Background: Upper cervical cord atrophy and lesions have been shown to be associated with disease and disability progression already in early relapsing-remitting multiple sclerosis (RRMS). However, their longitudinal relationship remains unclear. Objective: To investigate the cross-sectional and longitudinal relation between focal T2 cervical cord lesion volume (CCLV) and regional and global mean upper cervical cord area (UCCA), and their relations with disability. Methods: Over a two-year interval, subjects with RRMS (n = 36) and healthy controls (HC, n = 16) underwent annual clinical and MRI examinations. UCCA and CCLV were obtained from Cl through C4 level. Linear mixed model analysis was performed to investigate the relation between UCCA, CCLV, and disability over time. Results: UCCA at baseline was significantly lower in RRMS subjects compared to HCs = 0.003), but did not decrease faster over time (p >= 0.144). UCCA and CCLV were independent of each other at any of the time points or cervical levels, and over time. Lower baseline UCCA, but not CCLV, was related to worsening of both upper and lower extremities function over time. Conclusion: UCCA and CCLV are independent from each other, both cross-sectionally and longitudinally, in early MS. Lower UCCA, but not CCLV, was related to increasing disability over time.

Background: Although cognition in multiple sclerosis (MS) is assessed by means of several neuropsychological tests, only a few tools exist to investigate patients' perspectives on cognitive functioning. Objective: To develop a new questionnaire aimed at exploring patients' self-perception with respect to cognition in Italian MS patients. Methods: A total of 120 relapsing-remitting MS (RRMS) patients and 120 matched healthy controls (HC) completed a 25-item questionnaire called the Sclerosi Multipla Autovalutazione Cognitiva (SMAC). The Symbol Digit Modalities Test (SDMT), the Delis-Kaplan Executive Function System Sorting Test (D-KEFS ST), the Beck Depression Inventory (BDI-II), and the Fatigue Scale (FSS) were also administered to the patients. Results: Significantly higher SMAC scores were displayed by RRMS patients compared with HC (30.1 ± 16.9 vs. 23.4 ± 10.4, p = 0.003). SMAC inversely correlated with SDMT (r = −0.31, p < 0.001), D-KEFS ST FSC (r = −0.21, p = 0.017), D-KEFS ST FSD (r = −0.22, p = 0.015) and D-KEFS ST SR (r = −0.19, p = 0.035) and positively correlated with FSS (r = 0.42, p < 0.001) and BDI-II (r = 0.59, p < 0.001). Cronbach's alpha coefficient for the questionnaire was 0.94. Conclusion: Preliminary findings suggest that SMAC is a promising patient-reported outcome to be included in MS neuropsychological evaluation and thus warrants being further tested and developed.

Fat embolism syndrome (FES) is characterized by cerebral, respiratory, and cutaneous manifestations following orthopedic trauma. Cerebral fat embolism (CFE) is a subtype of FES. We report a case of subarachnoidal fat embolism due to a sacral trauma presenting with a migraine attack.

To identify baseline factors associated with disease activity in patients with relapsing–remitting multiple sclerosis (RRMS) under teriflunomide treatment. This was an independent, multi-centre, retrospective post-marketing study. We analysed data of 1,507 patients who started teriflunomide since October 2014 and were regularly followed in 28 Centres in Italy. We reported the proportions of patients who discontinued treatment (after excluding 32 lost to follow-up) and who experienced clinical disease activity, i.e., relapse(s) and/or confirmed disability worsening, as assessed by the Expanded Disability Status Scale (EDSS). Decision tree-based analysis was performed to identify baseline factors associated with clinical disease activity during teriflunomide treatment. At database lock (September 2020), approximately 29% of patients (430 out of 1,475) discontinued teriflunomide because of disease activity (~ 46%), adverse events (~ 37%), poor tolerability (~ 15%), pregnancy planning (~ 2%). Approximately 28% of patients experienced disease activity over a median follow-up of 2.75 years: ~ 9% had relapses but not disability worsening; ~ 13% had isolated disability worsening; ~ 6% had both relapses and disability worsening. The most important baseline factor associated with disease activity (especially disability worsening) was an EDSS > 4.0 (p < 0.001). In patients with moderate disability level (EDSS 2.0–4.0), disease activity occurred more frequently in case of ≥ 1 pre-treatment relapses (p = 0.025). In patients with milder disability level (EDSS < 2.0), disease activity occurred more frequently after previous exposure to ≥ 2 disease-modifying treatments (p = 0.007). Our study suggests a place-in-therapy for teriflunomide in naïve patients with mild disability level or in those who switched their initial treatment for poor tolerability. Adverse events related with teriflunomide were consistent with literature data, without any new safety concern.

No study has investigated red nucleus (RN) atrophy in multiple sclerosis (MS) despite cerebellum and its connections are elective sites of MS-related pathology. In this study, we explore RN atrophy in early MS phases and its association with cerebellar damage (focal lesions and atrophy) and physical disability. Thirty-seven relapse-onset MS (RMS) patients having mean age of 35.6 ± 8.5 (18-56) years and mean disease duration of 1.1 ± 1.5 (0-5) years, and 36 age- and sex-matched healthy controls (HC) were studied. Cerebellar and RN lesions and volumes were analyzed on 3 T-MRI images. RMS did not differ from HC in cerebellar lobe volumes but significantly differed in both right (107.84 ± 13.95 mm3 vs. 99.37 ± 11.53 mm3 , p = .019) and left (109.71 ± 14.94 mm3 vs. 100.47 ± 15.78 mm3 , p = .020) RN volumes. Cerebellar white matter lesion volume (WMLV) inversely correlated with both right and left RN volumes (r = -.333, p = .004 and r = -.298, p = .010, respectively), while no correlation was detected between RN volumes and mean cortical thickness, cerebellar gray matter lesion volume, and supratentorial WMLV (right RN: r = -.147, p = .216; left RN: r = -.153, p = .196). Right, but not left, RN volume inversely correlated with midbrain WMLV (r = -.310, p = .008), while no correlation was observed between whole brainstem WMLV and either RN volumes (right RN: r = -.164, p = .164; left RN: r = -.64, p = .588). Finally, left RN volume correlated with vermis VIIb (r = .297, p = .011) and right interposed nucleus (r = .249, p = .034) volumes. We observed RN atrophy in early RMS, likely resulting from anterograde axonal degeneration starting in cerebellar and midbrain WML. RN atrophy seems a promising marker of neurodegeneration and/or cerebellar damage in RMS.

Background: Apart from IgG oligoclonal bands, no other biomarker has, to date, been validated for diagnostic and/or prognostic purposes in multiple sclerosis (MS). Aim: To investigate a wide panel of cytokines and chemokines in the cerebrospinal fluid (CSF) of relapsing-remitting MS (RRMS) patients and evaluate their association with clinical and magnetic resonance imaging (MRI) parameters, as well as their predictive clinical value. Methods: Fifty-one RRMS at clinical onset and 17 other not inflammatory neurological disorders (ONINDs) underwent brain MRI (including 3D-T1, 3D-FLAIR, and 3-DIR sequences) and CSF examination. Eighty-seven cytokines and chemokines were analyzed in CSF by Multiplex technology. Results: Compared to ONIND, CXCL-10, CXCL-11, CXCL-13, CCL-1, CCL-2, CCL-3, CCL-22, IL-16, and BAFF were significantly (p < 0.05) increased in RRMS CSF. However, only CCL-3 was associated with both MS diagnosis and IgGOB detection. Based on a 95%CI in ONIND (cut-off value: 0.798 pg/ml) and ROC analysis (cut-off value: 0.495 pg/ml), RRMS patients were stratified in CCL-3high (>0.736 pg/mL), CCL-3medium, and CCL-3low (<0.495 pg/ml). Survival analysis disclosed a strong association between high CCL-3 values and disease reactivation (OR = 4.9, 95%CI: 1.8-13.3, p < 0.005) in the following 2 years. Conclusions: CCL-3 deserves further investigation as a candidate prognostic biomarker for RRMS.

Cerebellar dysfunctions have been associated to depressive disorders and cognitive impairment in neurodegenerative diseases. The objective is to analyze the associations between cerebellar atrophy, depression, and fatigue in the early phases of relapse-onset multiple sclerosis (RRMS). Sixty-one RRMS patients and 50 healthy controls (HC) were enrolled and clinically evaluated by means of expanded disability status scale (EDSS), Rao’s brief repeatable battery of neuropsychological tests (BRB-NT), Delis-Kaplan executive function system sorting test, beck depression inventory II (BDI-II), and fatigue severity scale (FSS). The relationships between MRI variables and clinical scores were assessed. Depressed RRMS (dRRMS) had significantly lower Vermis Crus I volume compared with not depressed RRMS (ndRRMS) (p = 0.009). Vermis Crus I volume was lower in dRRMS suffering from fatigue than in ndRRMS without fatigue (p = 0.01). The hierarchical regression models which included demographic and clinical data (age, sex, and disease duration, FSS or BDI-II) and cerebellar volumes disclosed that cerebellar lobule right V atrophy explained an increase of 4% of the variability in FSS (p = 0.25) and Vermis Crus I atrophy explained an increase of 6% of variability in BDI-II (p = 0.049). Since clinical onset, atrophy of specific cerebellar lobules associates with important clinical aspects of RRMS. Cerebellar pathology may be one of the determinants of fatigue and depression that contribute to worsen disability in RRMS.

Background:Cortical lesions (CLs) are typical of multiple sclerosis (MS) and have been recently incorporated in MS diagnostic criteria. Thus, the 'no evidence of disease activity' (NEDA) definition should now include CLs. The aim of this study was to evaluate the NEDA3 + CL status in natalizumab- or fingolimod-treated relapsing remitting MS (RMS) patients. Methods:Natalizumab- or fingolimod-treated RMS patients were enrolled in a 2-year longitudinal study based on clinical and magnetic resonance imaging (MRI) evaluations performed respectively biannually and annually. CLs were detected by double inversion recovery. The NEDA3 + CL condition was evaluated at baseline (T0) and at the end of the first (T1) and second (T2) year. Results:Of the 137 RMS patients included in the study, 86 were propensity-matched. At T2, the annualized relapse rate was lower on natalizumab (p = 0.021), but the effect on white matter lesions (p = 0.29) and the proportion of NEDA-3 patients (p = 0.14) were similar in the two treatment arms. At T2, 11.6% natalizumab- and 62.8% fingolimod-treated patients had new CLs (p < 0.001) and a higher proportion of natalizumab-treated patients (55.8% versus 11.6%, p < 0.001) achieved the NEDA3 + CL status (hazard ratio 5.2, p < 0.001). Conclusion:The incorporation of CLs in the NEDA-3 definition highlighted the higher efficacy of natalizumab versus fingolimod in suppressing disease activity in RMS patients.

Background. The pathological significance and the diagnostic usefulness of intrathecal lc and X free light chain (FLC) synthesis in Multiple Sclerosis (MS) are debated. Methods. Paired cerebrospinal fluid (CSF) and serum specimens from 70 relapsing remitting MS (RAMS), 40 with and 30 without CSF restricted IgG Oligoclonal Band (IgGOB), and 37 from healthy controls (HC) were analyzed. IgG, IgM, kappa FLC and lambda FLC concentrations and indexes were evaluated. All RAMS performed MRI to estimate white and grey matter (WM) pathology. Results. In HC, no intrathecal kappa or lambda FLC synthesis was found, and kappa FLC and lambda FLC Indexes were reciprocally correlated (r = 0.67, p < 0.001). In RAMS, intrathecal kappa FLC or lambda FLC synthesis was demonstrated in respectively 66% and 43% of the cases, the Q(kappa/lambda) ratio was significantly higher compared to HC (17.0 +/- 31.3 vs 0.79 +/- 0.20, p < 0.001) and the correlation between kappa FLC Index and lambda FLC Index was weak (r:0.38, p < 0.05). Intrathecal IgG synthesis was associated with kappa FLC Index (IgG Index: r2 = 0.53, ji = 0.73, p < 0.001; IgG(Loc) : r(2) = 0.37, beta = 0.61, p < 0.001; IgG(IF):r(2) = 0.69, beta = 0.83, p < 0.001), but not with lambda FLC Index, while intrathecal IgM synthesis correlated with XFLC Index (IgM Index: r = 0.41, p < 0.001; IgM(Loc): r = 0.34, p < 0.005; r = 0.45, p < 0.001), but not with kappa FLC Index. 26% of RAMS patients without CSF-restricted IgGOB had increased kappa FLCLoc. Finally, no associations were observed between any CSF and MRI parameters. Conclusions. The demonstration of intrathecal kappa FLC synthesis may further improve the diagnostic usefulness of CSF examination in RAMS. The marked in- creased in Q(kappa/lambda) further suggests a deregulated B-cell activation in MS pathology.

Background: Cortical lesions (CLs) are typical of multiple sclerosis (MS) and have been recently incorporated in MS diagnostic criteria. Thus, the ‘no evidence of disease activity’ (NEDA) definition should now include CLs. The aim of this study was to evaluate the NEDA3 + CL status in natalizumabor fingolimod-treated relapsing remitting MS (RMS) patients. Methods: Natalizumabor fingolimod-treated RMS patients were enrolled in a 2-year longitudinal study based on clinical and magnetic resonance imaging (MRI) evaluations performed respectively biannually and annually. CLs were detected by double inversion recovery. The NEDA3 + CL condition was evaluated at baseline (T0) and at the end of the first (T1) and second (T2) year. Results: Of the 137 RMS patients included in the study, 86 were propensity-matched. At T2, the annualized relapse rate was lower on natalizumab (p = 0.021), but the effect on white matter lesions (p = 0.29) and the proportion of NEDA-3 patients (p = 0.14) were similar in the two treatment arms. At T2, 11.6% natalizumaband 62.8% fingolimod-treated patients had new CLs (p < 0.001) and a higher proportion of natalizumab-treated patients (55.8% versus 11.6%, p < 0.001) achieved the NEDA3 + CL status (hazard ratio 5.2, p < 0.001). Conclusion: The incorporation of CLs in the NEDA-3 definition highlighted the higher efficacy of natalizumab versus fingolimod in suppressing disease activity in RMS patients.