Preliminary evidence of blunted humoral response to SARS-CoV-2 mRNA vaccine in multiple sclerosis patients treated with ocrelizumab

Objectives: Several concerns regard the immunogenicity of SARS-CoV-2 vaccines in people with multiple sclerosis (pwMS), since the majority of them is treated with immunomodulating/immunosuppressive disease modifying therapies. Here we report the first data on the humoral response to mRNA SARS-CoV-2 vaccine in a case series of 4 pwMS treated with ocrelizumab (OCR) as compared to a group of healthy subjects (HS). Methods: We collected serum samples at 0, 14, 21 days after the first dose and 7 days after the second dose of BNT162b2-mRNA-Covid-19 vaccine from 55 health-care workers and 4 relapsing pwMS on OCR, with no history of Covid-19 infection. Sera were tested using the LIAISON®SARS-CoV-2 TrimericS-IgG assay (DiaSorin-S.p.A.) for the detection of IgG antibodies to SARS-CoV-2 spike protein. The anti-spike IgGtiters were expressed in Binding Antibody Units (BAU), an international standard unit. Results: At baseline all subjects were negative for anti-spike IgG. Seven days after the second dose of vaccine all HS mounted a significant humoral response (geometric mean 2010.4 BAU/mL C.I. 95% 1512.7-2672) while the 4 pwMS showed a lower response (range <4.81-175 BAU/mL). Discussion: Humoral response to BNT162b2-mRNA-vaccine in pwMS treated with OCR was clearly blunted. Further data are urgently needed to confirm and expand these preliminary results and to develop strategies to optimize the response to SARSCoV-2 vaccines in pwMS on OCR

Prediction of the information processing speed performance in multiple sclerosis using a machine learning approach in a large multicenter magnetic resonance imaging data set

Many patients with multiple sclerosis (MS) experience information processing speed (IPS) deficits, and the Symbol Digit Modalities Test (SDMT) has been recommended as a valid screening test. Magnetic resonance imaging (MRI) has markedly improved the understanding of the mechanisms associated with cognitive deficits in MS. However, which structural MRI markers are the most closely related to cognitive performance is still unclear. We used the multicenter 3T-MRI data set of the Italian Neuroimaging Network Initiative to extract multimodal data (i.e., demographic, clinical, neuropsychological, and structural MRIs) of 540 MS patients. We aimed to assess, through machine learning techniques, the contribution of brain MRI structural volumes in the prediction of IPS deficits when combined with demographic and clinical features. We trained and tested the eXtreme Gradient Boosting (XGBoost) model following a rigorous validation scheme to obtain reliable generalization performance. We carried out a classification and a regression task based on SDMT scores feeding each model with different combinations of features. For the classification task, the model trained with thalamus, cortical gray matter, hippocampus, and lesions volumes achieved an area under the receiver operating characteristic curve of 0.74. For the regression task, the model trained with cortical gray matter and thalamus volumes, EDSS, nucleus accumbens, lesions, and putamen volumes, and age reached a mean absolute error of 0.95. In conclusion, our results confirmed that damage to cortical gray matter and relevant deep and archaic gray matter structures, such as the thalamus and hippocampus, is among the most relevant predictors of cognitive performance in MS

A Semiautomatic Method for Multiple Sclerosis Lesion Segmentation on Dual-Echo MR Imaging: Application in a Multicenter Context

BACKGROUND AND PURPOSE: The automatic segmentation of MS lesions could reduce time required for image processing together with inter- and intraoperator variability for research and clinical trials. A multicenter validation of a proposed semiautomatic method for hyperintense MS lesion segmentation on dual-echo MR imaging is presented. MATERIALS AND METHODS: The classification technique used is based on a region-growing approach starting from manual lesion identification by an expert observer with a final segmentation-refinement step. The method was validated in a cohort of 52 patients with relapsing-remitting MS, with dual-echo images acquired in 6 different European centers. RESULTS: We found a mathematic expression that made the optimization of the method independent of the need for a training dataset. The automatic segmentation was in good agreement with the manual segmentation (dice similarity coefficient = 0.62 and root mean square error = 2 mL). Assessment of the segmentation errors showed no significant differences in algorithm performance between the different MR scanner manufacturers (P > .05). CONCLUSIONS: The method proved to be robust, and no center-specific training of the algorithm was required, offering the possibility for application in a clinical setting. Adoption of the method should lead to improved reliability and less operator time required for image analysis in research and clinical trials in MS

Characterizing 1-year development of cervical cord atrophy across different MS phenotypes: A voxel-wise, multicentre analysis

Background: Spatio-temporal evolution of cord atrophy in multiple sclerosis (MS) has not been investigated yet. Objective: To evaluate voxel-wise distribution and 1-year changes of cervical cord atrophy in a multicentre MS cohort. Methods: Baseline and 1-year 3D T1-weighted cervical cord scans and clinical evaluations of 54 healthy controls (HC) and 113 MS patients (14 clinically isolated syndromes (CIS), 77 relapsing-remitting (RR), 22 progressive (P)) were used to investigate voxel-wise cord volume loss in patients versus HC, 1-year volume changes and clinical correlations (SPM12). Results: MS patients exhibited baseline cord atrophy versus HC at anterior and posterior/lateral C1/C2 and C4–C6 (p < 0.05, corrected). While CIS patients showed baseline volume increase at C4 versus HC (p < 0.001, uncorrected), RRMS exhibited posterior/lateral C1/C2 atrophy versus CIS, and PMS showed widespread cord atrophy versus RRMS (p < 0.05, corrected). At 1 year, 13 patients had clinically worsened. Cord atrophy progressed in MS, driven by RRMS, at posterior/lateral C2 and C3–C6 (p < 0.05, corrected). CIS patients showed no volume changes, while PMS showed circumscribed atrophy progression. Baseline cord atrophy at posterior/lateral C1/C2 and C3–C6 correlated with concomitant and 1-year disability (r = −0.40/–0.62, p < 0.05, corrected). Conclusions: Voxel-wise analysis characterized spinal cord neurodegeneration over 1 year across MS phenotypes and helped to explain baseline and 1-year disability

Prediction of the information processing speed performance in multiple sclerosis using a machine learning approach in a large multicenter magnetic resonance imaging data set

Many patients with multiple sclerosis (MS) experience information processing speed (IPS) deficits, and the Symbol Digit Modalities Test (SDMT) has been recommended as a valid screening test. Magnetic resonance imaging (MRI) has markedly improved the understanding of the mechanisms associated with cognitive deficits in MS. However, which structural MRI markers are the most closely related to cognitive performance is still unclear. We used the multicenter 3T-MRI data set of the Italian Neuroimaging Network Initiative to extract multimodal data (i.e., demographic, clinical, neuropsychological, and structural MRIs) of 540 MS patients. We aimed to assess, through machine learning techniques, the contribution of brain MRI structural volumes in the prediction of IPS deficits when combined with demographic and clinical features. We trained and tested the eXtreme Gradient Boosting (XGBoost) model following a rigorous validation scheme to obtain reliable generalization performance. We carried out a classification and a regression task based on SDMT scores feeding each model with different combinations of features. For the classification task, the model trained with thalamus, cortical gray matter, hippocampus, and lesions volumes achieved an area under the receiver operating characteristic curve of 0.74. For the regression task, the model trained with cortical gray matter and thalamus volumes, EDSS, nucleus accumbens, lesions, and putamen volumes, and age reached a mean absolute error of 0.95. In conclusion, our results confirmed that damage to cortical gray matter and relevant deep and archaic gray matter structures, such as the thalamus and hippocampus, is among the most relevant predictors of cognitive performance in MS

COVID-19 outbreak in Italy: an opportunity to evaluate extended interval dosing of ocrelizumab in MS patients

introduction during the COVID-19 pandemic, ocrelizumab (OCR) infusions for MS patients were often re-scheduled because of MS center's disruption and concerns regarding immunosuppression. The aim of the present study was to assess changes in OCR schedule during the first wave of pandemic in italy and to evaluate the effect of delayed infusion on clinical/radiological endpoints.methods data were extracted from the Italian MS register database. standard interval dosing was defined as an infusion interval &lt;= 30 weeks, while extended interval dosing was defined as an infusion interval &gt; 30 weeks at the time of the observation period. clinico-demographics variables were tested as potential predictors for treatment delay. time to first relapse and time to first MRI event were evaluated. Cumulative hazard curves were reported along their 95% confidence intervals. a final sample of one-thousand two patients with MS from 65 centers was included in the analysis: 599 pwMS were selected to evaluate the modification of OCR infusion intervals, while 717 pwRMS were selected to analyze the effect of infusion delay on clinical/MRI activity. results mean interval between two OCR infusions was 28.1 weeks before pandemic compared to 30.8 weeks during the observation period, with a mean delay of 2.74 weeks (p &lt; 0.001). No clinico-demographic factors emerged as predictors of infusion postponement, except for location of MS centers in the north of italy. clinical relapses (4 in SID, 0 in EID) and 17 MRI activity reports (4 in SID, 13 in EID) were recorded during follow-up period. discussion despite the significant extension of OCR infusion interval during the first wave of pandemic in Italy, a very small incidence of clinical/radiological events was observed, thus suggesting durable efficacy of OCR, as well as the absence of rebound after its short-term suspension

Exploring in vivo multiple sclerosis brain microstructural damage through T1w/T2w ratio: a multicentre study

Objectives: To evaluate white matter and grey matter T1-weighted (w)/T2w ratio (T1w/T2w ratio) in healthy controls and patients with multiple sclerosis, and its association with clinical disability. Methods: In this cross-sectional study, 270 healthy controls and 434 patients with multiple sclerosis were retrospectively selected from 7 European sites. T1w/T2w ratio was obtained from brain T2w and T1w scans after intensity calibration using eyes and temporal muscle. Results: In healthy controls, T1w/T2w ratio increased until 50-60 years both in white and grey matter. Compared with healthy controls, T1w/T2w ratio was significantly lower in white matter lesions of all multiple sclerosis phenotypes, and in normal-appearing white matter and cortex of patients with relapsing-remitting and secondary progressive multiple sclerosis (p≤0.026), but it was significantly higher in the striatum and pallidum of patients with relapsing-remitting, secondary progressive and primary progressive multiple sclerosis (p≤0.042). In relapse-onset multiple sclerosis, T1w/T2w ratio was significantly lower in white matter lesions and normal-appearing white matter already at Expanded Disability Status Scale (EDSS) <3.0 and in the cortex only for EDSS ≥3.0 (p≤0.023). Conversely, T1w/T2w ratio was significantly higher in the striatum and pallidum for EDSS ≥4.0 (p≤0.005). In primary progressive multiple sclerosis, striatum and pallidum showed significantly higher T1w/T2w ratio beyond EDSS=6.0 (p≤0.001). In multiple sclerosis, longer disease duration, higher EDSS, higher brain lesional volume and lower normalised brain volume were associated with lower lesional and cortical T1w/T2w ratio and a higher T1w/T2w ratio in the striatum and pallidum (β from -1.168 to 0.286, p≤0.040). Conclusions: T1w/T2w ratio may represent a clinically relevant marker sensitive to demyelination, neurodegeneration and iron accumulation occurring at the different multiple sclerosis phases

Association of Gray Matter Atrophy Patterns with Clinical Phenotype and Progression in Multiple Sclerosis

OBJECTIVES: Grey matter (GM) involvement is clinically relevant in multiple sclerosis (MS). Using source-based morphometry (SBM), we characterized GM atrophy and its 1-year evolution across different MS phenotypes. METHODS: Clinical and MRI data were obtained at 8 European sites from 170 healthy controls (HCs) and 398 MS patients (34 clinically isolated syndromes [CIS], 226 relapsing-remitting [RR], 95 secondary progressive [SP] and 43 primary progressive [PP] MS). Fifty-seven HC and 144 MS underwent 1-year follow-up. Baseline GM loss, atrophy progression and correlations with disability and 1-year clinical worsening were assessed. RESULTS: SBM identified 26 cerebellar, subcortical, sensory, motor and cognitive GM components. GM atrophy was found in MS vs HC in almost all components (p=range<0.001-0.04). Compared to HCs, CIS patients showed circumscribed subcortical, cerebellar, temporal and salience GM atrophy, while RRMS patients exhibited widespread GM atrophy. Cerebellar, subcortical, sensorimotor, salience and fronto-parietal GM atrophy was found in PPMS patients vs HCs, and SPMS vs RRMS. At 1-year, 21 (15%) patients had clinically worsened. GM atrophy progressed in MS in subcortical, cerebellar, sensorimotor, and fronto-temporo-parietal components. Baseline higher disability was associated (R2=0.65) with baseline lower normalized brain volume (beta=-0.13, p=0.001), greater sensorimotor GM atrophy (beta=-0.12, p=0.002) and longer disease duration (beta=0.09, p=0.04). Baseline normalized GM volume (odds ratio=0.98, p=0.008) and cerebellar GM atrophy (odds ratio=0.40, p=0.01) independently predicted clinical worsening (area-under-the-curve=0.83). CONCLUSION: GM atrophy differed across disease phenotypes and progressed at 1-year in MS. In addition to global atrophy measures, sensorimotor and cerebellar GM atrophy explained baseline disability and clinical worsening

Relation of sensorimotor and cognitive cerebellum functional connectivity with brain structural damage in patients with multiple sclerosis and no disability

Background and purpose To investigate the relationship between the functional connectivity (FC) of the sensorimotor and cognitive cerebellum and measures of structural damage in patients with multiple sclerosis (MS) and no physical disability. Methods We selected 144 relapsing-remitting MS patients with an Expanded Disability Status Scale score of &lt;= 1.5 and 98 healthy controls from the Italian Neuroimaging Network Initiative database. From multimodal 3T magnetic resonance imaging (MRI), including functional MRI at rest, we calculated lesion load, cortical thickness, and white matter, cortical gray matter, and caudate, putamen, thalamic, and cerebellar volumes. Voxel-wise FC of the sensorimotor and cognitive cerebellum was assessed with seed-based analysis, and multiple regression analysis was used to evaluate the relationship between FC and structural damage. Results Whole brain, white matter, caudate, putamen, and thalamic volumes were reduced in patients compared to controls, whereas cortical gray matter was not significantly different in patients versus controls. Both the sensorimotor and cognitive cerebellum showed a widespread pattern of increased and decreased FC that were negatively associated with structural measures, indicating that the lower the FC, the greater the tissue loss. Lastly, among multiple structural measures, cortical gray matter and white matter volumes were the best predictors of cerebellar FC alterations. Conclusions Increased and decreased cerebellar FC with several brain areas coexist in MS patients with no disability. Our data suggest that white matter loss hampers FC, whereas, in the absence of atrophy, cortical volume represents the framework for FC to increase

Quality of care provided by Multiple Sclerosis Centers during Covid-19 pandemic: Results of an Italian multicenter patient-centered survey

Background: Covid-19 pandemic impacted on management of people with Multiple Sclerosis (pwMS). Level of satisfaction of pwMS regarding the care received by the staff of Multiple Sclerosis Centers (MSCs) during the pandemic was not fully investigated. In a large patient-centered multicenter study, the therapeutic adherence and quality of care of MSCs was assessed. Methods: In April-May 2021, an online survey was widespread by 16 Italian MSCs. Frequencies, percentages and/or means and standard deviations were calculated to describe the sample. ANOVAs were performed to evaluate the effect of sociodemographic and clinical variables on overall pwMS' rating of MSC assistance. Results: 1670 pwMS completed the survey (67.3% women). During the pandemic, 88% did not change their disease modifying therapy schedule, and 89.1% reached their MSCs with no or little difficulties. Even if only 1.3% of participants underwent a tele-health follow-up visit with their MSC staff, the 80.1% believed that tele-health services should be improved regardless of pandemic. 92% of participants were satisfied of how their MSC took charge of their needs; ANOVAs revealed an effect of disease duration on pwMS' level of satisfaction on MSCs management during the pandemic. Conclusions: The results revealed an efficient MSCs response to Covid-19 pandemic and provided the basis for the implementing of tele-health services that would further improve the taking charge of patients, particularly those with longer disease, higher disability, and/or living far from their MSC