@article{pmid35781765,

title = {Long-term follow-up (up to 11 years) of an Italian pediatric MS cohort treated with Natalizumab: a multicenter, observational study},

author = {Damiano Baroncini and Angelo Ghezzi and Clara Guaschino and Lucia Moiola and Massimo Filippi and Antonio Ianniello and Carlo Pozzilli and Roberta Lanzillo and Vincenzo Brescia-Morra and Monica Margoni and Paolo Gallo and Graziella Callari and Luigi Grimaldi and Giacomo Lus and Massimiliano Calabrese and Marta Simone and Girolama Alessandra Marfia and Sarah Rasia and Daniela Cargnelutti and Giancarlo Comi and Mauro Zaffaroni and },

doi = {10.1007/s10072-022-06211-8},

issn = {1590-3478},

year  = {2022},

date = {2022-11-01},

journal = {Neurol Sci},

volume = {43},

number = {11},

pages = {6415--6423},

abstract = {BACKGROUND: Natalizumab (NAT) has a strong impact on disease activity of aggressive pediatric multiple sclerosis (MS), with no difference in safety profile compared to adult MS. However, available data are limited by short follow-up. Our aim was to report long-term follow-up data (up to 11 years) of a large Italian pediatric MS cohort treated with NAT.nnMATERIALS AND METHODS: We retrospectively collected data of pediatric MS patients treated with NAT included in a previous study and prospectively followed in Italian MS centers. We compared disease activity pre, during, and post-NAT and we performed survival analyses of time to evidence of disease activity (EDA) during NAT, time to reach EDA post-NAT, and time to NAT discontinuation.nnRESULTS: Ninety-two patients were included from 19 MS centers in Italy. At NAT initiation, cohort's characteristics were as follows: 55 females; 14.7 ± 2.4 (mean ± SD) years of age; 34 naïve to disease modifying therapies; 1-year pre-NAT annualized relapse rate (ARR): 2.2 ± 1.2; EDSS (median [IQR]): 2.5 [2.0-3.0]; gadolinium-enhancing lesions: 2 [1-5]; 41 JCV positives. During NAT treatment (61.9 ± 35.2 mean infusions), ARR lowered to 0.08 ± 0.23 (p < 0.001), EDSS score to 1.5 [1.0-2.5] at last infusion (p < 0.001), and 51% patients had EDA (21% after 6 months of rebaseline). No serious adverse events were reported. Forty-nine patients discontinued NAT, mainly due to PML concern; the majority (29/49) had disease reactivation in the subsequent 12 months, of which three with a clinical rebound.nnCONCLUSION: NAT treatment maintains its high efficacy for a long time in pediatric MS patients, with no new safety issues.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35296189,

title = {Natalizumab treatment and pregnancy in multiple sclerosis: A reappraisal of maternal and infant outcomes after 6 years},

author = {Emilio Portaccio and Luisa Pastò and Lorenzo Razzolini and Lucia Moiola and Vittorio Martinelli and Pietro Annovazzi and Angelo Ghezzi and Mauro Zaffaroni and Roberta Lanzillo and Vincenzo Brescia Morra and Francesca Rinaldi and Paolo Gallo and Claudio Gasperini and Damiano Paolicelli and Marta Simone and Carlo Pozzilli and Laura De Giglio and Paola Cavalla and Eleonora Cocco and Maria Giovanna Marrosu and Francesco Patti and Claudio Solaro and Giancarlo Comi and Massimo Filippi and Maria Trojano and Maria Pia Amato},

doi = {10.1177/13524585221079598},

issn = {1477-0970},

year  = {2022},

date = {2022-11-01},

journal = {Mult Scler},

volume = {28},

number = {13},

pages = {2137--2141},

abstract = {OBJECTIVES: To assess the impact of timing of natalizumab cessation/redosing on long-term maternal and infant outcomes in 72 out of the original 74 pregnancies of the Italian Pregnancy Dataset in multiple sclerosis (MS).nnMETHODS: Maternal outcomes in patients who received natalizumab until conception and restarted the drug within 1 month after delivery ("treatment approach," (TA)) and patients who stopped natalizumab before conception and/or restarted the drug later than 1 month after delivery ("conservative approach," (CA)) were compared through multivariable Cox regression analyses. Pediatric outcomes were assessed through a semi-structured questionnaire.nnRESULTS: After a mean follow-up of 6.1 years, CA (hazard ratio (HR) = 4.1, 95% CI 1.6-10.6,  = 0.003) was the only predictor of relapse occurrence. Worsening on the Expanded Disability Status Scale (EDSS) was associated with higher annualized relapse-rate during the follow-up (HR = 3.3, 95% CI 1.4-7.9  = 0.007). We found no major development abnormalities in children.nnDISCUSSION: Our data confirm that TA reduces the risk of disease activity; we did not observe an increase in major development abnormalities in the child.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35735030,

title = {Breakthrough SARS-CoV-2 infections in MS patients on disease-modifying therapies},

author = {Irene Schiavetti and Cinzia Cordioli and Maria Laura Stromillo and Maria Teresa Ferrò and Alice Laroni and Eleonora Cocco and Gaia Cola and Livia Pasquali and Maria Teresa Rilla and Elisabetta Signoriello and Rosa Iodice and Alessia Di Sapio and Roberta Lanzillo and Francesca Caleri and Pietro Annovazzi and Antonella Conte and Giuseppe Liberatore and Francesca Ruscica and Renato Docimo and Simona Bonavita and Monica Ulivelli and Paola Cavalla and Francesco Patti and Diana Ferraro and Marinella Clerico and Paolo Immovilli and Massimiliano Di Filippo and Marco Salvetti and Maria Pia Sormani},

doi = {10.1177/13524585221102918},

issn = {1477-0970},

year  = {2022},

date = {2022-11-01},

journal = {Mult Scler},

volume = {28},

number = {13},

pages = {2106--2111},

abstract = {BACKGROUND: Patients with multiple sclerosis (pwMS) treated with anti-CD20 or fingolimod showed a reduced humoral response to SARS-CoV-2 vaccines.nnOBJECTIVE: In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection in pwMS on different disease-modifying therapies (DMTs).nnMETHODS: Data on the number of vaccinated patients and the number of patients with a breakthrough infection were retrospectively collected in 27 Italian MS centers. We estimated the rate of breakthrough infections and of infection requiring hospitalization per DMT.nnRESULTS: 19,641 vaccinated pwMS were included in the database. After a median follow-up of 8 months, we observed 137 breakthrough infections. Compared with other DMTs, the rate of breakthrough infections was significantly higher on ocrelizumab (0.57% vs 2.00%, risk ratio (RR) = 3.55, 95% CI = 2.74-4.58,  < 0.001) and fingolimod (0.58% vs 1.62%, RR = 2.65, 95% CI = 1.75-4.00,  < 0.001), while there were no significant differences in any other DMT group. In the ocrelizumab group the hospitalization rate was 16.7% versus 19.4% in the pre-vaccination era (RR = 0.86,  = 0.74) and it was 3.9% in all the other DMT groups versus 11.9% in the pre-vaccination period (RR = 0.33,  = 0.02).nnCONCLUSIONS: The risk of breakthrough SARS-CoV-2 infections is higher in patients treated with ocrelizumab and fingolimod, and the rate of severe infections was significantly reduced in all the DMTs excluding ocrelizumab.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36356024,

title = {Persistence with Botulinum Toxin Treatment for Spasticity Symptoms in Multiple Sclerosis},

author = {Federica Novarella and Antonio Carotenuto and Paolo Cipullo and Rosa Iodice and Emanuele Cassano and Antonio Luca Spiezia and Nicola Capasso and Maria Petracca and Fabrizia Falco and Carmine Iacovazzo and Giuseppe Servillo and Roberta Lanzillo and Vincenzo Brescia Morra and Marcello Moccia},

doi = {10.3390/toxins14110774},

issn = {2072-6651},

year  = {2022},

date = {2022-11-01},

journal = {Toxins (Basel)},

volume = {14},

number = {11},

abstract = {Botulinum toxin (BT) is an effective treatment for spasticity symptoms in multiple sclerosis (MS). Despite its wide use in clinical practices, only few studies have explored long-term persistence. We aim to evaluate the rate of discontinuation of BT treatment and the correlation with MS, spasticity, and injection variables. This retrospective study on 3-year prospectively collected data included 122 MS patients receiving BT injections for spasticity. We collected MS clinical variables (disease durations, Expanded Disability Status Scales [EDSSs], disease-modifying treatments [DMT], and Symbol Digit Modalities Tests [SDMTs]), modified Ashworth scales [MASs], concomitant treatments, and injection variables (formulation, dose, number of injections, and intervals between injections). A total of 14 out of the 122 patients discontinued BT after a mean time of 3.0 ± 1.5 years. In the Cox regression model including the MS clinical variables, the probability of BT discontinuations increased in patients with DMT changes during follow-ups (HR = 6.34; 95%Cl = 2.47, 18.08;  < 0.01) and with impaired SDMTs (HR = 1.20; 95%Cl = 1.04, 1.96;  < 0.01). In the model including the spasticity variables, there were no associations between BT discontinuation and MAS or other spasticity treatments. In the model including the injection variables, the probability of discontinuation decreased by 80% for each cumulative injection (HR = 0.16; 95%Cl = 0.05, 0.45;  < 0.01), but increased by 1% for each additional day over the 3-month interval between injections (HR = 1.27; 95%Cl = 1.07, 1.83;  < 0.01). BT discontinuation was associated with concomitant MS-related issues (e.g., treatment failure and DMT change) and the presence of cognitive impairment, which should be accounted for when planning injections. The interval between injections should be kept as short as possible from regulatory and clinical perspectives to maximize the response across all of the spasticity symptoms and to reduce discontinuation in the long term.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36096690,

title = {Investigating Functional Network Abnormalities and Associations With Disability in Multiple Sclerosis},

author = {Antonio Carotenuto and Paola Valsasina and Menno M Schoonheim and Jeroen J G Geurts and Frederik Barkhof and Antonio Gallo and Gioacchino Tedeschi and Silvia Tommasin and Patrizia Pantano and Massimo Filippi and Maria A Rocca and },

doi = {10.1212/WNL.0000000000201264},

issn = {1526-632X},

year  = {2022},

date = {2022-11-01},

journal = {Neurology},

volume = {99},

number = {22},

pages = {e2517--e2530},

abstract = {BACKGROUND AND OBJECTIVES: In multiple sclerosis (MS), functional networks undergo continuous reconfiguration and topography changes over the disease course. In this study, we aimed to investigate functional network to pography abnormalities in MS and their association with disease phenotype, clinical and cognitive disability, and structural MRI damage.nnMETHODS: This is a multicenter cross-sectional study. Enrolled participants performed MRI and neurologic and neuropsychological assessment. Network topography was assessed on resting state fMRI data using degree centrality, which counted the number of functional connections of each gray matter voxel with the rest of the brain. SPM12 age-adjusted, sex-adjusted, scanner-adjusted, framewise displacement, and gray matter-volume adjusted analysis of variance and multivariable regressions were used ( < 0.05, family-wise error [FWE] corrected).nnRESULTS: We enrolled 971 patients with MS (624 female patients; mean age = 43.1 ± 11.8 years; 47 clinically isolated syndrome [CIS], 704 relapsing-remitting MS [RRMS], 145 secondary progressive MS [SPMS], and 75 primary progressive MS [PPMS]) and 330 healthy controls (186 female patients; mean age = 41.2 ± 13.3 years). Patients with MS showed reduced centrality in the salience and sensorimotor networks as well as increased centrality in the default-mode network vs controls ( < 0.05, FWE). Abnormal centrality was already found in CIS vs controls and in RRMS vs CIS ( < 0.001, uncorrected); however, it became more severe in SPMS vs RRMS ( < 0.05, FWE) and in PPMS vs controls ( < 0.001, uncorrected). Cognitively impaired patients (39%) showed reduced centrality in the salience network and increased centrality in the default-mode network vs cognitively preserved patients ( < 0.001, conjunction analysis). More severe disability correlated with increased centrality in the right precuneus ( = 0.18,  < 0.05 FWE). Higher T2 lesion volume and brain/gray matter atrophy were associated with reduced centrality in the bilateral insula and cerebellum ( = range -0.17/-0.15 and 0.26/0.28, respectively;  < 0.05, FWE). Higher brain/gray matter atrophy was also associated with increased centrality in the default-mode network ( = range -0.31/-0.22,  < 0.05, FWE).nnDISCUSSION: Patients with MS presented with reduced centrality in the salience and primary sensorimotor networks and increased centrality in the default-mode network. Centrality abnormalities were specific for different disease phenotypes and associated with clinical and cognitive disability, hence suggesting that voxel-wise centrality analysis may reflect pathologic substrates underpinning disability accrual.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36069572,

title = {Off-Adherence Keeping (OAK) observational study: intentional off-adherence immunomodulatory multiple sclerosis treatment},

author = {Marco Peresson and Salvatore Cottone and Vincenzo Brescia Morra and Giuseppe Salemi and Antonio Gallo and Paola Valentino and Luca Prosperini},

doi = {10.2217/nmt-2021-0016},

issn = {1758-2032},

year  = {2022},

date = {2022-10-01},

journal = {Neurodegener Dis Manag},

volume = {12},

number = {5},

pages = {241--251},

abstract = { To evaluate how improved treatment adherence with a lower-frequency regimen/treatment of intramuscular (IM) IFNβ-1a impacts therapeutic effectiveness in relapsing-remitting multiple sclerosis (MS) patients switching from a higher-frequency injectable regimen/treatment.  Italian patients with relapsing-remitting MS and prior poor adherence to high-frequency injectable treatments (n = 181) were followed for 24 months after starting IM IFNβ-1a.  During the study, 97.4% of patients were treatment adherent; 22.1% of patients reported a relapse. The estimated probability of remaining relapse-free after 2 years was 78%. A high dropout rate (52.5%) led to small sample size and reduced statistical power.  Intramuscular IFNβ-1a treatment was associated with high adherence and a low relapse rate. Unfortunately, low patient retention limited the generalizability of these findings.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36289652,

title = {Correlation between Retinal Vascularization and Disease Aggressiveness in Amyotrophic Lateral Sclerosis},

author = {Gilda Cennamo and Daniela Montorio and Francesco Pio Ausiello and Luigifilippo Magno and Rosa Iodice and Alberto Mazzucco and Valentina Virginia Iuzzolino and Gianmaria Senerchia and Vincenzo Brescia Morra and Maria Nolano and Ciro Costagliola and Raffaele Dubbioso},

doi = {10.3390/biomedicines10102390},

issn = {2227-9059},

year  = {2022},

date = {2022-09-01},

journal = {Biomedicines},

volume = {10},

number = {10},

abstract = {Abnormalities in retinal vascularization and neural density have been found in many neurodegenerative diseases; however, conflicting results are described in Amyotrophic Lateral Sclerosis (ALS). The aim of the present study was, therefore, to systematically analyze retinal layers and vascularization by means of spectral-domain (SD-OCT) and optical coherence tomography angiography (OCT-A) in ALS patients. We enrolled 48 ALS patients and 45 healthy controls. ALS patients were divided into three groups: slow progressors (n = 10), intermediate progressors (n = 24) and fast progressors (n = 14), according to the disease progression rate. For SD-OCT, we evaluated the Subfoveal choroidal thickness (SFCT), ganglion cell complex (GCC) and retinal nerve fiber layer (RNFL). Regarding the OCT-A, we assessed the vessel density (VD) in superficial and deep capillary plexuses, radial peripapillary capillary plexus, choriocapillary and the foveal avascular zone (FAZ) area. SD-OCT exam did not show any significant differences in GCC and RNFL thickness between patients and controls and among the three ALS groups. The SFCT was statistically greater in patients compared with controls (357.95 ± 55.15 µm vs. 301.3 ± 55.80 µm, p < 0.001); interestingly, the SFCT was thicker in patients with slow and intermediate disease progression than in those with fast disease progression (394.45 ± 53.73 µm vs. 393.09 ± 42.17 µm vs. 267.71 ± 56.24 µm, p < 0.001). OCT-A did not reveal any significant results. Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-r) and disease duration did not correlate with any of the OCT parameters, except for SFCT with ALSFRS-r (r = 0.753, p = 0.024). This study demonstrated the possible association between choroidal thickness and disease activity in ALS. OCT could be a useful biomarker in the management of the disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35877104,

title = {Disease-Modifying Treatments and Time to Loss of Ambulatory Function in Patients With Primary Progressive Multiple Sclerosis},

author = {Emilio Portaccio and Mattia Fonderico and Pietro Iaffaldano and Luisa Pastò and Lorenzo Razzolini and Angelo Bellinvia and Giovanna De Luca and Paolo Ragonese and Francesco Patti and Vincenzo Brescia Morra and Eleonora Cocco and Patrizia Sola and Matilde Inglese and Giacomo Lus and Carlo Pozzilli and Davide Maimone and Alessandra Lugaresi and Paola Gazzola and Giancarlo Comi and Ilaria Pesci and Daniele Spitaleri and Marta Rezzonico and Marika Vianello and Carlo Avolio and Francesco O Logullo and Franco Granella and Marco Salvetti and Mauro Zaffaroni and Giuseppe Lucisano and Massimo Filippi and Maria Trojano and Maria Pia Amato and },

doi = {10.1001/jamaneurol.2022.1929},

issn = {2168-6157},

year  = {2022},

date = {2022-09-01},

journal = {JAMA Neurol},

volume = {79},

number = {9},

pages = {869--878},

abstract = {IMPORTANCE: Except for ocrelizumab, treatment options in primary progressive multiple sclerosis (PPMS) are lacking.nnOBJECTIVE: To investigate the effectiveness of DMTs on the risk of becoming wheelchair dependent in a real-world population of patients with PPMS.nnDESIGN, 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.nnMAIN OUTCOMES AND MEASURES: The risk of reaching an EDSS score of 7.0 was assessed through multivariable Cox regression models.nnEXPOSURES: 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).nnRESULTS: 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 < .001), superimposed relapses (aHR, 2.37; 95% CI, 1.24-4.54; P = .009), and DMT exposure (aHR, 1.75; 95% CI, 1.04-2.94; P = .03) were associated with a higher risk of an EDSS score of 7.0, whereas the interaction term between DMT and superimposed relapses was associated with a reduced risk of EDSS score of 7.0 (aHR, 0.33; 95% CI, 0.16-0.71; P = .004). Similar findings were obtained when treatment according to DMT class was considered and when DMT was included as a time-dependent covariate. These results were confirmed in the subgroup of patients with available magnetic resonance imaging data.nnCONCLUSIONS AND RELEVANCE: Results of this comparative effectiveness research study suggest that inflammation also occurs in patients with PPMS, may contribute to long-term disability, and may be associated with a reduced risk of becoming wheelchair dependent by current licensed DMTs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36180219,

title = {Exposure to natalizumab throughout pregnancy: effectiveness and safety in an Italian cohort of women with multiple sclerosis},

author = {Doriana Landi and Francesca Bovis and Alfonso Grimaldi and Pietro Osvaldo Annovazzi and Antonio Bertolotto and Alessia Bianchi and Giovanna Borriello and Vincenzo Brescia Morra and Sebastiano Bucello and Maria Chiara Buscarinu and Francesca Caleri and Marco Capobianco and Ruggero Capra and Maria Cellerino and Diego Centonze and Raffaella Cerqua and Clara Grazia Chisari and Marinella Clerico and Eleonora Cocco and Gaia Cola and Cinzia Cordioli and Erica Curti and Alessandro d'Ambrosio and Emanuele D'Amico and Giovanna De Luca and Massimiliano Di Filippo and Sonia Di Lemme and Roberta Fantozzi and Diana Ferraro and Elisabetta Ferraro and Antonio Gallo and Claudio Gasperini and Franco Granella and Matilde Inglese and Roberta Lanzillo and Lorena Lorefice and Giacomo Lus and Simona Malucchi and Monica Margoni and Giorgia Mataluni and Massimiliano Mirabella and Lucia Moiola and Carolina Gabri Nicoletti and Viviana Nociti and Francesco Patti and Federica Pinardi and Emilio Portaccio and Carlo Pozzilli and Paolo Ragonese and Sarah Rasia and Giuseppe Salemi and Elisabetta Signoriello and Francesca Vitetta and Rocco Totaro and Maria Pia Sormani and Maria Pia Amato and Girolama Alessandra Marfia},

doi = {10.1136/jnnp-2022-329657},

issn = {1468-330X},

year  = {2022},

date = {2022-09-01},

journal = {J Neurol Neurosurg Psychiatry},

abstract = {OBJECTIVE: Assessing the risk of clinical and radiological reactivation during pregnancy and post partum in women with multiple sclerosis (MS) treated with natalizumab (NTZ) throughout pregnancy (LONG_EXP) compared with women interrupting treatment before (NO_EXP) and within >-30 days and ≤90 days from conception (SHORT_EXP), and describing newborns' outcomes.nnMETHODS: Maternal clinical and radiological outcomes and obstetric and fetal outcomes were retrospectively collected and compared among groups (NO_EXP, SHORT_EXP, LONG_EXP). Predictors of clinical and radiological reactivation were investigated through univariable and multivariable analysis.nnRESULTS: 170 eligible pregnancies from 163 women referring to 29 Italian MS centres were included. Annualised relapse rate (ARR) was significantly lower in LONG_EXP (n=66, 0.02 (0.001-0.09)) compared with NO_EXP (n=31, 0.43 (0.21-0.75), p=0.002) and SHORT_EXP (n=73, 0.46 (0.30-0.66), p=0.0004) during pregnancy, and in LONG_EXP (0.12 (0.05-0.24)) compared with SHORT_EXP (0.30 (0.17-0.50), p=0.008) during post partum. Gadolinium-enhancing (Gd+) lesions were less frequent in LONG_EXP (n=6/50, 2.00%) compared with NO_EXP (n=9/21, 42.86%) and SHORT_EXP after delivery (n=17/49, 34.69%, p=0.010).Delaying NTZ resumption after delivery significantly increased the risk of relapses (OR=1.29 (95% CI 1.07 to 1.57), p=0.009) and Gd+ lesions (OR=1.49 (95% CI 1.17 to 1.89, p=0.001). Newborns' weight, length, head circumference and gestational age did not differ among groups after adjusting for confounders. Anaemia was tracked in 4/69 LONG_EXP newborns. Congenital anomaly rate was within the expected range for the untreated MS population.nnCONCLUSIONS: Our findings indicate that in women with MS treated with NTZ before conception, continuation of NTZ throughout pregnancy and its early resumption after delivery mitigate the risk of clinical and radiological reactivation. This approach has no major impact on newborns' outcomes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36079156,

title = {Quality of Life Changes in Early-Onset Multiple Sclerosis: A 4-Year Follow-Up Study},

author = {Laura Rosa and Maria Petracca and Antonio Carotenuto and Pasquale Dolce and Kyrie Piscopo and Francesca Dicé and Francesca Lauro and Antonio Luca Spiezia and Marcello Moccia and Luigi Lavorgna and Carmine Iacovazzo and Giuseppe Servillo and Nelson Mauro Maldonato and Alessandro Chiodi and Vincenzo Brescia Morra and Roberta Lanzillo},

doi = {10.3390/jcm11175226},

issn = {2077-0383},

year  = {2022},

date = {2022-09-01},

journal = {J Clin Med},

volume = {11},

number = {17},

abstract = {This study investigates longitudinal changes in health-related quality of life (HRQoL) in early-onset multiple sclerosis (MS) patients and explores the impact of disease activity (relapses) on such changes. People with MS (PwMS) onset between 12 and 25 years of age were followed longitudinally. At baseline and at year 4, patients were asked to fill the Paediatric Quality of life inventory (PedsQL). Demographic and clinical features were collected at both time points. Longitudinal within-group comparison of HRQoL total score and sub-scores was performed via paired samples t-test. The effect of relapses on the HRQoL changes over time was explored via linear mixed-effects analysis. No longitudinal changes were observed in the overall PedsQL score, nor in the physical, school and psychological functioning. An increase in the social functioning subscale (p < 0.001) and a decrease in the emotional subscale (p = 0.006) were observed. The change in social functioning, but not the one in the emotional subscale, was affected by the occurrence of relapses (p = 0.044). In conclusion, stimulating the patients to accept their emotional responses to health-related limitations, while preserving their social and relational resources seems key to the preservation of an adequate QoL over time in juvenile-onset MS.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35940683,

title = {Optimal Emergency Department Care Practices for Persons Living With Dementia: A Scoping Review},

author = {Scott M Dresden and Zachary Taylor and Peter Serina and Maura Kennedy and Annie B Wescott and Teresita Hogan and Manish N Shah and Ula Hwang and },

doi = {10.1016/j.jamda.2022.05.024},

issn = {1538-9375},

year  = {2022},

date = {2022-08-01},

journal = {J Am Med Dir Assoc},

volume = {23},

number = {8},

pages = {1314.e1--1314.e29},

abstract = {OBJECTIVES: To summarize research on optimal emergency department (ED) care practices for persons living with dementia (PLWDs) and develop research priorities.nnDESIGN: Systematic scoping review.nnSETTINGS AND PARTICIPANTS: PLWDs in the ED.nnMETHODS: The following Patient-Intervention-Comparison-Outcome (PICO) questions were developed: PICO 1, What components of emergency department care improve patient-centered outcomes for persons with dementia? PICO 2, How do emergency care needs for persons with dementia differ from other patients in the emergency department? A scoping review was conducted following PRISMA-ScR guidelines and presented to the Geriatric Emergency care Applied Research 2.0 Advancing Dementia Care network to inform research priorities.nnRESULTS: From the 6348 publications identified, 23 were abstracted for PICO 1 and 26 were abstracted for PICO 2. Emergency care considerations for PLWDs included functional dependence, behavioral and psychological symptoms of dementia, and identification of and management of pain. Concerns regarding ED care processes, the ED environment, and meeting a PWLD's basic needs were described. A comprehensive geriatric assessment and dedicated ED unit, a home hospital program, and a low-stimulation bed shade and contact-free monitor all showed improvement in patient-centered or health care use outcomes. However, all were single-site studies evaluating different outcomes. These results informed the following research priorities: (1) training and dementia care competencies; (2) patient-centric and care partner-centric evaluation interventions; (3) the impact of community- and identity-based factors on ED care for PLWDs; (4) economic or other implementation science measures to address viability; and (5) environmental, operational, personnel, system, or policy changes to improve ED care for PLWDs.nnCONCLUSIONS AND IMPLICATIONS: A wide range of components of both ED care practices and ED care needs for PLWDs have been studied. Although many interventions show positive results, the lack of depth and reproducible results prevent specific recommendations on best practices in ED care for PLWDs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35292909,

title = {Association Between Institutional Affiliations of Academic Editors and Authors in Medical Journals},

author = {Raffaele Palladino and Rossella Alfano and Marcello Moccia and Francesco Barone-Adesi and Azeem Majeed and Maria Triassi and Christopher Millett},

doi = {10.1007/s11606-022-07483-8},

issn = {1525-1497},

year  = {2022},

date = {2022-08-01},

journal = {J Gen Intern Med},

volume = {37},

number = {11},

pages = {2911--2913},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35325059,

title = {Progression is independent of relapse activity in early multiple sclerosis: a real-life cohort study},

author = {Emilio Portaccio and Angelo Bellinvia and Mattia Fonderico and Luisa Pastò and Lorenzo Razzolini and Rocco Totaro and Daniele Spitaleri and Alessandra Lugaresi and Eleonora Cocco and Marco Onofrj and Franco Di Palma and Francesco Patti and Davide Maimone and Paola Valentino and Paolo Confalonieri and Alessandra Protti and Patrizia Sola and Giacomo Lus and Giorgia Teresa Maniscalco and Vincenzo Brescia Morra and Giuseppe Salemi and Franco Granella and Ilaria Pesci and Roberto Bergamaschi and Umberto Aguglia and Marika Vianello and Marta Simone and Vito Lepore and Pietro Iaffaldano and Massimo Filippi and Maria Trojano and Maria Pia Amato},

doi = {10.1093/brain/awac111},

issn = {1460-2156},

year  = {2022},

date = {2022-08-01},

journal = {Brain},

volume = {145},

number = {8},

pages = {2796--2805},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35772230,

title = {A polynomial regression-based approach to estimate relaxation rate maps suitable for multiparametric segmentation of clinical brain MRI studies in multiple sclerosis},

author = {Maria Agnese Pirozzi and Mario Tranfa and Mario Tortora and Roberta Lanzillo and Vincenzo Brescia Morra and Arturo Brunetti and Bruno Alfano and Mario Quarantelli},

doi = {10.1016/j.cmpb.2022.106957},

issn = {1872-7565},

year  = {2022},

date = {2022-08-01},

journal = {Comput Methods Programs Biomed},

volume = {223},

pages = {106957},

abstract = {BACKGROUND AND OBJECTIVE: Relaxation parameter maps (RPMs) calculated from spin-echo data have provided a basis for the segmentation of normal brain tissues and white matter lesions in multiple sclerosis (MS) MRI studies. However, Conventional Spin-Echo (CSE) sequences, once the core of clinical MRI studies, have been largely replaced by faster ones, which do not allow the calculation a-posteriori of RPMs from clinical studies. Aim of the study was to develop and validate a method to estimate RPMs (pseudo-RPMs) from routine clinical MRI protocols (including 3D-Gradient Echo T1w, FLAIR and fast-T2w sequences), suitable for fully automatic multiparametric segmentation of normal-appearing and pathological brain tissues in MS.nnMETHODS: The proposed method processes spatially normalized clinical MRI studies through a multistep pipeline, to collect a set of data points of matched signal intensities (from MRI studies) and relaxation parameters (from a CSE-derived digital template and an MS lesion database), which are then fitted by a multiple and multivariate 4-th degree polynomial regression, providing pseudo-RPMs. The method was applied to a dataset of 59 clinical MRI studies providing pseudo-RPMs that were segmented through a method originally developed for the CSE-derived RPMs. Results of the segmentation in 12 studies were used to iteratively optimize method parameters. Accuracy of segmentation of normal-appearing brain tissues from the pseudo-RPMs was assessed by comparing their age-related changes, as measured in 47 clinical studies, against those measured acquired using CSE sequences in a comparable dataset of 47 patients. Lesion segmentation was validated against manual segmentation carried out by three neuroradiologists.nnRESULTS: Age-related changes of normal-appearing brain tissue volumes measured using the pseudo-RPMs substantially overlapped those measured using the RPMs obtained from CSE sequences, and segmentation of MS lesions showed a moderate-high spatial overlap with manual segmentation, comparable to that achieved by the widely used Lesion Segmentation Tool on FLAIR images, with a greater volumetric agreement.nnCONCLUSIONS: The proposed approach allows calculation from clinical studies of pseudo-RPMs, which are equivalent to those obtainable from CSE sequences, avoiding the need for the acquisition of additional, dedicated sequences for segmentation purposes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35284989,

title = {Stratification of multiple sclerosis patients using unsupervised machine learning: a single-visit MRI-driven approach},

author = {Giuseppe Pontillo and Simone Penna and Sirio Cocozza and Mario Quarantelli and Michela Gravina and Roberta Lanzillo and Stefano Marrone and Teresa Costabile and Matilde Inglese and Vincenzo Brescia Morra and Daniele Riccio and Andrea Elefante and Maria Petracca and Carlo Sansone and Arturo Brunetti},

doi = {10.1007/s00330-022-08610-z},

issn = {1432-1084},

year  = {2022},

date = {2022-08-01},

journal = {Eur Radiol},

volume = {32},

number = {8},

pages = {5382--5391},

abstract = {OBJECTIVES: To stratify patients with multiple sclerosis (pwMS) based on brain MRI-derived volumetric features using unsupervised machine learning.nnMETHODS: The 3-T brain MRIs of relapsing-remitting pwMS including 3D-T1w and FLAIR-T2w sequences were retrospectively collected, along with Expanded Disability Status Scale (EDSS) scores and long-term (10 ± 2 years) clinical outcomes (EDSS, cognition, and progressive course). From the MRIs, volumes of demyelinating lesions and 116 atlas-defined gray matter regions were automatically segmented and expressed as z-scores referenced to external populations. Following feature selection, baseline MRI-derived biomarkers entered the Subtype and Stage Inference (SuStaIn) algorithm, which estimates subgroups characterized by distinct patterns of biomarker evolution and stages within subgroups. The trained model was then applied to longitudinal MRIs. Stability of subtypes and stage change over time were assessed via Krippendorf's α and multilevel linear regression models, respectively. The prognostic relevance of SuStaIn classification was assessed with ordinal/logistic regression analyses.nnRESULTS: We selected 425 pwMS (35.9 ± 9.9 years; F/M: 301/124), corresponding to 1129 MRI scans, along with healthy controls (N = 148; 35.9 ± 13.0 years; F/M: 77/71) and external pwMS (N = 80; 40.4 ± 11.9 years; F/M: 56/24) as reference populations. Based on 11 biomarkers surviving feature selection, two subtypes were identified, designated as "deep gray matter (DGM)-first" subtype (N = 238) and "cortex-first" subtype (N = 187) according to the atrophy pattern. Subtypes were consistent over time (α = 0.806), with significant annual stage increase (b = 0.20; p < 0.001). EDSS was associated with stage and DGM-first subtype (p ≤ 0.02). Baseline stage predicted long-term disability, transition to progressive course, and cognitive impairment (p ≤ 0.03), with the latter also associated with DGM-first subtype (p = 0.005).nnCONCLUSIONS: Unsupervised learning modelling of brain MRI-derived volumetric features provides a biologically reliable and prognostically meaningful stratification of pwMS.nnKEY POINTS: • The unsupervised modelling of brain MRI-derived volumetric features can provide a single-visit stratification of multiple sclerosis patients. • The so-obtained classification tends to be consistent over time and captures disease-related brain damage progression, supporting the biological reliability of the model. • Baseline stratification predicts long-term clinical disability, cognition, and transition to secondary progressive course.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35689866,

title = {Monoclonal antibodies for mild-to-moderate COVID-19 in multiple sclerosis: A case series},

author = {Marcello Moccia and Antonio Riccardo Buonomo and Riccardo Scotto and Giulio Viceconte and Mariano Nobile and Roberta Lanzillo and Vincenzo Brescia Morra and Ivan Gentile and },

doi = {10.1016/j.jns.2022.120306},

issn = {1878-5883},

year  = {2022},

date = {2022-08-01},

journal = {J Neurol Sci},

volume = {439},

pages = {120306},

abstract = {We reported on five people with MS, using immunodepleting disease modifying treatments (anti-CD20 monoclonal antibodies and sphingosine-one-phosphate modulators) and with reduced COVID-19 vaccine response, who had mild-to-moderate symptomatic COVID-19, and were treated with anti-SARS-CoV-2 monoclonal antibodies. In particular, we showed the possibility to use monoclonal antibodies to speed-up recovery from COVID-19 in MS, in the absence of any COVID-19 residuals or MS changes (e.g., relapses or disability).},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35596582,

title = {Magnetic Resonance Imaging Evaluation of Perivascular Space Abnormalities in Neuromyelitis Optica},

author = {Laura Cacciaguerra and Antonio Carotenuto and Elisabetta Pagani and Damiano Mistri and Marta Radaelli and Vittorio Martinelli and Massimo Filippi and Maria A Rocca},

doi = {10.1002/ana.26419},

issn = {1531-8249},

year  = {2022},

date = {2022-08-01},

journal = {Ann Neurol},

volume = {92},

number = {2},

pages = {173--183},

abstract = {OBJECTIVE: Astrocytes outline the perivascular space (PVS) and regulate fluid exchange through the aquaporin-4 water channel. As neuromyelitis optica is an autoimmune astrocytopathy targeting aquaporin-4, we hypothesized that it could be associatied with PVS abnormalities.nnMETHODS: A total of 34 patients, and 46 age- and sex-matched healthy controls from two independent cohorts (exploratory and validation dataset) underwent a standardized 3.0-T magnetic resonance imaging protocol including conventional and diffusion tensor imaging. Susceptibility-weighted imaging was also acquired in the exploratory dataset. We evaluated macroscopic and microstructural abnormalities of PVS in terms of enlargement and water diffusivity (DTI-ALPS index). In the exploration dataset, a susceptibility-weighted sequence was used to draw the regions of interest for the DTI-ALPS index calculation in areas having veins perpendicular to lateral ventricles. Between-group comparisons, correlations, and regression models were run to assess associations between PVS abnormalities, and clinical and magnetic resonance imaging variables.nnRESULTS: Patients had a higher frequency of severe PVS enlargement in the centrum semiovale (29.4% vs 8.7%), which correlated with brain atrophy, deep grey matter atrophy, and poorer cognitive performance (r-values range: -0.44, -0.36; p values: 0.01-0.046). In both datasets, patients had reduced DTI-ALPS index compared with controls (p values 0.004-0.038). Lower DTI-ALPS index, deep gray matter volume, and cortical volume could discriminate between patients and controls (R  = 0.62), whereas lower DTI-ALPS index, higher number of myelitis, and higher T2-lesion volume were associated with worse disability (R  = 0.55).nnINTERPRETATION: Patients with neuromyelitis optica spectrum disorder are characterized by abnormal enlargement and impaired water diffusion along the PVS, whose clinical implications suggest a direct correlation with disease pathogenesis and severity. ANN NEUROL 2022;92:173-183.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34919648,

title = {Glymphatic system impairment in multiple sclerosis: relation with brain damage and disability},

author = {Antonio Carotenuto and Laura Cacciaguerra and Elisabetta Pagani and Paolo Preziosa and Massimo Filippi and Maria A Rocca},

doi = {10.1093/brain/awab454},

issn = {1460-2156},

year  = {2022},

date = {2022-08-01},

journal = {Brain},

volume = {145},

number = {8},

pages = {2785--2795},

abstract = {Recent evidence has shown the existence of a CNS 'waste clearance' system, defined as the glymphatic system. Glymphatic abnormalities have been described in several neurodegenerative conditions, including Alzheimer's and Parkinson's disease. Glymphatic function has not been thoroughly explored in multiple sclerosis, where neurodegenerative processes are intermingled with inflammatory processes. We aimed to investigate glymphatic system function in multiple sclerosis and to evaluate its association with clinical disability, disease course, demyelination and neurodegeneration, quantified using different MRI techniques. In this retrospective study, we enrolled 71 multiple sclerosis patients (49 relapsing-remitting and 22 progressive multiple sclerosis) and 32 age- and sex-matched healthy control subjects. All subjects underwent neurological and MRI assessment including high-resolution T1, T2 and double inversion recovery sequences, diffusion and susceptibility weighted imaging. We calculated the diffusion along perivascular space index, a proxy for glymphatic function, cortical and deep grey matter volume, white and cortical grey matter lesion volume and normal-appearing white matter microstructural damage. Multiple sclerosis patients showed an overall lower diffusion along perivascular space index versus healthy controls (estimated mean difference: -0.09, P = 0.01). Both relapsing-remitting and progressive multiple sclerosis patients had lower diffusion along perivascular space index versus healthy controls (estimated mean difference: -0.06, P = 0.04 for relapsing-remitting and -0.19, P = 0.001 for progressive multiple sclerosis patients). Progressive multiple sclerosis patients showed lower diffusion along perivascular space index versus relapsing-remitting multiple sclerosis patients (estimated mean difference: -0.09, P = 0.03). In multiple sclerosis patients, lower diffusion along perivascular space index was associated with more severe clinical disability (r = -0.45, P = 0.001) and longer disease duration (r = -0.37, P = 0.002). Interestingly, we detected a negative association between diffusion along perivascular space index and disease duration in the first 4.13 years of the disease course (r = -0.38, P = 0.04) without any association thereafter (up to 34 years of disease duration). Lower diffusion along perivascular space index was associated with higher white (r = -0.36, P = 0.003) and cortical (r = -0.41, P = 0.001) lesion volume, more severe cortical (r = 0.30, P = 0.007) and deep (r = 0.42, P = 0.001) grey matter atrophy, reduced fractional anisotropy (r = 0.42, P = 0.001) and increased mean diffusivity (r = -0.45, P = 0.001) in the normal-appearing white matter. Our results suggest that the glymphatic system is impaired in multiple sclerosis, especially in progressive stages. Impaired glymphatic function was associated with measures of both demyelination and neurodegeneration and reflects a more severe clinical disability. These findings suggest that glymphatic impairment may be a pathological mechanism underpinning multiple sclerosis. The dynamic interplay with other pathological substrates of the disease deserves further investigation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35487032,

title = {Impact of an anti-infective screening and monitoring protocol together with infectious disease consultation in preventing infective adverse events in patients treated with anti-CD20/CD52 agents for multiple sclerosis},

author = {Emanuela Zappulo and Antonio Riccardo Buonomo and Marcello Moccia and Biagio Pinchera and Riccardo Villari and Maria Petracca and Roberta Lanzillo and Riccardo Scotto and Antonio Carotenuto and Giulio Viceconte and Nicola Schiano Moriello and Luca Bruno and Ivan Gentile and Vincenzo Brescia Morra},

doi = {10.1016/j.msard.2022.103814},

issn = {2211-0356},

year  = {2022},

date = {2022-07-01},

journal = {Mult Scler Relat Disord},

volume = {63},

pages = {103814},

abstract = {BACKGROUND: Monoclonal antibodies have been a milestone in the treatment of multiple sclerosis (MS). Infective complications have been observed in patients on agents targeting lymphoid cells' surface antigens, namely anti-CD52 (alemtuzumab) and anti-CD20 agents (ocrelizumab and rituximab). Despite increasing emerging data, there is no standardized consensus regarding pre-treatment testing, vaccinations, and patient education before and during MS therapy or optimal infection-control strategies.nnMETHODS: We led a retrospective/prospective real-life study to evaluate the effectiveness of a program of screening and prophylaxis for infective adverse events in patients with multiple sclerosis and related disorders treated with drugs directed against CD20/52 antigens. All patients referring to the MS Clinical Care and Research Center, University of Naples "Federico II", who started on alemtuzumab, ocrelizumab or rituximab (off-label use) from 1 November 2015 to 30 June 2019 were recruited. From the 1st of February 2018 patients underwent a microbiological screening and were evaluated by an infectious disease specialist (IDs) before monoclonal antibodies infusion to rule out active infections. We evaluated incidence of infective complications and predictors before (retrospectively)and after (prospectively) the introduction of the above-mentioned anti-infective program.nnRESULTS: We enrolled 275 patients, 104 retrospectively (pre-intervention group, PRE) and 171 prospectively (post-intervention group, POST). In PRE group, most patients were treated with alemtuzumab (58% vs 32%, p < 0.001), were more frequently DMT naïve (48% vs 36%, p = 0.044) or had received fingolimod in the past (48% vs 28%, p = 0.044) and the follow-up period was longer than in POST group (750 vs 191 days, p < 0.001). In POST group, patients were older (median age 47 vs 42 years, p = 0.030) and mostly received OCR (54% vs 14%, p < 0.001). Lymphopenia at baseline was significantly more commonly observed in PRE arm (47% vs 8%, p < 0.001). A total of 39 patients (38%) in PRE arm and 42 patients (25% in POST) group experienced one or more infections (p = 0.022); severe infections were significantly more common in PRE patients (23% vs 14%, p = 0.022). Our anti-infective program was associated with a lower IAE incidence both at univariate and multivariate analysis (aHR of infective events in PRE group: 3.652 [CI: 9.03-94.19], p < 0.001). Moreover, DMT naïve patients significantly experienced fewer infective complications (aHR: 0.470, [CI: 1.02-2.55], p = 0.040).nnCONCLUSIONS: A risk mitigation program including infectious disease consultation and standardized screening and prophylactic protocols was effective in reducing infective adverse events in patients receiving anti CD20/CD52 agents for MS.},

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pubstate = {published},

tppubtype = {article}

}