iuliano, Elisabetta Cartechini, Cavit Boz, Karolina Hankiewicz, Eva Havrdova, Eduardo Aguera-Morales, J William L Brown, Jérôme De Seze, Bruno Stankoff, Olivier Heinzlef, Gilles Defer, Alexandre Prat, Chantal Nifle, Maria José Sá, Marc Debouverie, Daniele Spitaleri, Aude Maurousset, Thibault Moreau, Christine Lebrun-Frenay, Hélène Zéphir, University of Melbourne, Recherche en Pharmaco-épidémiologie et Recours aux Soins (REPERES), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP), École des Hautes Études en Santé Publique [EHESP] (EHESP), Département Méthodes quantitatives en santé publique (METIS), Collectif de recherche handicap, autonomie et société inclusive (CoRHASI), Swinburne University of Technology [Melbourne], Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Charles University [Prague], Università degli studi di Catania [Catania], Università degli studi 'G. d'Annunzio' Chieti-Pescara [Chieti-Pescara] (Ud'A), Università degli Studi di Modena e Reggio Emilia (UNIMORE), University of Queensland [Brisbane], Monash University [Clayton], UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, UCL - (SLuc) Service de biochimie médicale, UCL - (SLuc) Service de neurologie, Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Charles University [Prague] (CU), Adaptation, mesure et évaluation en santé. Approches interdisciplinaires (APEMAC), Université de Lorraine (UL), Service de neurologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), University of Bari Aldo Moro (UNIBA), University of Catania [Italy], Hospital Virgen Macarena, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), CHU Toulouse [Toulouse], INSERM, Neurocentre Magendie, U1215, Physiopathologie de la Plasticité Neuronale, F-33000 Bordeaux, France, CIC Bordeaux, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Dokuz Eylül Üniversitesi = Dokuz Eylül University [Izmir] (DEÜ), CIC Strasbourg (Centre d’Investigation Clinique Plurithématique (CIC - P) ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)-Hôpital de Hautepierre [Strasbourg]-Nouvel Hôpital Civil de Strasbourg, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Lille, Fernando Pessoa University, Azienda Ospedaleria Universitaria di Modena, CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Universitaire de Nice (CHU Nice), Karadeniz Technical University (KTU), Università degli Studi di Macerata = University of Macerata (UNIMC), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre hospitalier universitaire de Nantes (CHU Nantes), University of Newcastle [Australia] (UoN), Zuyderland Hospital [Heerlen, The Netherlands], Ondokuz Mayis University, University of Parma = Università degli studi di Parma [Parme, Italie], Amiri hospital, University of Salerno (UNISA), Université Catholique de Louvain = Catholic University of Louvain (UCL), Hasselt University (UHasselt), San Giuseppe Moscati Hospital [Avellino, Italie], Bakirkoy Matern & Childrens State Hosp, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Universidad de Córdoba [Cordoba], Hospital Donostia, CHU Clermont-Ferrand, Hôpital de la Timone [CHU - APHM] (TIMONE), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), CHI Poissy-Saint-Germain, Université de la Manouba [Tunisie] (UMA), University of Debrecen, Hôpital Charles Nicolle [Rouen], CHU Amiens-Picardie, CHU de la Martinique [Fort de France], CHU Limoges, CHU Henri Mondor, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Centre Hospitalier Sud Francilien, CH Evry-Corbeil, Centre Hospitalier de Saint-Denis [Ile-de-France], Centre Hospitalier René Dubos [Pontoise], This study was supported by the EDMUS Foundation and NHMRC [1140766,1129189, 1157717]. IR is supported by a MSIF-ARSEP McDonald fellowship grantand a Melbourne Research Scholarship. The MSBase Foundation is a not-for-profitorganization that receives support from Biogen, Novartis, Merck, Roche, Teva andSanofi Genzyme. The study was conducted separately and apart from the guidanceof the sponsors. The Observatoire Français de la Sclérose en Plaques (OFSEP) issupported by a grant provided by the French State and handled by the 'AgenceNationale de la Recherche,' within the framework of the 'Investments for the Future'program, under the reference ANR-10-COHO-002, by the Eugène Devic EDMUSFoundation against multiple sclerosis and by the ARSEP Foundation., ANR-10-COHO-0002,OFSEP,Observatoire Français de la Sclérose en Plaques(2010), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Roos I., Leray E., Frascoli F., Casey R., Brown J.W.L., Horakova D., Havrdova E.K., Debouverie M., Trojano M., Patti F., Izquierdo G., Eichau S., Edan G., Prat A., Girard M., Duquette P., Onofrj M., Lugaresi A., Grammond P., Ciron J., Ruet A., Ozakbas S., De Seze J., Louapre C., Zephir H., Sa M.J., Sola P., Ferraro D., Labauge P., Defer G., Bergamaschi R., Lebrun-Frenay C., Boz C., Cartechini E., Moreau T., Laplaud D., Lechner-Scott J., Grand'Maison F., Gerlach O., Terzi M., Granella F., Alroughani R., Iuliano G., Van Pesch V., Van Wijmeersch B., Spitaleri D.L.A., Soysal A., Berger E., Prevost J., Aguera-Morales E., McCombe P., Castillo Trivino T., Clavelou P., Pelletier J., Turkoglu R., Stankoff B., Gout O., Thouvenot E., Heinzlef O., Sidhom Y., Gouider R., Csepany T., Bourre B., Al Khedr A., Casez O., Cabre P., Montcuquet A., Wahab A., Camdessanche J.-P., Maurousset A., Patry I., Hankiewicz K., Pottier C., Maubeuge N., Labeyrie C., Nifle C., Coles A., Malpas C.B., Vukusic S., Butzkueven H., Kalincik T., Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Università degli studi di Catania = University of Catania (Unict), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Neurocentre Magendie : Physiopathologie de la Plasticité Neuronale (U1215 Inserm - UB), Université de Bordeaux (UB)-Institut François Magendie-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nouvel Hôpital Civil de Strasbourg-Hôpital de Hautepierre [Strasbourg], Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE), University of Newcastle [Callaghan, Australia] (UoN), Ondokuz Mayis University (OMU), Università degli studi di Parma = University of Parma (UNIPR), Universidad de Córdoba = University of Córdoba [Córdoba], University of Debrecen Egyetem [Debrecen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), CHU Henri Mondor [Créteil], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Registrie, Male, medicine.medical_specialty, Treatment response, Pediatrics, Neurology, Lag, [SDV]Life Sciences [q-bio], Aucun, multiple sclerosis, 03 medical and health sciences, Disability Evaluation, 0302 clinical medicine, Multiple Sclerosis, Relapsing-Remitting, Recurrence, medicine, Humans, Treatment effect, Disabled Persons, Registries, 030304 developmental biology, 0303 health sciences, business.industry, Multiple sclerosis, Delayed onset, medicine.disease, 3. Good health, Clinical neurology, therapeutic lag, multiple sclerosi, Disease Progression, Disabled Person, Observational study, Female, observational study, Neurology (clinical), business, 030217 neurology & neurosurgery, Human
Abstract: International audience; Objective: To explore the associations of patient and disease characteristics with the duration of therapeutic lag for relapses and disability progression.Background: Therapeutic lag represents the delay from initiation of therapy to attainment of full treatment effect. Understanding the determinants of therapeutic lag provides valuable information for personalised choice of therapy in multiple sclerosis (MS).Design/Methods: Data from MSBase, a multinational MS registry, and OFSEP, the French national registry, were used. Patients diagnosed with MS, minimum 1-year exposure to MS treatment, minimum 3-year pre-treatment follow up and yearly review were included in the analysis. By studying incidence of relapses and 6-month confirmed disability progression, the duration of therapeutic lag was calculated by identifying the first local minimum of the first derivative after treatment start in subgroups stratified by patient and disease characteristics. Pairwise analyses of univariate predictors were performed. Combinations of determinants that consistently drove differences in therapeutic lag in pair by pair analyses were included in the final model.Results: Baseline EDSS, ARR and sex were associated with duration of therapeutic lag on disability progression in univariate and pairwise bivariable analyses. In the final model, therapeutic lag was 27.8 weeks shorter in females with ARR6 compared to those with EDSS>=6 (26.6, 18.2–34.9 vs 54.3, 47.2–61.5). Baseline EDSS, ARR, sex and MS phenotype were associated with duration of therapeutic lag on relapses in univariate analyses. Pairwise bivariable analyses of the pairs of determinants suggested ependently associated with therapeutic lag. In the final model, therapeutic lag was shortest in those with RRMS and EDSS
Published: 2021
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32. Natalizumab Versus Fingolimod in Patients with Relapsing-Remitting Multiple Sclerosis: A Subgroup Analysis From Three International Cohorts

Author: Mark Slee, Guillermo Izquierdo, Per Soelberg Soerensen, Karen Schreiber, Alexandre Prat, Francois Grand'Maison, Maria Trojano, Franco Granella, Pierre Duquette, David Laplaud, Elisabeth Maillart, Henrik Kahr Mathiesen, Bassem Yamout, Cavit Boz, Jean Pelletier, Corinne Pottier, Jette L. Frederiksen, Claudia Christina Pfleger, Tomas Kalincik, Olivier Gout, Daniele Spitaleri, Marc Girard, Marco Onofrj, Jérôme De Seze, Helmut Butzkueven, Emmanuelle Leray, Philippe Cabre, Julie Prevost, Abullatif Al-Khedr, Aude Maurousset, Eric Berger, Sifat Sharmin, Ivania Patry, Pamela A. McCombe, Patrizia Sola, Olga Skibina, Diana Ferraro, Pierre Clavelou, Francesco Patti, Finn Sellebjerg, Niels Koch-Henriksen, Alexis Montcuquet, Recai Turkoglu, Romain Casey, Bart Van Wijmeersch, Hélène Zéphir, Pierre Grammond, Dana Horakova, Davide Maimone, Serkan Ozakbas, Céline Labeyrie, Murat Terzi, Aurélie Ruet, Steve Vucic, Jonathan Ciron, Tünde Csépány, Nicolas Maubeuge, Bruno Stankoff, Mathilde Lefort, Katherine Buzzard, Karolina Hankiewicz, Jean-Philippe Camdessanché, Raed Alroughani, Michael Broksgaard Jensen, Pierre Labauge, Olivier Casez, Peter Vestergaard Rasmussen, Bertrand Bourre, Olivier Heinzlef, Gilles Defer, Gilles Edan, Alessandra Lugaresi, Abir Wahab, Melinda Magyari, Anneke van der Walt, Eva Havrdova, Johanna Balslev Andersen, Chantal Nifle, Stephan Bramow, Marc Debouverie, Thibault Moreau, Sandra Vukusic, Christine Lebrun-Frenay, Jeannette Lechner-Scott, Eric Thouvenot, Sharmin S., Lefort M., Andersen J.B., Leray E., Horakova D., Havrdova E.K., Alroughani R., Izquierdo G., Ozakbas S., Patti F., Onofrj M., Lugaresi A., Terzi M., Grammond P., Grand'Maison F., Yamout B., Prat A., Girard M., Duquette P., Boz C., Trojano M., McCombe P., Slee M., Lechner-Scott J., Turkoglu R., Sola P., Ferraro D., Granella F., Prevost J., Maimone D., Skibina O., Buzzard K., Van der Walt A., Van Wijmeersch B., Csepany T., Spitaleri D., Vucic S., Casey R., Debouverie M., Edan G., Ciron J., Ruet A., De Seze J., Maillart E., Zephir H., Labauge P., Defer G., Lebrun-Frenay C., Moreau T., Berger E., Clavelou P., Pelletier J., Stankoff B., Gout O., Thouvenot E., Heinzlef O., Al-Khedr A., Bourre B., Casez O., Cabre P., Montcuquet A., Wahab A., Camdessanche J.-P., Maurousset A., Patry I., Hankiewicz K., Pottier C., Maubeuge N., Labeyrie C., Nifle C., Laplaud D., Koch-Henriksen N., Sellebjerg F.T., Soerensen P.S., Pfleger C.C., Rasmussen P.V., Jensen M.B., Frederiksen J.L., Bramow S., Mathiesen H.K., Schreiber K.I., Magyari M., Vukusic S., Butzkueven H., Kalincik T., University of Melbourne, Recherche en Pharmaco-épidémiologie et Recours aux Soins (REPERES), Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP), CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Copenhagen = Københavns Universitet (UCPH), École des Hautes Études en Santé Publique [EHESP] (EHESP), Charles University [Prague] (CU), Amiri hospital, Hospital Virgen Macarena, Dokuz Eylül Üniversitesi = Dokuz Eylül University [Izmir] (DEÜ), University of Catania [Italy], G.F. Ingrassia Hospital, Università degli studi 'G. d'Annunzio' Chieti-Pescara [Chieti-Pescara] (Ud'A), Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Institute of Neurological Science of Bologna (IRCCS), Ondokuz Mayis University (OMU), American University of Beirut Faculty of Medicine and Medical Center (AUB), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Karadeniz Technical University (KTU), Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), University of Queensland [Brisbane], Royal Brisbane & Women's Hospital [Brisbane, Australia] (RBWH), Flinders University [Adelaide, Australia], University of Newcastle [Callaghan, Australia] (UoN), Azienda Ospedaleria Universitaria di Modena, Università degli studi di Parma = University of Parma (UNIPR), University Hospital Parma, Monash University [Melbourne], The Alfred Hospital, Hasselt University (UHasselt), University of Debrecen Egyetem [Debrecen], San Giuseppe Moscati Hospital [Avellino, Italie], Westmead Hospital [Sydney], Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fondation Eugène Devic EDMUS, Adaptation, mesure et évaluation en santé. Approches interdisciplinaires (APEMAC), Université de Lorraine (UL), Service de neurologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Neurocentre Magendie : Physiopathologie de la Plasticité Neuronale (U1215 Inserm - UB), Université de Bordeaux (UB)-Institut François Magendie-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC Bordeaux, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC Strasbourg (Centre d’Investigation Clinique Plurithématique (CIC - P) ), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nouvel Hôpital Civil de Strasbourg-Hôpital de Hautepierre [Strasbourg], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Lille, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Hôpital Pasteur [Nice] (CHU), Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Clermont-Ferrand, Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Hôpital de la Timone [CHU - APHM] (TIMONE), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), CHI Poissy-Saint-Germain, Service de neurologie [Amiens], CHU Amiens-Picardie, Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Centre Hospitalier Universitaire [Grenoble] (CHU), CHU de la Martinique [Fort de France], Service de Neurologie [CHU Limoges], CHU Limoges, CHU Henri Mondor [Créteil], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Service de Neurologie [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Hôpital Sud Francilien Corbeil Essonne, Centre Hospitalier de Saint-Denis [Ile-de-France], Centre Hospitalier René Dubos [Pontoise], Hôpital de la Milétrie, Centre hospitalier universitaire de Poitiers (CHU Poitiers), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre Hospitalier de Versailles André Mignot (CHV), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Aarhus University Hospital, Aalborg University [Denmark] (AAU), University Hospital of Northern Sealand, Rigshospitalet [Copenhagen], Copenhagen University Hospital, The Royal Melbourne Hospital, 1140766, National Health and Medical Research Council, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Copenhagen = Københavns Universitet (KU), Università degli Studi di Bologna, University of Bari Aldo Moro (UNIBA), University of Newcastle [Australia] (UoN), University of Parma = Università degli studi di Parma [Parme, Italie], University of Debrecen, Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Toulouse [Toulouse], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Henri Mondor, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Ondokuz Mayis University, Centre de recherche en neurosciences de Lyon (CRNL), Physiopathologie de la Plasticité Neuronale (Neurocentre Magendie - U1215 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)-Hôpital de Hautepierre [Strasbourg]-Nouvel Hôpital Civil de Strasbourg, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Male, medicine.medical_specialty, Multiple Sclerosis, Internationality, Subgroup analysis, Rate ratio, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Natalizumab, Multiple Sclerosis, Relapsing-Remitting, 030225 pediatrics, Internal medicine, Secondary Prevention, Medicine, Humans, Immunologic Factors, Pharmacology (medical), Longitudinal Studies, Registries, 10. No inequality, Expanded Disability Status Scale, business.industry, Proportional hazards model, Fingolimod Hydrochloride, Multiple sclerosis, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Middle Aged, medicine.disease, Fingolimod, 3. Good health, multiple sclerosis, sex, age, natalizumab, fingolimod, big data, Psychiatry and Mental health, Cohort, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, Immunosuppressive Agents, medicine.drug, Follow-Up Studies
Abstract: Introduction: Natalizumab has proved to be more effective than fingolimod in reducing disease activity in relapsing-remitting multiple sclerosis (RRMS). Whether this association is universal for all patient groups remains to be determined. Objective: The aim of this study was to compare the relative effectiveness of natalizumab and fingolimod in RRMS subgroups defined by the baseline demographic and clinical characteristics of interest. Methods: Patients with RRMS who were given natalizumab or fingolimod were identified in a merged cohort from three international registries. Efficacy outcomes were compared across subgroups based on patients’ sex, age, disease duration, Expanded Disability Status Scale (EDSS) score, and disease and magnetic resonance imaging (MRI) activity 12 months prior to treatment initiation. Study endpoints were number of relapses (analyzed withweighted negative binomial generalized linear model) and 6-month confirmed disability worsening and improvement events (weighted Cox proportional hazards model), recorded during study therapy. Each patient was weighted using inverse probability of treatment weighting based on propensity score. Results: A total of 5148 patients (natalizumab 1989; fingolimod 3159) were included, with a mean ± standard deviation age at baseline of 38 ± 10 years, and the majority (72%) were women. The median on-treatment follow-up was 25 (quartiles 15–41) months. Natalizumab was associated with fewer relapses than fingolimod (incidence rate ratio [IRR]; 95% confidence interval [CI]) in women (0.76; 0.65–0.88); in those aged ≤38 years (0.64; 0.54–0.76); in those withdisease duration ≤7 years (0.63; 0.53–0.76); in those with EDSS score 38 years (1.34; 1.04–1.73); those with disease duration >7 years (1.33; 1.01–1.74); those with EDSS score
Published: 2021
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33. Natalizumab, Fingolimod and Dimethyl Fumarate Use and Pregnancy-Related Relapse and Disability in Women With Multiple Sclerosis

Author: Raymond Hupperts, Pierre Duquette, Tomas Uher, Wei Zhen Yeh, Karolina Vodehnalova, Suzanne Hodgkinson, Ayse Altintas, Celia Oreja-Guevara, Serkan Ozakbas, Michael Barnett, Tamara Castillo-Triviño, Francois Grand'Maison, Jeannette Lechner-Scott, Daniele Spitaleri, Olga Skibina, Vilija Jokubaitis, Franco Granella, Tomas Kalincik, Elisabetta Cartechini, Pierre Grammond, Melissa Gresle, Richard A L Macdonell, Jim Stankovich, Dana Horakova, Marco Onofrj, Vincent Van Pesch, Sara Eichau, Recai Turkoglu, Roberto Bergamaschi, Albert Saiz, Raed Alroughani, Aysun Soysal, Helmut Butzkueven, Radek Ampapa, Putu Ayu Widyastuti, Cavit Boz, Francesco Patti, Pamela A. McCombe, Patrizia Sola, Murat Terzi, Maria Pia Amato, Anneke van der Walt, Eva Havrdova, Maria José Sá, Bassem Yamout, Davide Maimone, and UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire
Subjects: medicine.medical_specialty, Pregnancy, Clinically isolated syndrome, Obstetrics, business.industry, Hazard ratio, Odds ratio, medicine.disease, Fingolimod, Article, 03 medical and health sciences, 0302 clinical medicine, Natalizumab, Cohort, medicine, Gestation, 030212 general & internal medicine, Neurology (clinical), business, 030217 neurology & neurosurgery, medicine.drug
Abstract: ObjectiveTo investigate pregnancy-related disease activity in a contemporary multiple sclerosis (MS) cohort.MethodsUsing data from the MSBase Registry, we included pregnancies conceived after December 31, 2010, in women with relapsing-remitting MS or clinically isolated syndrome. Predictors of intrapartum relapse and postpartum relapse and disability progression were determined by clustered logistic regression or Cox regression analyses.ResultsWe included 1,998 pregnancies from 1,619 women with MS. Preconception annualized relapse rate (ARR) was 0.29 (95% confidence interval 0.27–0.32), fell to 0.19 (0.14–0.24) in the third trimester, and increased to 0.59 (0.51–0.67) in early postpartum. Among women who used fingolimod or natalizumab, ARR before pregnancy was 0.37 (0.28–0.49) and 0.29 (0.22–0.37), respectively, and increased during pregnancy. Intrapartum ARR decreased with preconception dimethyl fumarate use. ARR spiked after delivery across all DMT groups. Natalizumab continuation into pregnancy reduced the odds of relapse during pregnancy (odds ratio 0.76 per month [0.60–0.95], p = 0.017). DMT reinitiation with natalizumab protected against postpartum relapse (hazard ratio [HR] 0.11 [0.04–0.32], p < 0.0001). Breastfeeding women were less likely to relapse (HR 0.61 [0.41–0.91], p = 0.016). We found that 5.6% of pregnancies were followed by confirmed disability progression, predicted by higher relapse activity in pregnancy and postpartum.ConclusionIntrapartum and postpartum relapse probabilities increased among women with MS after natalizumab or fingolimod cessation. In women considered to be at high relapse risk, use of natalizumab before pregnancy and continued up to 34 weeks gestation with early reinitiation after delivery is an effective option to minimize relapse risks. Strategies of disease-modifying therapy use have to be balanced against potential fetal/neonatal complications.
Published: 2021

34. The Impact of Covid-19 Lockdown on Stroke Admissions and Treatments in Campania

Author: Giorgia Teresa Maniscalco, Vincenzo Palma, Simona Salvatore, Daniele Spitaleri, Florindo D'Onofrio, Maria Pia Mazzaferro, Giuseppe Leone, Salvatore Ascione, Vincenzo Andreone, Valentino Manzo, Paolo Candelaresi, Daniele Giuseppe Romano, Gioacchino Martusciello, Giovanna Servillo, Elisa Capone, Renato Saponiero, Carla Schettino, Paolo Barone, Mario Muto, Stefania Miniello, and Rosa Napoletano
Subjects: Male, medicine.medical_specialty, Time Factors, Coronavirus disease 2019 (COVID-19), medicine.medical_treatment, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Clinical Neurology, Article, Time-to-Treatment, 03 medical and health sciences, 0302 clinical medicine, Patient Admission, Pandemic, Lockdown, medicine, Humans, Thrombolytic Therapy, Stroke, Medical attention, Aged, Retrospective Studies, Thrombectomy, Aged, 80 and over, business.industry, Incidence (epidemiology), Incidence, Rehabilitation, Retrospective cohort study, Thrombolysis, Middle Aged, medicine.disease, Italy, Emergency medicine, Female, Surgery, Neurology (clinical), business, Covid-19, Cardiology and Cardiovascular Medicine, 030217 neurology & neurosurgery
Abstract: Objectives The enforcement of complete lockdown with home confinement has been necessary to limit SARS-CoV-2 contagions in Italy, one the most affected countries worldwide. Simultaneously, in several Emergency Departments, a reduction in cardio- and cerebrovascular presentations was noticed. This study analyses the impact of Covid-19 pandemic and lockdown measures on the incidence of stroke, in Campania, the most densely-populated region in Italy. Materials and Methods We retrospectively analyzed data regarding acute stroke patients presenting at 5 Campania stroke hubs, before and after the issue of lockdown in Italy on March 9th, 2020. Results Compared to the pre-lockdown, we observed a significant reduction in the number of acute reperfusion treatments in stroke (P for interact 0.001); however the global number of patients presenting with acute stroke did not significantly differ. The time to reach medical attention was significantly longer in the lockdown phase (230 versus 154 min, P 0.016). For patients who underwent acute reperfusion treatment we also observed significantly longer time-to-imaging (30 versus 40 min, P 0.0005) and a trend to longer time-to-needle (75 versus 90 min P 0.23), but not time-to-groin. Conclusions This study showed the reduction in acute reperfusion treatments for acute ischemic stroke and the slowdown of stroke pathways, during the lockdown phase of Covid-19 pandemic, in Campania, the third-most-populous and the most-densely populated Italian Region. In the next future, the risk for high-grade disability and death, due to delayed or even avoided hospital presentation due to fear of contagion, may be high.
Published: 2021
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35. Hypercalcemia and Nephrogenic Diabetes Insipidus: Rare and Life-Threatening Effects of Lithium Intoxication

Author: Vincenzo Palma, Daniele Spitaleri, Maria Lieto, Arturo de Falco, and Valentina Scarano
Subjects: medicine.medical_specialty, Lithium (medication), medicine.medical_treatment, Medicine (miscellaneous), Gastroenterology, Therapeutic index, nephrogenic diabetes insipidus, Internal medicine, Lithium Toxicity, Hypercalcemia, Nephrogenic Diabetes Insipidus, Hypernatremia, medicine, Adverse effect, lcsh:R5-920, Hyperparathyroidism, hypernatremia, business.industry, Thyroid, hypercalcemia, Nephrogenic diabetes insipidus, medicine.disease, medicine.anatomical_structure, lithium toxicity, Business, Management and Accounting (miscellaneous), Hemodialysis, lcsh:Medicine (General), business, Neurology, Psychiatry, Internal Medicine, Nephrology, General medicine, medicine.drug
Abstract: Lithium is the most effective therapy for bipolar and schizoaffective disorders. Despite its efficacy, lithium has a narrow therapeutic index and adverse effects are frequent. Lithium intoxication (LI) generally affects brain, but less frequently can affect kidneys, thyroid, and parathyroid. Here, we report the case of a patient with lithium neurotoxic effects complicated by parathyroid and renal adverse effects. The patient was a 52-year-old woman treated with lithium, who was recently diagnosed with hypercalcemia and hyperparathyroidism. She was admitted for severe agitation, confusion, and diffuse tremor. Despite serum lithium and calcium normalization, laboratory tests revealed a life-threatening hypernatremia caused by nephrogenic diabetes insipidus (NDI). Hemodialysis was started, but after the first treatment the patient died for cardiac arrest. Neurological symptoms of LI may occur even if the dosage is close to the normal therapeutic range. Hypercalcemia and NDI are rare, but should be promptly diagnosed and treated. In case of poor clinical outcome, hemodialysis should be performed independently of lithium serum level.
Published: 2020
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36. Disability outcomes of early cerebellar and brainstem symptoms in multiple sclerosis

Author: Bassem Yamout, Alessandra Lugaresi, Pierre Duquette, Anneke van der Walt, Eva Havrdova, Jose Luis Sanchez-Menoyo, Alexandre Prat, Raymond Hupperts, Vincent Van Pesch, Cristina Ramo-Tello, Jeannette Lechner-Scott, Francois Grand’ Maison, Guillermo Izquierdo, Steve Vucic, Roberto Bergamaschi, Cavit Boz, Ayse Altintas, Vahid Shaygannejad, Aysun Soysal, Youssef Sidhom, Tomas Kalincik, Charles B Malpas, Marc Girard, Serkan Ozakbas, Julie Prevost, Raed Alroughani, Catherine Larochelle, Michael Barnett, Daniele Spitaleri, Pamela A. McCombe, Thor Petersen, Mark Slee, Helmut Butzkueven, Maria Trojano, Franco Granella, Minh Le, Yara Dadalti Fragoso, Pierre Grammond, Radek Ampapa, Riadh Gouider, Gerardo Iuliano, Recai Turkoglu, Murat Terzi, Eugenio Pucci, Sifat Sharmin, Diana Ferraro, Sara Eichau, Patrizia Sola, Dana Horakova, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, Le M., Malpas C., Sharmin S., Horakova D., Havrdova E., Trojano M., Izquierdo G., Eichau S., Ozakbas S., Lugaresi A., Prat A., Girard M., Duquette P., Larochelle C., Alroughani R., Bergamaschi R., Sola P., Ferraro D., Grammond P., Grand' Maison F., Terzi M., Boz C., Hupperts R., Butzkueven H., Pucci E., Granella F., Van Pesch V., Soysal A., Yamout B.I., Lechner-Scott J., Spitaleri D.L.A., Ampapa R., Turkoglu R., Iuliano G., Ramo-Tello C., Sanchez-Menoyo J.L., Sidhom Y., Gouider R., Shaygannejad V., Prevost J., Altintas A., Fragoso Y.D., McCombe P.A., Petersen T., Slee M., Barnett M.H., Vucic S., Van Der Walt A., and Kalincik T.
Subjects: Pediatrics, medicine.medical_specialty, Multivariate analysis, Multiple Sclerosis, brainstem, Multiple sclerosis, Cohort Studies, 03 medical and health sciences, Therapeutic approach, Disability Evaluation, 0302 clinical medicine, disability outcome, medicine, Humans, Multiple sclerosi, Disabled Persons, 030304 developmental biology, 0303 health sciences, Expanded Disability Status Scale, cerebellar, early symptomatology, prognostic marker, business.industry, medicine.disease, Natural history, Neurology, Cohort, Disease Progression, Neurology (clinical), Brainstem, Presentation (obstetrics), business, 030217 neurology & neurosurgery, Brain Stem
Abstract: Background:Cerebellar and brainstem symptoms are common in early stages of multiple sclerosis (MS) yet their prognostic values remain unclear.Objective:The aim of this study was to investigate long-term disability outcomes in patients with early cerebellar and brainstem symptoms.Methods:This study used data from MSBase registry. Patients with early cerebellar/brainstem presentations were identified as those with cerebellar/brainstem relapse(s) or functional system score ⩾ 2 in the initial 2 years. Early pyramidal presentation was chosen as a comparator. Andersen-Gill models were used to compare cumulative hazards of (1) disability progression events and (2) relapses between patients with and without early cerebellar/brainstem symptoms. Mixed effect models were used to estimate the associations between early cerebellar/brainstem presentations and expanded disability status scale (EDSS) scores.Results:The study cohort consisted of 10,513 eligible patients, including 2723 and 3915 patients with early cerebellar and brainstem symptoms, respectively. Early cerebellar presentation was associated with greater hazard of progression events (HR = 1.37, p Conclusion:Early cerebellar presentation is associated with unfavourable outcomes, while early brainstem presentation is associated with favourable prognosis. These presentations may be used as MS prognostic markers and guide therapeutic approach.
Published: 2020
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37. Impulse control disorders in chronic migraine with medication overuse after onabotulinumtoxinA: A single-center prospective cohort study

Author: Arturo de Falco, Daniele Spitaleri, Florindo d’Onofrio, Simona Raimo, G. Casucci, Antonio Costanzo, D'Onofrio, F., de Falco, A., Costanzo, A, Spitaleri, D., Casucci, G., and Raimo, S
Subjects: Adult, Male, Pediatrics, medicine.medical_specialty, Migraine Disorders, Comorbidity, Single Center, 03 medical and health sciences, 0302 clinical medicine, Chronic Migraine, Quality of life, Risk Factors, Physiology (medical), medicine, Headache Disorders, Secondary, Prevalence, Humans, Prospective Studies, Botulinum Toxins, Type A, Prospective cohort study, business.industry, General Medicine, Middle Aged, Anxiety Disorders, Disruptive, Impulse Control, and Conduct Disorders, Neurology, Neuromuscular Agents, 030220 oncology & carcinogenesis, Quality of Life, Anxiety, Surgery, Female, Neurology (clinical), Headache Disorders, medicine.symptom, business, Medication overuse, 030217 neurology & neurosurgery, Psychopathology
Abstract: Chronic migraine (CM) with medication overuse headache (MOH) is one of the most common and disabling chronic headache disorders associated with both frequencies of use of medication and behavioral alterations, including psychopathology and psychological drug dependence. Several previous studies on large patient samples have demonstrated the efficacy of Onabotulinum toxin A (OnabotA) on physical symptomatology treatment of headache, but effects on behavioral alterations remain still debate. Our study investigated the effects of OnabotA on psychiatric comorbidities and on quality of life of patients with CM and MOH that failed on traditional therapies. OnabotA was injected, according to the PREEMPT paradigm, 40 patients with CM and MOH and data on headache-related impairment, before and after the OnabotA injections were collected from the patient's headache diaries. Data on depressive, anxiety symptomatology and impulse control disorders also were collected by means of self-report scales and a semi-structured interview. After six months, patients with CM and MOH showed a significant decrease in monthly headache attacks (from 19.3 ± 5.9 to 11.8 ± 8.5, p = 0.003), monthly headache days (from 23 ± 8.9 to 11.1 ± 6.2, p = 0.001), numbers of analgesics used per month (from 18.2 ± 6.3 to 8.5 ± 4.7, p < 0.0001). The anxiety symptomatology (p ≤ 0.003) and impulse control disorders (from 30% to 10%), but not depressive symptomatology (p = 0.81), were significantly reduced from throughout the study. The treatment with OnabotA proved beneficial effects on anxiety symptomatology and on impulse control disorders in our clinical practice with CM and MOH and further studies should shed light in larger patient samples on long-term behavioural effects.
Published: 2020

38. Association of Sustained Immunotherapy with Disability Outcomes in Patients with Active Secondary Progressive Multiple Sclerosis

Author: Sifat Sharmin, Daniele Spitaleri, Diana Ferraro, Tomas Kalincik, Marc Girard, Pierre Duquette, Sara Eichau, Roberto Bergamaschi, Guillermo Izquierdo, Charles B Malpas, Francois Grand'Maison, Maria Trojano, Alexandre Prat, Pierre Grammond, R. Hupperts, Catherine Larochelle, Nathaniel Lizak, Vincent Van Pesch, Eva Havrdova, Dana Horakova, Patrizia Sola, Murat Terzi, Alessandra Lugaresi, Cavit Boz, and DIPARTIMENTO DI SCIENZE BIOMEDICHE E NEUROMOTORIE
Subjects: Adult, Male, medicine.medical_specialty, Lower risk, Drug Administration Schedule, Multiple sclerosis, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Natalizumab, Internal medicine, Medicine, Humans, Disabled Persons, 030212 general & internal medicine, Longitudinal Studies, Prospective Studies, Risk factor, Prospective cohort study, treatment, business.industry, Proportional hazards model, Hazard ratio, Correction, Multiple Sclerosis, Chronic Progressive, Fingolimod, Treatment Outcome, disability, inflammation, Female, progression, prognosis, Neurology (clinical), Immunotherapy, business, 030217 neurology & neurosurgery, Multiple sclerosis, disability, progression, treatment, prognosis, inflammation, medicine.drug, Cohort study, Follow-Up Studies
Abstract: none 24 si Importance: It is unclear whether relapses and disease-modifying therapies are associated with the rate of disability accumulation in patients with secondary progressive multiple sclerosis (SPMS). Objective: To examine the association of relapses with the rate of disability accumulation in patients with SPMS and to assess whether treatment before or during the secondary progressive phase can slow the progression of disability accumulation. Design, Setting, and Participants: In this observational cohort study, patient data were prospectively collected from the MSBase international registry between January 1, 1995, and February 1, 2018. Among 53680 patients in the MSBase registry, 4997 patients with SPMS (using the Lorscheider definition) were identified. Of those, 1621 patients were eligible for study inclusion based on sufficient follow-up before and after the onset of SPMS. Data were analyzed from November 15, 2017, to January 13, 2020. Exposures: The association between disability accumulation and several clinical and demographic variables, including relapses and exposure to immunotherapy, was evaluated. Main Outcomes and Measures: Two outcomes were analyzed as measures of disability accumulation during SPMS: The rate of disability accumulation during the secondary progressive phase (change relative to the reference population of patients with MS and absolute change) and the risk of becoming wheelchair dependent. A third outcome, the cumulative risk of experiencing confirmed disability progression events, was used for a secondary analysis. Outcomes were evaluated using multivariable mixed models (ie, linear and Cox models). Results: Of 1621 patients eligible for inclusion, 1103 patients (68.0%) were female, with a mean (SD) age at MS onset of 33.9 (10.6) years. A total of 661 patients (40.8%) experienced superimposed relapses during SPMS. Therapy receipt and relapses during early relapsing-remitting MS were not associated with disability accumulation during the secondary progressive phase. Higher relapse rates during the secondary progressive disease stage were associated with an increased risk of becoming wheelchair dependent (hazard ratio [HR], 1.87; 95% CI, 1.17-3.00; P =.009). Among patients who experienced superimposed relapses during SPMS, greater receipt of disease-modifying therapies was significantly associated with a reduced rate of disability progression and a lower risk of becoming wheelchair dependent. Conclusions and Relevance: In this study, the rate of disability progression after the onset of SPMS was not associated with the early disease course and treatment decisions. Relapses during SPMS were associated with accelerated disability progression and represent an accessible treatment target. Disease-modifying therapy was associated with improvements in disability outcomes among patients with active relapses during SPMS. The study's results suggest that inflammatory disease activity remains a substantial yet modifiable component of SPMS. open Lizak N.; Malpas C.B.; Sharmin S.; Havrdova E.K.; Horakova D.; Izquierdo G.; Eichau S.; Lugaresi A.; Duquette P.; Girard M.; Prat A.; Larochelle C.; Trojano M.; Grand'maison F.; Grammond P.; Sola P.; Ferraro D.; Hupperts R.; Bergamaschi R.; Boz C.; Van Pesch V.; Spitaleri D.; Terzi M.; Kalincik T. Lizak N.; Malpas C.B.; Sharmin S.; Havrdova E.K.; Horakova D.; Izquierdo G.; Eichau S.; Lugaresi A.; Duquette P.; Girard M.; Prat A.; Larochelle C.; Trojano M.; Grand'maison F.; Grammond P.; Sola P.; Ferraro D.; Hupperts R.; Bergamaschi R.; Boz C.; Van Pesch V.; Spitaleri D.; Terzi M.; Kalincik T.
Published: 2020

39. Early clinical markers of aggressive multiple sclerosis

Author: Tomas Kalincik, Marc Girard, Guillermo Izquierdo, Cristina Ramo-Tello, Francois Grand'Maison, Ali Manouchehrinia, Youssef Sidhom, Charles B Malpas, Alexandre Prat, Maria Trojano, Franco Granella, Pamela A. McCombe, Rana Karabudak, Murat Terzi, Eugenio Pucci, Raymond Hupperts, Vincent Van Pesch, Pierre Grammond, Sifat Sharmin, Richard A L Macdonell, Ayse Altintas, Riadh Gouider, Recai Turkoglu, Diana Ferraro, Alessandra Lugaresi, Pierre Duquette, Helmut Butzkueven, Serkan Ozakbas, Sara Eichau, Izanne Roos, Daniele Spitaleri, Yara Dadalti Fragoso, Mark Slee, Roberto Bergamaschi, Jan Hillert, Edgardo Cristiano, Thor Petersen, Eva Havrdova, Javier Olascoaga, Cavit Boz, Patrizia Sola, Freek Verheul, Aysun Soysal, Tomas Olsson, Dana Horakova, Ondokuz Mayıs Üniversitesi, Malpas C.B., Manouchehrinia A., Sharmin S., Roos I., Horakova D., Havrdova E.K., Trojano M., Izquierdo G., Eichau S., Bergamaschi R., Sola P., Ferraro D., Lugaresi A., Prat A., Girard M., Duquette P., Grammond P., Grand'Maison F., Ozakbas S., van Pesch V., Granella F., Hupperts R., Pucci E., Boz C., Sidhom Y., Gouider R., Spitaleri D., Soysal A., Petersen T., Verheul F., Karabudak R., Turkoglu R., Ramo-Tello C., Terzi M., Cristiano E., Slee M., McCombe P., Macdonell R., Fragoso Y., Olascoaga J., Altintas A., Olsson T., Butzkueven H., Hillert J., Kalincik T., Altıntaş, Ayşe (ORCID 0000-0002-8524-5087 & YÖK ID 11611), School of Medicine, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, and UCL - (SLuc) Service de neurologie
Subjects: Male, PROGRESSION, Disease, multiple sclerosis, 01 natural sciences, THERAPY, Severity of Illness Index, Aggressive disease, 010104 statistics & probability, Disability Evaluation, 0302 clinical medicine, PROGNOSTIC-FACTORS, Multiple Sclerosi, Disability, Multiple sclerosis, Precision medicine, Prediction, R PACKAGE, Age of Onset, AcademicSubjects/SCI01870, Neurosciences and neurology, IMPAIRMENT, Cohort, Disease Progression, RELAPSE RATE, Female, Cohort study, Human, Adult, medicine.medical_specialty, Multiple Sclerosis, precision medicine, BRAIN MRI, Sensitivity and Specificity, 03 medical and health sciences, Internal medicine, Severity of illness, medicine, Humans, 0101 mathematics, Letters to the Editor, Expanded Disability Status Scale, business.industry, NATURAL-HISTORY, prediction, medicine.disease, PREDICTIVE-VALUE, Confidence interval, disability, AcademicSubjects/MED00310, Neurology (clinical), Age of onset, business, aggressive disease, 030217 neurology & neurosurgery, LONG-TERM DISABILITY
Abstract: Patients with the 'aggressive' form of multiple sclerosis accrue disability at an accelerated rate, typically reaching Expanded Disability Status Score (EDSS) ≥ 6 within 10 years of symptom onset. Several clinicodemographic factors have been associated with aggressive multiple sclerosis, but less research has focused on clinical markers that are present in the first year of disease. The development of early predictive models of aggressive multiple sclerosis is essential to optimize treatment in this multiple sclerosis subtype. We evaluated whether patients who will develop aggressive multiple sclerosis can be identified based on early clinical markers. We then replicated this analysis in an independent cohort. Patient data were obtained from the MSBase observational study. Inclusion criteria were (i) first recorded disability score (EDSS) within 12 months of symptom onset; (ii) at least two recorded EDSS scores; and (iii) at least 10 years of observation time, based on time of last recorded EDSS score. Patients were classified as having 'aggressive multiple sclerosis' if all of the following criteria were met: (i) EDSS ≥ 6 reached within 10 years of symptom onset; (ii) EDSS ≥ 6 confirmed and sustained over ≥6 months; and (iii) EDSS ≥ 6 sustained until the end of follow-up. Clinical predictors included patient variables (sex, age at onset, baseline EDSS, disease duration at first visit) and recorded relapses in the first 12 months since disease onset (count, pyramidal signs, bowel-bladder symptoms, cerebellar signs, incomplete relapse recovery, steroid administration, hospitalization). Predictors were evaluated using Bayesian model averaging. Independent validation was performed using data from the Swedish Multiple Sclerosis Registry. Of the 2403 patients identified, 145 were classified as having aggressive multiple sclerosis (6%). Bayesian model averaging identified three statistical predictors: age > 35 at symptom onset, EDSS ≥ 3 in the first year, and the presence of pyramidal signs in the first year. This model significantly predicted aggressive multiple sclerosis [area under the curve (AUC) = 0.80, 95% confidence intervals (CIs): 0.75, 0.84, positive predictive value = 0.15, negative predictive value = 0.98]. The presence of all three signs was strongly predictive, with 32% of such patients meeting aggressive disease criteria. The absence of all three signs was associated with a 1.4% risk. Of the 556 eligible patients in the Swedish Multiple Sclerosis Registry cohort, 34 (6%) met criteria for aggressive multiple sclerosis. The combination of all three signs was also predictive in this cohort (AUC = 0.75, 95% CIs: 0.66, 0.84, positive predictive value = 0.15, negative predictive value = 0.97). Taken together, these findings suggest that older age at symptom onset, greater disability during the first year, and pyramidal signs in the first year are early indicators of aggressive multiple sclerosis., National Health and Medical Research Council of Australia; Roche; Merck; Biogen; Novartis; Bayer Schering; Sanofi Genzyme; Teva
Published: 2020
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40. Reduced Admissions for Cerebrovascular Events during COVID-19 Outbreak in Italy

Author: Simona Sacco, Stefano Ricci, Raffaele Ornello, Paolo Eusebi, Luca Petraglia, Danilo Toni, Eugenia Rota, Gianluca Bruzzone, Lucia Testa, Roberta Bongioanni, Mara Rosso, Carmelo Labate, Roberto Tarletti, Roberto Cantello, Thomas Fleetwood, Fabio Melis, Daniele Imperiale, Salvatore Amarù, Monica Reggiani, Luigi Ruiz, Elia Cipriano, Delfina Ferrandi, Patrizia Julita, Liana Africa, Piero Meinieri, Maria Federica Grasso, Serena Servo, Roberto Cavallo, Gigliola Chianale, Andrea Naldi, Paolo Cerrato, Elisa Rubino, Alessia Giossi, Valentina Puglisi, Luisa Vinciguerra, Ignazio Santilli, Bianca Maria Bordo, Simona Marcheselli, Julia Bottini, Caterina Mariotto D’Alessandro, Giuseppe Micieli, Anna Cavallini, Isabella Canavero, Francesco Muscia, Graziamaria Nuzzaco, Alfonso Ciccone, Giorgio Silvestrelli, Andrea Salmaggi, Davide Sangalli, Carla Zanferrari, Simona Fanucchi, Michela Ranieri, Simone Beretta, Carlo Ferrarese, Francesco Pasini, Francesco Santangelo, Nicoletta Checcarelli, Sandro Beretta, Paola Bazzi, Massimo Camerlingo, Marcello Tognozzi, Giorgio Caneve, Alessandro Adami, Rocco Quatrale, Adriana Critelli, Luigi Bartolomei, Maela Masato, Francesco Perini, Antonella De Boni, Caterina Disco, Claudio Baracchini, Alessio Pieroni, Roberto Lerario, Monia Russo, Alberto Polo, Alessandra Danese, Luca Valentinis, Antonio Baldi, Simone Tonello, Francesco Paladin, Agnese Tonon, Bruno Bonetti, Manuel Cappellari, Francesco Teatini, Roberto Currò Dossi, Enrica Franchini, Bruno Giometto, Valeria Bignamini, Paolo Manganotti, Marcello Naccarato, Gian Luigi Gigli, Simone Lorenzut, Giovanni Merlino, Mariarosaria Valente, Michele Rana, Carolina Gentile, Tiziana Tassinari, Annalisa Sugo, Valentina Saia, Maurizio Balestrino, Alberto Coccia, Cinzia Finocchi, Franco Valzania, Maria Luisa Zedde, Giulia Toschi, Marco Longoni, Matteo Paolucci, Valeria Tugnoli, Pietro Querzani, Marina Padroni, Stefano Meletti, Guido Bigliardi, Maria Luisa Dall’Acqua, Andrea Zini, Mauro Gentile, Ludovica Migliaccio, Alberto Chiti, Rossana Tassi, Giuseppe Martini, Patrizia Nencini, Maria Lamassa, Michelangelo Mancuso, Giovanni Orlandi, Elena Ferrari, Roberto Marconi, Simone Gallerini, Vincenzo Groggia, Gino Volpi, Chiara Menichetti, Stefano Spolveri, Mauro Silvestrini, Giovanna Viticchi, Laura Buratti, Giuseppe Pelliccioni, Eleonora Potente, Tatiana Mazzoli, Erica Marsili, Silvia Cenciarelli, Antonella Picchioni, Franco Costantini, Carlo Colosimo, Maurizio Paciaroni, Valeria Caso, Maurizia Rasura, Mario Beccia, Nicola Falcone, Marisa Di Stefano, Emanuela Cecconi, Sabrina Anticoli, Francesca Romana Pezzella, Marilena Mangiardi, Maurizio Plocco, Maria Magarelli, Carlo Emanuele Saggese, Irene Berto, Maria Concetta Altavista, Cinzia Roberti, Marina Diomedi, Fabrizio Sallustio, Alessandro Rocco, Letizia Maria Cupini, Novella Bonaffini, Maria Vittoria De Angelis, Anna Digiovanni, Marianna Rispoli, Berardino Orlandi, Federica De Santis, Enrico Colangeli, Francesco Di Blasio, Caterina Di Carmine, Pierluigi Tocco, Maurizio Melis, Jessica Moller, Valeria Saddi, Antonio Manca, Antonio Baule, Antonello Caddeo, Nicola Iorio, Rosa Napoletano, Maria di Gregorio, Giampiero Volpe, Florindo D’Onofrio, Daniele Spitaleri, Leonardo Barbarini, Gaetano Barbagallo, Marcella Caggiula, Bonaventura Ardito, Domenico Di Noia, Pietro Di Viesti, Maurizio Angelo Leone, Vincenzo Inchingolo, Marco Petruzzellis, Federica Rizzo, Mariantonietta Savarese, Alfredo Petrone, Franco Galati, Luciano Arcudi, Damiano Branca, Paolo Aridon, Valentina Arnao, Rosa Musolino, Cristina Dell’Aera, Isabella Francalanza, Luigi Grimaldi, Matilde Gammino, Antonello Giordano, Giuseppe Zelante, Enzo Sanzaro, Antonio Gasparro, Sacco, Simona, Ricci, Stefano, Ornello, Raffaele, Eusebi, Paolo, Petraglia, Luca, Toni, Danilo, and paolo, aridon
Subjects: disease outbreak, Male, medicine.medical_treatment, 030204 cardiovascular system & hematology, Italy, cerebral hemorrhage, disease outbreaks, incidence, ischemic attack, transient, 0302 clinical medicine, Epidemiology, 80 and over, Medicine, Thrombolytic Therapy, Acute ischemic stroke, Thrombectomy, Aged, 80 and over, Ischemic Attack, Transient, Incidence (epidemiology), Endovascular Procedures, Middle Aged, Hospitalization, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Settore MED/26 - Neurologia, Female, Cardiology and Cardiovascular Medicine, Aged, COVID-19, Cerebral Hemorrhage, Humans, Ischemic Attack, Transient, Ischemic Stroke, medicine.medical_specialty, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Revascularization, Settore MED/26, 03 medical and health sciences, Advanced and Specialized Nursing, business.industry, Outbreak, Emergency medicine, Brief Reports, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: Supplemental Digital Content is available in the text., Background and Purpose: We aimed to investigate the rate of hospital admissions for cerebrovascular events and of revascularization treatments for acute ischemic stroke in Italy during the coronavirus disease 2019 (COVID-19) outbreak. Methods: The Italian Stroke Organization performed a multicenter study involving 93 Italian Stroke Units. We collected information on hospital admissions for cerebrovascular events from March 1 to March 31, 2020 (study period), and from March 1 to March 31, 2019 (control period). Results: Ischemic strokes decreased from 2399 in 2019 to 1810 in 2020, with a corresponding hospitalization rate ratio (RR) of 0.75 ([95% CI, 0.71–0.80] P
Published: 2020

41. Redefining the Multiple Sclerosis Severity Score (MSSS): The effect of sex and onset phenotype

Author: Riadh Gouider, Talal Al-Harbi, Krisztian Kasa, Ingrid van der Mei, Carmen Adella Sirbu, Richard Roxburgh, Alessandra Lugaresi, Daniele Spitaleri, Karim Kotkata, Steve Simpson, Javier Olascoaga, Edgardo Cristiano, Raed Alroughani, Tomas Kalincik, Cameron Shaw, Attila Sas, Bruce V. Taylor, Jim Stankovich, Ayse Altintas, Bassem Yamout, Yuan Zhou, Suzi B. Claflin, José C. Álvarez-Cermeño, Tünde Csépány, José Luis Sánchez Menoyo, Guy Laureys, Danny Decoo, Helmut Butzkueven, Seyed Aidin Sajedi, Leigh Blizzard, Franco Granella, Christopher McGuigan, Yara Dadalti Fragoso, Jorge Millán-Pascual, Eugenio Pucci, Allan G. Kermode, Todd A. Hardy, Stella Hughes, Zhou Y., Claflin S.B., Stankovich J., van der Mei I., Simpson S., Roxburgh R.H., Kalincik T., Blizzard L., Lugaresi A., Alroughani R., Sajedi S.A., Butzkueven H., Pucci E., Spitaleri D.L.A., Granella F., Cristiano E., Yamout B., Hughes S., Gouider R., Sanchez Menoyo J.L., Olascoaga J., McGuigan C., Shaw C., Kermode A.G., Kasa K., Al-Harbi T., Altintas A., Laureys G., Fragoso Y., Hardy T.A., Csepany T., Sirbu C.-A., Decoo D., Sas A., Alvarez-Cermeno J.C., Kotkata K., Millan-Pascual J., and Taylor B.V.
Subjects: Male, medicine.medical_specialty, Multiple Sclerosis, Severity of Illness Index, Disability Evaluation, 03 medical and health sciences, 0302 clinical medicine, Recurrence, Internal medicine, medicine, Humans, Disability progression, Multiple sclerosi, 030304 developmental biology, 0303 health sciences, business.industry, Multiple sclerosis, onset phenotype, medicine.disease, Phenotype, Clinical neurology, disability progression, Neurology, Disease Progression, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, Multiple Sclerosis Severity Score
Abstract: Background: The Multiple Sclerosis Severity Score (MSSS) is a widely used measure of the disability progression rate. However, the global MSSS may not be the best basis for comparison between all patient groups. Objective: We evaluated sex-specific and onset phenotype–specific MSSS matrices to determine if they were more effective than the global MSSS as a basis for comparison within these subsets. Methods: Using a large international dataset of multiple sclerosis (MS) patient records and the original MSSS algorithm, we constructed global, sex-specific and onset phenotype–specific MSSS matrices. We compared matrices using permutation analysis. Results: Our final dataset included 30,203 MS cases, with 28.9% males and 6.5% progressive-onset cases. Our global MSSS matrix did not differ from previously published data ( p > 0.05). The progressive-onset-specific matrix differed significantly from the relapsing-onset-specific matrix ( p Conclusion: The differences in the disability accrual rate between progressive- and relapsing-onset MS have a significant effect on MSSS. An onset-specific MSSS should be used when comparing the rate of disability progression among progressive-onset cases and for mixed cohorts.
Published: 2020

42. Prediction of on-treatment disability worsening in RRMS with the MAGNIMS score

Author: Jeannette Lechner-Scott, Patrizia Sola, Pierre Grammond, Daniele Spitaleri, Jose Luis Sanchez-Menoyo, Raed Alroughani, Maria Trojano, Franco Granella, Tomas Kalincik, Cavit Boz, Diana Ferraro, Pamela A. McCombe, Bart Van Wijmeersch, Serkan Ozakbas, Alessandra Lugaresi, Raymond Hupperts, Guillermo Izquierdo, Francois Grand'Maison, Maria Pia Sormani, Vilija Jokubaitis, Steve Vucic, Eugenio Pucci, Marco Onofrj, Helmut Butzkueven, Amy Kunchok, Kunchok A., Lechner-Scott J., Granella F., Trojano M., Alroughani R., Sola P., Ferraro D., Lugaresi A., Onofrj M., Ozakbas S., Izquierdo G., Grammond P., Luis Sanchez-Menoyo J., Van Wijmeersch B., Boz C., Pucci E., McCombe P., Grand'Maison F., Spitaleri D., Vucic S., Hupperts R., Jokubaitis V., Sormani M.P., Butzkueven H., and Kalincik T.
Subjects: medicine.medical_specialty, outcomes, Cohort Studies, Multiple sclerosis, Neoplasm Recurrence, Multiple Sclerosis, Relapsing-Remitting, medicine, Humans, magnetic resonance imaging, Multiple sclerosi, therapy, medicine.diagnostic_test, Interferon beta, business.industry, Disease progression, Magnetic resonance imaging, prediction, medicine.disease, Clinical neurology, Neurology, Relapsing remitting, prognosis, outcome, Disease Progression, Neurology (clinical), Radiology, Neoplasm Recurrence, Local, business, prognosi, Cohort study
Abstract: Background: The magnetic resonance imaging in multiple sclerosis (MAGNIMS) score combines relapses and magnetic resonance imaging (MRI) lesions to predict disability outcomes in relapsing–remitting multiple sclerosis (RRMS) treated with interferon-β. Objective: To validate the MAGNIMS score and extend to other disease-modifying therapies (DMTs). To examine the prognostic value of gadolinium contrast-enhancing (Gd+) lesions. Methods: This RRMS MSBase cohort study ( n = 2293) used a Cox model to examine the prognostic value of relapses, MRI activity and the MAGNIMS score for disability worsening during treatment with interferon-β and three other DMTs. Results: Three new T2 lesions (hazard ratio (HR) = 1.60, p = 0.028) or two relapses (HR = 2.24, p = 0.002) on interferon-β (for 12 months) were predictive of disability worsening over 4 years. MAGNIMS score = 2 (1 relapse and ⩾3 T2 lesions or ⩾2 relapses) was associated with a greater risk of disability worsening on interferon-β (HR = 2.0, p = 0.001). In pooled cohort of four DMTs, similar associations were seen (MAGNIMS score = 2: HR = 1.72, p = 0.001). Secondary analyses demonstrated that the addition of Gd+ to the MAGNIMS did not materially improve its prediction of disability worsening. Conclusion: We have validated the MAGNIMS score in RRMS and extended its application to three other DMTs: 1 relapse and ⩾3 T2 lesions or ⩾2 relapses predicted worsening of disability. Contrast-enhancing lesions did not substantially improve the prognostic score.
Published: 2020

43. Risk of secondary progressive multiple sclerosis: A longitudinal study

Author: Michael Barnett, Bhim Singhal, Maria Trojano, Franco Granella, Neil Shuey, Guillermo Izquierdo, Dana Horakova, Helmut Butzkueven, Talal Al-Harbi, Maria Laura Saladino, Cameron Shaw, Adam Fambiatos, Bart Van Wijmeersch, Serkan Ozakbas, Tünde Csépány, Freek Verheul, Cavit Boz, Tim Spelman, Pierre Duquette, Jeannette Lechner-Scott, Bassem Yamout, Roberto Bergamaschi, Vincent Van Pesch, Claudio Solaro, Edgardo Cristiano, Patrizia Sola, Vilija Jokubaitis, Jae Kwan Jun, Alessandra Lugaresi, Javier Olascoaga, Aysun Soysal, Thor Petersen, Mark Slee, Raed Alroughani, Francois Grand'Maison, Orla Gray, Tomas Kalincik, Marc Girard, Gerardo Iuliano, Anneke van der Walt, Eva Havrdova, Jose Luis Sanchez-Menoyo, Radek Ampapa, Julie Prevost, Steve Vucic, Pamela A. McCombe, Recai Turkoglu, Yara Dadalti Fragoso, Jordana Hughes, Olga Skibina, Murat Terzi, Eugenio Pucci, Diana Ferraro, Pierre Grammond, Fraser Moore, Ayse Altintas, Suzanne Hodgkinson, Youssef Sidhom, Norma Deri, Alexandre Prat, Raymond Hupperts, Daniele Spitaleri, Bruce V. Taylor, Fambiatos A., Jokubaitis V., Horakova D., Kubala Havrdova E., Trojano M., Prat A., Girard M., Duquette P., Lugaresi A., Izquierdo G., Grand'Maison F., Grammond P., Sola P., Ferraro D., Alroughani R., Terzi M., Hupperts R., Boz C., Lechner-Scott J., Pucci E., Bergamaschi R., Van Pesch V., Ozakbas S., Granella F., Turkoglu R., Iuliano G., Spitaleri D., McCombe P., Solaro C., Slee M., Ampapa R., Soysal A., Petersen T., Sanchez-Menoyo J.L., Verheul F., Prevost J., Sidhom Y., Van Wijmeersch B., Vucic S., Cristiano E., Saladino M.L., Deri N., Barnett M., Olascoaga J., Moore F., Skibina O., Gray O., Fragoso Y., Yamout B., Shaw C., Singhal B., Shuey N., Hodgkinson S., Altintas A., Al-Harbi T., Csepany T., Taylor B., Hughes J., Jun J.-K., van der Walt A., Spelman T., Butzkueven H., Kalincik T., Ondokuz Mayıs Üniversitesi, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, and UCL - (SLuc) Service de neurologie
Subjects: Adult, Male, Risk, medicine.medical_specialty, Longitudinal study, Immunologic Factors, multiple sclerosis, Severity of Illness Index, 03 medical and health sciences, 0302 clinical medicine, Multiple Sclerosis, Relapsing-Remitting, disease modifying therapies, prognostics, Internal medicine, Severity of illness, Medicine, Humans, Longitudinal Studies, 030304 developmental biology, 0303 health sciences, business.industry, Multiple sclerosis, Disease progression, prediction, Multiple Sclerosis, Chronic Progressive, medicine.disease, SPMS, Clinical neurology, Natural history, Neurology, multiple sclerosi, disease modifying therapie, Disease Progression, Secondary progressive multiple sclerosis, Female, Neurology (clinical), business, prognostic, 030217 neurology & neurosurgery
Abstract: Turkoglu, Recai/0000-0001-9724-851X; Ferraro, Diana/0000-0003-4818-3806; McCombe, Pamela/0000-0003-2704-8517; Altintas, Ayse/0000-0002-8524-5087; Jokubaitis, Vilija G./0000-0002-3942-4340; Slee, Mark/0000-0003-4323-2453; Lugaresi, Alessandra/0000-0003-2902-5589; van Pesch, Vincent/0000-0003-2885-9004; Vucic, Steve/0000-0002-8323-873X WOS: 000481049900001 PubMed: 31397221 Background: The risk factors for conversion from relapsing-remitting to secondary progressive multiple sclerosis remain highly contested. Objective: The aim of this study was to determine the demographic, clinical and paraclinical features that influence the risk of conversion to secondary progressive multiple sclerosis. Methods: Patients with adult-onset relapsing-remitting multiple sclerosis and at least four recorded disability scores were selected from MSBase, a global observational cohort. The risk of conversion to objectively defined secondary progressive multiple sclerosis was evaluated at multiple time points per patient using multivariable marginal Cox regression models. Sensitivity analyses were performed. Results: A total of 15,717 patients were included in the primary analysis. Older age (hazard ratio (HR) = 1.02, p < 0.001), longer disease duration (HR = 1.01, p = 0.038), a higher Expanded Disability Status Scale score (HR = 1.30, p < 0.001), more rapid disability trajectory (HR = 2.82, p < 0.001) and greater number of relapses in the previous year (HR = 1.07, p = 0.010) were independently associated with an increased risk of secondary progressive multiple sclerosis. Improving disability (HR = 0.62, p = 0.039) and disease-modifying therapy exposure (HR = 0.71, p = 0.007) were associated with a lower risk. Recent cerebral magnetic resonance imaging activity, evidence of spinal cord lesions and oligoclonal bands in the cerebrospinal fluid were not associated with the risk of conversion. Conclusion: Risk of secondary progressive multiple sclerosis increases with age, duration of illness and worsening disability and decreases with improving disability. Therapy may delay the onset of secondary progression. National Health and Medical Research Council of AustraliaNational Health and Medical Research Council of Australia [1083539, 1129189, 1140766]; BiogenBiogen; RocheRoche Holding; Bayer ScheringBayer AG; Sanofi Genzyme; Teva; MerckMerck & Company; NovartisNovartis The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was financially supported by National Health and Medical Research Council of Australia (project grants 1083539 and 1129189 and fellowship 1140766). The MSBase Foundation is a not-for-profit organisation that receives support from Merck, Biogen, Roche, Novartis, Bayer Schering, Sanofi Genzyme and Teva. The study was conducted separately and apart from the guidance of the sponsors.
Published: 2020
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44. Nabiximols discontinuation rate in a large population of patients with multiple sclerosis: a 18-month multicentre study

Author: Damiano Paolicelli, Assunta Bianco, Simona Pontecorvo, Paola Valentino, Elisabetta Capello, Roberta Lanzillo, M. Danni, Alberto Gajofatto, Gianfranco Costantino, Claudio Solaro, Roberto Bruno Bossio, Daniele Spitaleri, Giacomo Lus, Simona Bonavita, Mauro Zaffaroni, Pasquale Annunziata, Edoardo Sessa, Roberto Bergamaschi, Claudio Gasperini, Letizia Castelli, Diego Centonze, Salvatore Cottone, Loredana Petrucci, Vincenzo Brescia Morra, Marco Rovaris, Mario Zappia, Paola Cavalla, Angelica Guareschi, Gabriella Spinicci, Isabella Righini, Francesco Patti, Giorgia Teresa Maniscalco, Manuela Matta, Federica Esposito, Clara Grazia Chisari, Chisari, Clara Grazia, Solaro, Claudio, Annunziata, Pasquale, Bergamaschi, Roberto, Bianco, Assunta, Bonavita, Simona, Brescia Morra, Vincenzo, Bruno Bossio, Roberto, Capello, Elisabetta, Castelli, Letizia, Cavalla, Paola, Costantino, Gianfranco, Centonze, Diego, Cottone, Salvatore, Danni, Maura Chiara, Esposito, Federica, Gajofatto, Alberto, Gasperini, Claudio, Guareschi, Angelica, Lanzillo, Roberta, Lus, Giacomo, Maniscalco, Giorgia Teresa, Matta, Manuela, Paolicelli, Damiano, Petrucci, Loredana, Pontecorvo, Simona, Righini, Isabella, Rovaris, Marco, Sessa, Edoardo, Spinicci, Gabriella, Spitaleri, Daniele, Valentino, Paola, Zaffaroni, Mauro, Zappia, Mario, and Patti, Francesco
Subjects: Adult, Male, medicine.medical_specialty, Multiple Sclerosis, Time Factors, Nabiximols, Delta-δ-tetrahydrocannabinol, cannabidiol: oromucosal spray, therapy continuation, therapy abandon, long-term clinical outcome, Settore MED/26, digestive system, 030226 pharmacology & pharmacy, Efficacy, 03 medical and health sciences, Drug withdrawal, 0302 clinical medicine, Internal medicine, mental disorders, Cannabidiol, Humans, Medicine, Dronabinol, Prospective Studies, Adverse effect, Prospective cohort study, business.industry, organic chemicals, Middle Aged, medicine.disease, digestive system diseases, Discontinuation, Clinical trial, Drug Combinations, Psychiatry and Mental health, Treatment Outcome, surgical procedures, operative, Withholding Treatment, Patient Compliance, Female, Surgery, Neurology (clinical), business, 030217 neurology & neurosurgery, medicine.drug
Abstract: IntroductionDelta-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 methodsThis 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.ResultsA 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, pDiscussionTHC: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.
Published: 2020

45. Corrigendum to Longitudinal machine learning modeling of MS patient trajectories improves predictions of disability progression: [Computer Methods and Programs in Biomedicine, Volume 208, (September 2021) 106180]

Author: Thijs Becker, Celia Oreja-Guevara, Francois Grand'Maison, Ludwig Kappos, Yves Moreau, Vincent Van Pesch, Jens Kuhle, Jose Luis Sanchez-Menoyo, Riadh Gouider, Liesbet M. Peeters, Patrizia Sola, Jeannette Lechner-Scott, Tomas Kalincik, Murat Terzi, Raed Alroughani, Sara Eichau, Bart Van Wijmeersch, Serkan Ozakbas, Daniele Spitaleri, Fraser Moore, Edward De Brouwer, Tünde Csépány, Pierre Grammond, Maria Trojano, Franco Granella, Cavit Boz, Davide Maimone, Tamara Castillo Trivio, Oliver Gerlach, Marco Onofrj, Vahid Shaygannejad, Roberto Bergamaschi, Aysun Soysal, Cristina Ramo-Tello, Gerardo Iuliano, Claudio Solaro, Elisabetta Cartechini, Eduardo Aguera-Morales, Katherine Buzzard, Eva Havrdova, Maria José Sá, and Ramo-Tello, Cristina/0000-0001-8643-5053
Subjects: medicine.medical_specialty, Computer science, business.industry, MEDLINE, Health Informatics, Programming method, Computer Science Applications, Text mining, medicine, Disability progression, Medical physics, business, Software, Biomedicine, Volume (compression)
Published: 2022
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46. Posterior reversible encephalopathy syndrome overlapping contrast-induced encephalopathy after coronary angiography

Author: Daniele Spitaleri, Arturo de Falco, Fabrizio A. de Falco, Marta Simone, and Florindo d’Onofrio
Subjects: medicine.medical_specialty, Neurology, medicine.diagnostic_test, business.industry, media_common.quotation_subject, Encephalopathy, Magnetic resonance imaging, Posterior reversible encephalopathy syndrome, Dermatology, General Medicine, Electroencephalography, medicine.disease, Psychiatry and Mental health, medicine, Contrast (vision), Neurology (clinical), Neurosurgery, Radiology, business, media_common, Neuroradiology
Published: 2019
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47. Progression independent of relapse activity in early multiple sclerosis patients

Author: Franco Di Palma, Angelo Bellinvia, Marta Simone, Eleonora Cocco, Vito Lepore, Lorenzo Razzolini, Paola Valentino, Maria Pia Amato, Francesco Patti, Massimo Filippi, Daniele Spitaleri, Pietro Iaffaldano, Luisa Pastò, Rocco Totaro, Davide Maimone, Giacomo Lus, A. Protti, Ilaria Pesci, Patrizia Sola, Marco Onofrj, Mattia Fonderico, Alessandra Lugaresi, Roberto Bergamaschi, Giorgia Teresa Maniscalco, M. Vianello, Vincenzo Brescia Morra, Maria Trojano, Franco Granella, Emilio Portaccio, Paolo Confalonieri, Umberto Aguglia, and Giuseppe Salemi
Subjects: Oncology, medicine.medical_specialty, Neurology, business.industry, Internal medicine, Multiple sclerosis, medicine, Neurology (clinical), medicine.disease, business
Published: 2021
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48. Longitudinal machine learning modeling of MS patient trajectories improves predictions of disability progression

Author: Jeannette Lechner-Scott, Bart Van Wijmeersch, Serkan Ozakbas, Maria José Sá, Vahid Shaygannejad, Marco Onofrj, Tomas Kalincik, Ludwig Kappos, Gerardo Iuliano, Patrizia Sola, Eva Havrdova, Roberto Bergamaschi, Pierre Grammond, Raed Alroughani, Jose Luis Sanchez-Menoyo, Davide Maimone, Tamara Castillo Trivio, Celia Oreja-Guevara, Aysun Soysal, Murat Terzi, Thijs Becker, Francois Grand'Maison, Jens Kuhle, Edward De Brouwer, Maria Trojano, Franco Granella, Yves Moreau, Vincent Van Pesch, Tünde Csépány, Cristina Ramo-Tello, Fraser Moore, Riadh Gouider, Liesbet M. Peeters, Cavit Boz, Claudio Solaro, Daniele Spitaleri, Sara Eichau, Oliver Gerlach, Katherine Buzzard, Elisabetta Cartechini, Eduardo Aguera-Morales, DE BROUWER, Edward, BECKER, Thijs, Moreau, Yves, Havrdova, Eva, Trojano, Maria, Eichau, Sara, Ozakbas, Serkan, Onofrj, Marco, Grammond, Pierre, Kuhle, Jens, Kappos, Ludwig, Sola, Patrizia, Cartechini, Elisabetta, Lechner-Scott, Jeannette, Alroughani, Raed, Gerlach, Oliver, Kalincik, Tomas, Granella, Franco, Grand'maison, Francois, Bergamaschi, Roberto, José Sá, Maria, VAN WIJMEERSCH, Bart, Soysal, Aysun, Sanchez-Menoyo, Jose, Solaro, Claudio, Boz, Cavit, Iuliano, Gerardo, Buzzard, Katherine, Aguera-Morales, Eduardo, Terzi, Murat, Trivio, Tamara, Spitaleri, Daniele, Van Pesch, Vincent, Shaygannejad, Vahid, Moore, Fraser, Oreja-Guevara, Celia, Maimone, Davide, Gouider, Riadh, Csepany, Tunde, Ramo-Tello, Cristina, PEETERS, Liesbet, UCL - SSS/IONS/NEUR - Clinical Neuroscience, and UCL - (SLuc) Service de neurologie
Subjects: Technology, Computer science, Health Informatics, Machine learning, computer.software_genre, THERAPY, Health informatics, 030218 nuclear medicine & medical imaging, Multiple sclerosis, 03 medical and health sciences, Engineering, 0302 clinical medicine, Computer Science, Theory & Methods, Humans, Electronic health records, Medical history, Disability progression, Engineering, Biomedical, Science & Technology, Longitudinal data, business.industry, Disease progression, MULTIPLE-SCLEROSIS, Precision medicine, Real-world data, Computer Science Applications, Clinical trial, Recurrent neural network, Recurrent neural networks, Ranking, REGISTRY, Computer Science, Computer Science, Interdisciplinary Applications, Neural Networks, Computer, Artificial intelligence, business, Life Sciences & Biomedicine, computer, Medical Informatics, 030217 neurology & neurosurgery, Software
Abstract: BACKGROUND AND OBJECTIVES: Research in Multiple Sclerosis (MS) has recently focused on extracting knowledge from real-world clinical data sources. This type of data is more abundant than data produced during clinical trials and potentially more informative about real-world clinical practice. However, this comes at the cost of less curated and controlled data sets. In this work we aim to predict disability progression by optimally extracting information from longitudinal patient data in the real-world setting, with a special focus on the sporadic sampling problem. METHODS: We use machine learning methods suited for patient trajectories modeling, such as recurrent neural networks and tensor factorization. A subset of 6682 patients from the MSBase registry is used. RESULTS: We can predict disability progression of patients in a two-year horizon with an ROC-AUC of 0.85, which represents a 32% decrease in the ranking pair error (1-AUC) compared to reference methods using static clinical features. CONCLUSIONS: Compared to the models available in the literature, this work uses the most complete patient history for MS disease progression prediction and represents a step forward towards AI-assisted precision medicine in MS. ispartof: COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE vol:208 ispartof: location:Ireland status: published
Published: 2021
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49. Non-alcoholic Wernicke-Korsakoff syndrome heralding non-Hodgkin lymphoma progression

Author: Marta Simone, Arturo de Falco, Daniele Spitaleri, and Fabrizio A. de Falco
Subjects: medicine.medical_specialty, Wernicke–Korsakoff syndrome, Neurology, business.industry, Non alcoholic, Dermatology, General Medicine, medicine.disease, Gastroenterology, Lymphoma, 03 medical and health sciences, Psychiatry and Mental health, 0302 clinical medicine, Internal medicine, medicine, Hodgkin lymphoma, 030212 general & internal medicine, Neurology (clinical), Neurosurgery, Glutamic acid metabolism, business, 030217 neurology & neurosurgery, Neuroradiology
Published: 2018
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50. Immunotherapy prevents long-term disability in relapsing multiple sclerosis over 15 years

Author: Steve Vucic, Francois Grand'Maison, Orla Gray, Stella Hughes, Guillermo Izquierdo, Jeannette Lechner-Scott, Patrizia Sola, Maria Laura Saladino, Charles B Malpas, Michael Barnett, Vahid Shaygannejad, Carmen-Adella Sîrbu, Eugenio Pucci, Cristina Ramo-Tello, Murat Terzi, Jose Luis Sanchez-Menoyo, Bhim Singhal, Maria Trojano, Franco Granella, Neil Shuey, Vilija Jokubaitis, Sifat Sharmin, Pierre Duquette, Vincent Van Pesch, Alessandra Lugaresi, Mark Slee, Diana Ferraro, Magdolna Simó, Alexandre Prat, Cavit Boz, Allan G. Kermode, Raymond Hupperts, Dana Horakova, Pamela A. McCombe, Tünde Csépány, Daniele Spitaleri, Helmut Butzkueven, Imre Piroska, Cameron Shaw, Olga Skibina, Tomas Kalincik, Marc Girard, Roberto Bergamaschi, Julie Prevost, Csilla Rozsa, Fraser Moore, Attila Sas, Pierre Grammond, Edgardo Cristiano, Bruce V. Taylor, Radek Ampapa, Raed Alroughani, Suzanne Hodgkinson, Ernest Butler, Anneke van der Walt, Eva Havrdova, Tim Spelman, and Javier Olascoaga
Subjects: Pediatrics, medicine.medical_specialty, Pregnancy, business.industry, Incidence (epidemiology), medicine.medical_treatment, Multiple sclerosis, Hazard ratio, Marginal structural model, Disease, Immunotherapy, medicine.disease, 01 natural sciences, Confidence interval, 3. Good health, 010104 statistics & probability, 03 medical and health sciences, 0302 clinical medicine, medicine, 0101 mathematics, business, 030217 neurology & neurosurgery
Abstract: ObjectiveWhether immunotherapy improves long-term disability in multiple sclerosis has not been satisfactorily demonstrated. This study examined the effect of immunotherapy on long-term disability outcomes in relapsing-remitting multiple sclerosis.MethodsWe studied patients from MSBase followed for ≥1 year, with ≥3 visits, ≥1 visit per year and exposed to a multiple sclerosis therapy, and a subset of patients with ≥15-year follow-up. Marginal structural models were used to compare the hazard of 12-month confirmed increase and decrease in disability, EDSS step 6 and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously re-adjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability and MRI activity.Results14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval 0.43–0.82, p=0.0016), worsening of disability (0.56, 0.38-0.82, p=0.0026) and progress to EDSS step 6 (0.33, 0.19-0.59, p=0.00019). Among 1085 patients with ≥15-year follow-up, the treated patients were less likely to experience relapses (0.59, 0.50–0.70, p=10-9) and worsening of disability (0.81, 0.67-0.99, p=0.043).ConclusionsContinued treatment with multiple sclerosis immunotherapies reduces disability accrual (by 19-44%), the risk of need of a walking aid by 67% and the frequency of relapses (by 40-41%) over 15 years. A proof of long-term effect of immunomodulation on disability outcomes is the key to establishing its disease modifying properties.
Published: 2019
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