Towards a validated definition of the clinical transition to secondary progressive multiple sclerosis: A study from the Italian MS Register.

BACKGROUND: Definitions for reliable identification of transition from relapsing-remitting multiple sclerosis (MS) to secondary progressive (SP)MS in clinical cohorts are not available. OBJECTIVES: To compare diagnostic performances of two different data-driven SPMS definitions. METHODS: Data-driven SPMS definitions based on a version of Lorscheider's algorithm (DDA) and on the EXPAND trial inclusion criteria were compared, using the neurologist's definition (ND) as gold standard, in terms of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), Akaike information criterion (AIC) and area under the curve (AUC). RESULTS: A cohort of 10,240 MS patients with ⩾5 years of follow-up was extracted from the Italian MS Registry; 880 (8.5%) patients were classified as SPMS according to the neurologist definition, 1806 (17.6%) applying the DDA and 1134 (11.0%) with the EXPAND definition. The DDA showed greater discrimination power (AUC: 0.8 vs 0.6) and a higher sensitivity (77.1% vs 38.0%) than the EXPAND definition, with similar specificity (88.0% vs 91.5%). PPV and NPV were higher using the DDA than considering EXPAND definition (37.5% vs 29.5%; 97.6% vs 94.0%). CONCLUSION: Data-driven definitions demonstrated greater ability to capture SP transition than neurologist's definition and the global accuracy of DDA seems to be higher than the EXPAND definition.

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

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. MATERIALS 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. RESULTS: 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. CONCLUSION: NAT treatment maintains its high efficacy for a long time in pediatric MS patients, with no new safety issues.

A real-world study of alemtuzumab in a cohort of Italian patients.

BACKGROUND AND PURPOSE: Real-world data on alemtuzumab are limited and do not provide evidence of its effectiveness after various disease-modifying therapies (DMTs). Our aim was to provide real-world data on the impact of clinical variables and previous DMTs on clinical response to alemtuzumab. METHODS: Sixteen Italian multiple sclerosis centers retrospectively included patients who started alemtuzumab from January 2015 to December 2018, and recorded demographics, previous therapies, washout duration, relapses, Expanded Disability Status Scale (EDSS) score, and magnetic resonance imaging data. Negative binomial regression models were used to assess the effect of factors on annualized relapse (ARR) after alemtuzumab initiation. RESULTS: We studied 322 patients (mean age 36.8 years, median EDSS score 3, median follow-up 1.94 years). Previous treatments were: fingolimod (106), natalizumab (80), first-line oral agents (56), first-line injectables (interferon/glatiramer acetate; 30), and other drugs (15). Thirty-five patients were treatment-naïve. The pre-alemtuzumab ARR was 0.99 and decreased to 0.13 during alemtuzumab treatment (p < 0.001). The number of previous-year relapses was associated with alemtuzumab ARR (adjusted risk ratio [RR] 1.38, p = 0.009). Progression-free survival was 94.5% after 1 year, and 89.2% after 2 years of alemtuzumab treatment. EDSS score improvement occurred in 13.5% after 1 year, and 20.6% after 2 years. Re-baselining patients after 6 months of alemtuzumab treatment, led to no evidence of disease activity status in 71.6% after 1 year and 58.9% after 2 years. CONCLUSIONS: Alemtuzumab decreases ARR independent of previous therapy, including patients with disease activity during natalizumab treatment. Overall, 90% of patients showed no disease progression, and 20% an improvement after 2 years of alemtuzumab.

Switch from sequestering to anti-CD20 depleting treatment: disease activity outcomes during wash-out and in the first 6 months of ocrelizumab therapy.

OBJECTIVES: Switching between treatments is an opportunity for patients with multiple sclerosis (MS) to ameliorate disease control or safety. The aim of this study was to investigate the impact of switching from fingolimod (FTY) or natalizumab (NTZ) to ocrelizumab (OCR) on disease activity. METHODS: We retrospectively enrolled 165 patients treated with OCR from 11 MS centres. We assessed the association of demographic and clinical characteristics on relapse rate (RR) and activity on magnetic resonance imaging (MRI) during wash-out and after 6 months of treatment with OCR through univariable and multivariable negative binomial regression models. RESULTS: We registered a total of 35 relapses during the wash-out period. Previous treatment with FTY, relapses in the previous year, and relapsing-remitting course were associated with higher RR. In the first 6 months of OCR, 12 patients had clinical or MRI disease activity. Higher Expanded Disability Status Scale (EDSS) and higher lymphocyte count at OCR start were associated with a reduced probability of relapse. DISCUSSION AND CONCLUSION: This study confirms that withdrawal from sequestering agents as FTY increases the risk of relapses in the wash-out period. Nevertheless, starting OCR before achieving complete immune reconstitution could limit its effectiveness in the first 6 months probably because trapped lymphocytes escape the CD20-mediated depletion.

Etiological research in pediatric multiple sclerosis: A tool to assess environmental exposures (PEDiatric Italian Genetic and enviRonment ExposurE Questionnaire).

BACKGROUND: The etiology of pediatric-onset multiple sclerosis is unknown although putative genetic and environmental factors appear to be involved. Among children multiple sclerosis onset occurs closer to the susceptibility window thank in adults and the exposure to etiological environmental factors is more informative. An Italian multicentre case-control study (the PEDiatric Italian Genetic and enviRonment ExposurE, PEDIGREE study) was designed to investigate environmental exposures in pediatric-onset multiple sclerosis and their interaction with genetics. OBJECTIVES: To collect evidence on exposures to environmental risk factors in pediatric-onset multiple sclerosis, a questionnaire was developed for the Italian population (PEDIGREE Questionnaire) and is presented. METHODS: PEDIGREE Questionnaire develops from an existing tool used in case-control studies on pediatric-onset multiple sclerosis in US Americans, and was translated, adapted and tested for the contents perceived relevance, acceptability, feasibility and reliability in a population of Italian pediatric subjects and their parents recruited from clinics and general population. RESULTS: PEDIGREE Questionnaire contents were overall deemed relevant by the study population, acceptable for 100% participants and feasible for at least 98%. PEDIGREE Questionnaire degree of reliability ranged 56% to 72%. CONCLUSION: PEDIGREE Questionnaire proves to be an efficient tool to assess environmental exposures in the Italian pediatric population. We encourage the dissemination of population-specific questionnaires and shared methodology to optimize efforts in MS etiological research.

Risk of Persistent Disability in Patients With Pediatric-Onset Multiple Sclerosis.

Importance: Availability of new disease-modifying therapies (DMTs) and changes of therapeutic paradigms have led to a general improvement of multiple sclerosis (MS) prognosis in adults. It is still unclear whether this improvement also involves patients with pediatric-onset MS (POMS), whose early management is more challenging. Objective: To evaluate changes in the prognosis of POMS over time in association with changes in therapeutic and managing standards. Design, Setting, and Participants: Retrospective, multicenter, observational study. Data were extracted and collected in May 2019 from the Italian MS Registry, a digital database including more than 59 000 patients. Inclusion criteria were MS onset before age 18 years, diagnosis before January 2014, and disease duration of at least 3 years. Exclusion criteria were primary progressive MS, Expanded Disability Status Scale (EDSS) score of at least 8 one year after onset, unavailability of diagnosis date, and less than 2 EDSS score evaluations. Eligible patients were 4704 patients with POMS. According to these criteria, we enrolled 3198 patients, excluding 1506. Exposures: We compared time to reach disability milestones by epoch of MS diagnosis (<1993, 1993-1999, 2000-2006, and 2007-2013), adjusting for possible confounders linked to EDSS evaluations and clinical disease activity. We then analyzed the difference among the 4 diagnosis epochs regarding demographic characteristics, clinical disease activity at onset, and DMTs management. Main Outcomes and Measures: Disability milestones were EDSS score 4.0 and 6.0, confirmed in the following clinical evaluation and in the last available visit. Results: We enrolled 3198 patients with POMS (mean age at onset, 15.2 years; 69% female; median time to diagnosis, 3.2 years; annualized relapse rate in first 1 and 3 years, 1.3 and 0.6, respectively), with a mean (SD) follow-up of 21.8 (11.7) years. Median survival times to reach EDSS score of 4.0 and 6.0 were 31.7 and 40.5 years. The cumulative risk of reaching disability milestones gradually decreased over time, both for EDSS score of 4.0 (hazard ratio [HR], 0.70; 95% CI, 0.58-0.83 in 1993-1999; HR, 0.48; 95% CI, 0.38-0.60 in 2000-2006; and HR, 0.44; 95% CI, 0.32-0.59 in 2007-2013) and 6.0 (HR, 0.72; 95% CI, 0.57-0.90; HR, 0.44; 95% CI, 0.33-0.60; and HR, 0.30; 0.20-0.46). In later diagnosis epochs, a greater number of patients with POMS were treated with DMTs, especially high-potency drugs, that were given earlier and for a longer period. Demographic characteristics and clinical disease activity at onset did not change significantly over time. Conclusions and Relevance: In POMS, the risk of persistent disability has been reduced by 50% to 70% in recent diagnosis epochs, probably owing to improvement in therapeutic and managing standards.

MRI activity and extended interval of Natalizumab dosing regimen: a multicentre Italian study.

BACKGROUND: To minimize the risk of Progressive Multifocal Leukoencephalopathy and rebound in JCV-positive multiple sclerosis (MS) patients after 24 natalizumab doses, it has been proposed to extend the administrations interval. The objective is to evaluate the EID efficacy on MRI activity compared with the standard interval dosing (SID). METHODS: Observational, multicentre, retrospective cohort study, starting from the 24th natalizumab infusion to the loss of follow-up or 2 years after baseline. Three hundred and sixteen patients were enrolled. The median dose interval (MDI) following the 24th infusion was 5 weeks, with a bimodal distribution (modes at 4 and 6 weeks). Patients were grouped into 2 categories according to the mean number of weeks between doses: <5 weeks, SID; ≥5 weeks, EID. RESULTS: One hundred and eighty-seven patients were in the SID group (MDI = 4.5 weeks) and 129 in the EID group (MDI 6.1 weeks). The risk to develop active lesions on MRI is similar in SID and EID groups during the 6 and 12 months after the 24th natalizumab infusion, respectively 4.27% (95% CI:0.84-7.70) vs 4.71% (95% CI:0.16-9.25%) [p = 0.89] and 8.50% (95% CI:4.05-12.95) vs 6.55% (95% CI:2.11-11.00%) [p = 0.56]. The EID regimen does not appear to increase the occurrence of MRI activity during follow-up. CONCLUSION: There is no evidence of the reduced efficacy of natalizumab in an EID setting regarding the MRI activity. This observation supports the need for a bigger randomized study to assess the need to change the standard of the natalizumab dosing schedule, to better manage JCV-positive patients.

Cladribine vs other drugs in MS: Merging randomized trial with real-life data.

OBJECTIVE: Cladribine tablets were tested against placebo in randomized controlled trials (RCTs). In this study, the effectiveness of cladribine vs other approved drugs in patients with relapsing-remitting MS (RRMS) was compared by matching RCT to observational data. METHODS: Data from the pivotal trial assessing cladribine tablets vs placebo (CLARITY) were propensity score matched to data from the Italian multicenter database i-MuST. This database included 3,150 patients diagnosed between 2010 and 2018 at 24 Italian MS centers who started a disease-modifying drug. The annualized relapse rate (ARR) over 2 years from treatment start and the 24-week confirmed disability progression were compared between patients treated with cladribine and other approved drugs (interferon, glatiramer acetate, fingolimod, natalizumab, and dimethyl fumarate), with comparisons with placebo as a reference. Treatment effects were estimated by the inverse probability weighting negative binomial regression model for ARR and Cox model for disability progression. The treatment effect has also been evaluated according to baseline disease activity. RESULTS: All weighted baseline characteristics were well balanced between groups. All drugs tested had an effect vs placebo close to that detected in the RCT. Patients treated with cladribine had a significantly lower ARR compared with interferon (relapse ratio [RR] = 0.48; p < 0.001), glatiramer acetate (RR = 0.49; p < 0.001), and dimethyl fumarate (RR = 0.6; p = 0.001); a similar ARR to that with fingolimod (RR = 0.74; p = 0.24); and a significantly higher ARR than natalizumab (RR = 2.13; p = 0.014), confirming results obtained by indirect treatment comparisons from RCTs (network meta-analyses). The relative effect of cladribine tablets 10 mg (cumulative dose 3.5 mg/kg over 2 years) was higher in patients with high disease activity vs all treatments except fingolimod and natalizumab. Effects on disability progression were largely nonsignificant, probably due to lack of power for such analysis. CONCLUSION: In patients with RRMS, cladribine tablets showed lower ARR compared with matched patients who started interferon, glatiramer acetate, or dimethyl fumarate; was similar to fingolimod; and was higher than natalizumab. The beneficial effect of cladribine tablets was generally amplified in the subgroup of patients with high disease activity. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with RRMS, cladribine-treated patients had lower ARR compared with interferon, glatiramer acetate, or dimethyl fumarate; similar ARR compared with fingolimod; and higher ARR compared with natalizumab.

Cell-based assays for the detection of MOG antibodies: a comparative study.

BACKGROUND: The detection of antibodies to myelin oligodendrocyte glycoprotein (MOG) is fundamental for the identification of MOG antibody-associated disorders (MOGAD), and the differential diagnosis of acquired demyelinating syndromes of the CNS, among which multiple sclerosis (MS). We compared the diagnostic performance of four cell-based assays (CBAs) for their detection. METHODS: Consecutive sera from 204 patients with 'possible MOGAD' (55), MS (112), and other neurological disorders (OND, 37) were tested for MOG-IgG with a live-CBA with anti-heavy-and-light chain secondary-antibody (LCBA-IgGH+L), and a live-CBA for IgG1 (LCBA-IgG1). A subgroup of 71 patients was additionally tested with a live-CBA with anti-Fcγ secondary-antibody (LCBA-IgGFcγ), and a commercial fixed-CBA with anti-Fcγ secondary-antibody (FCBA-IgGFcγ). RESULTS: Fifty-seven/204 patients (27.9%) were MOG-IgG-positive. Sensitivity was 89.1% (CI:77.8-95.9) and specificity 93.3% (CI:88.0-96.7) for LCBA-IgGH+L, and 74.6% (CI:61.0-85.3) and 100% (CI:97.6-100) for LCBA-IgG1. Eighteen of 57 (31%) samples showed discrepant results (all negative on LCBA-IgG1); of these, three with 'possible MOGAD' showed high-titer MOG-IgG (≥ 1:640), and positivity for MOG-IgG2, whereas 15/18 had low-titer MOG-IgG (1:160/1:320) and mixed diagnoses (5 'possible MOGAD', 6 MS, 4 OND). In the subgroup analysis, sensitivity was 92.3% (CI:79.1-98.4) and specificity 97.0% (CI:83.8-99.9) for LCBA-IgGFcγ, and 87.2% (CI:72.6-95.7) and 97.0% (CI:83.8-99.9) for FCBA-IgGFcγ. CONCLUSIONS: LCBA-IgG1 showed the highest specificity but can miss MOG-IgG2 reactivities, whose meaning warrants further investigations. Titration of samples tested with LCBA-IgGH+L/ IgGFcγ is important for meaningful interpretation of the results. In the subgroup analysis, LCBA-IgGFcγ yielded the highest accuracy, and FCBA-IgGFcγ good specificity, but it was at risk of false-negative results.

First therapy choice in newly diagnosed Multiple Sclerosis patients: A multicenter Italian study.

BACKGROUND: The approval of an increasing number of disease modifying drugs for the treatment of Multiple Sclerosis (MS) creates new challenges for patients and clinicians on the first treatment choice. The main aim of this study was to assess factors impacting first therapy choice in a large Italian MS cohort. METHODS: Newly diagnosed relapsing-remitting (RR) MS patients (2010-2018) followed in 24 Italian MS centres were included in the study. We evaluated the association of baseline demographics, clinical and MRI characteristics to the first treatment choice by logistic regression models applied to pre-defined binary alternatives: dimethyl fumarate vs injectables (interferon and glatiramer acetate), teriflunomide vs injectables, fingolimod vs dimethyl fumarate and fingolimod vs natalizumab. RESULTS: We enrolled 3025 patients in the period between January 2010 and June 2018. Relapses in the previous year (OR = 2.75; p = 0.001), presence of spinal cord lesions (OR = 1.80; p = 0.002) and higher number (>9) of T2 lesions on the baseline brain MRI scan (OR = 1.65; p = 0.022) were the factors associated to dimethyl fumarate choice as first therapy vs an injectable drug. Older age (OR = 1.06; p < 0.001), male sex (OR = 2.29; p = 0.001) and higher EDSS (OR = 1.36; p < 0.001) were the factors associated with the choice of teriflunomide vs injectables. In more recent years, dimethyl fumarate (OR = 3.23; p < 0.001) and teriflunomide (OR = 2.53; p < 0.001) were chosen more frequently than injectables therapies. The main determinant for the choice of fingolimod as compared with dimethyl fumarate was a higher EDSS (OR = 1.56; p = 0.001), while there was a weak association with a longer disease duration (p = 0.068) and a longer time from onset to diagnosis (p = 0.085). Compared to fingolimod, natalizumab was preferred in patients with a younger age (OR = 0.95; p = 0.003) and higher EDSS (OR = 1.45; p = 0.007) and a shorter disease duration (OR = 0.52; p = 0.076). CONCLUSION: Many factors guided therapeutic decision for our Italian cohort of MS patients; they are mainly related to MS disease activity, baseline EDSS, disease duration and age.

Extending the Interval of Natalizumab Dosing: Is Efficacy Preserved?

Extending the natalizumab interval after the 24th administration could reduce the risk of progressive multifocal leukoencephalopathy (PML). The objective is to evaluate the noninferiority of the efficacy of an extended interval dosing (EID) compared with the standard interval dosing (SID) of natalizumab. It is an observational, multicenter (14 Italian centers), retrospective cohort study, starting from the 24th natalizumab infusion to the loss of follow-up or 2 years after baseline. Patients were grouped in 2 categories according to the mean number of weeks between doses: < 5 weeks, SID; ≥ 5 weeks, EID. Three hundred and sixty patients were enrolled. Median dose interval (MDI) following 24th infusion was 4.7 weeks, with a bimodal distribution (modes at 4 and 6 weeks). Two hundred and sixteen patients were in the SID group (MDI = 4.3 weeks) and 144 in the EID group (MDI 6.2 weeks). Annualized relapse rate was 0.060 (95% CI = 0.033-0.087) in the SID group and 0.039 (95% CI = 0.017-0.063) in the EID group. The non-inferiority of EID versus SID was satisfied. In conclusion, there is no evidence of a reduced efficacy of natalizumab in an EID setting. This observation confirms previous results and together with the emerging evidence of a reduced risk of PML associated to an EID, supports the need of a randomized study to assess the need to change the standard of the natalizumab dosing schedule.

Outcomes after fingolimod to alemtuzumab treatment shift in relapsing-remitting MS patients: a multicentre cohort study.

BACKGROUND: A high reactivation of multiple sclerosis (MS) was reported in patients treated with alemtuzumab after fingolimod. We aimed to understand whether this shift enhanced the risk for reactivation in a real-life cohort. METHODS: Subjects with relapsing MS, shifting from fingolimod to alemtuzumab were enrolled. We collected the following data: age, sex, disease duration, relapses after fingolimod withdrawal, new T2/gadolinium (Gd)-enhancing lesions in the last magnetic resonance imaging (MRI) during fingolimod and in the first, while on alemtuzumab, lymphocyte counts at alemtuzumab start, and Expanded Disability Status Scale (EDSS) before and after alemtuzumab. RESULTS: We enrolled 77 patients (women 61 (79%); mean age 36.2 years (SD 9.6), and disease duration 12.3 years (SD 6.8) at fingolimod discontinuation; median washout 1.8 months). The annualised relapse rate was 0.89 during fingolimod, 1.32 during washout, and 0.15 after alemtuzumab (p = 0.001). The EDSS changed from a median of 3 (IQR 2-4) at the end of fingolimod to 2.5 after alemtuzumab (IQR 1.5-4) (p = 0.013). The washout length and the lymphocyte count before alemtuzumab were not associated with EDSS change after alemtuzumab (p = 0.59 and p = 0.33, respectively). MRI activity decreased after alemtuzumab compared to that during fingolimod (p = 0.001). At alemtuzumab start, lymphocyte counts were < 0.8 × 103/mL in 21 patients. CONCLUSIONS: In our cohort, alemtuzumab reduced relapse, new T2/Gd-enhancing lesions, and EDSS score, as compared to the previous periods (fingolimod/washout). These results were not related to washout length or lymphocyte counts. Therefore, a rapid initiation of alemtuzumab after fingolimod does not seem to be a risk factor for MS reactivation.

Impact of natural menopause on multiple sclerosis: a multicentre study.

OBJECTIVE: To study the effect of natural menopause on multiple sclerosis clinical course. METHODS: This was an observational, retrospective, multicentre, cohort study. Menopause onset was defined by the final menstrual period (FMP) beyond which no menses occurred for 12 months. We included multiple sclerosis (MS) patients with FMP occurred after 2005 and a recorded follow-up of at least 2 years pre-FMP and post-FMP. We excluded patients with primary progressive course, iatrogenic menopause and with other confounders that could mask menopause onset. We compared relapse-rate and expanded disability status scale (EDSS) scores pre-FMP and post-FMP, searching for possible interactions with age, disease duration, cigarette smoking and nulliparity status. RESULTS: 148 patients were included (mean observation: 3.5 years pre-FMP and post-FMP). Most patients (92%) received disease-modifying therapies, mainly first-lines. After menopause the annualised relapse rate (ARR) significantly decreased (from 0.21±0.31 to 0.13± 0.24; p=0.005), while disability worsened (increase of mean 0.4 vs 0.2 points after menopause; p<0.001). Older age and long-lasting disease were associated with ARR reduction (p=0.013), but not with disability worsening. Cigarette smokers showed a trend to a higher disability accumulation after menopause (p=0.059). CONCLUSION: Natural menopause seems to be a turning point to a more progressive phase of MS. Relapse rate is also reduced after menopause, but this effect could be driven most by ageing and shifting to progressive phase in patients with long-lasting disease. Cigarette smoking could speed up disability progression after menopause.

Different MRI patterns in MS worsening after stopping fingolimod.

Objective: To analyze MRI images in patients with MS who experienced worsening of neurologic status (WNS) after stopping fingolimod (FTY). Methods: In this retrospective study, demographic, clinical, and radiologic data of patients with MS who experienced WNS after stopping FTY were retrospectively collected. We introduced the "δExpanded Disability Status Scale (EDSS)-ratio" to identify patients who, after FTY withdrawal, showed an inflammatory flare-up exceeding the highest lifetime disease activity level. Patients with δEDSS-ratio > 1 were enrolled in the study. Results: Eight patients were identified. The mean (SD) age of the 8 (7 female) patients was 35.3 (4.9) years. The mean FTY treatment duration was 3.1 (0.8) years. The mean FTY discontinuation-WNS interval was 4 (0.9) months. The 4 patients with δEDSS-ratio ≥ 2 developed severe monophasic WNS (EDSS score above 8.5), characterized by clinical features and MRI findings not typical of MS, which we classified as "tumefactive demyelination pattern" (TDL) and "Punctuated pattern" (PL). Conversely, patients whose δEDSS-ratio was between 1 and 2 had clinical features and brain MRI compatible with a more typical, even if aggressive, MS relapse. In patients with TDL and PL, the flare-up of inflammatory activity led to severe tissue damage resulting in T2 but also T1 lesion volume increase at 6-month follow-up. Conclusions: Peculiar MRI features (TDL and PL), different from a typical MS flare-up, might occur in some patients who experienced WNS after stopping FTY. Further studies, also involving immunologic biomarkers, are necessary to investigate TDL or PL pathophysiology.

Long-term follow-up of pediatric MS patients starting treatment with injectable first-line agents: A multicentre, Italian, retrospective, observational study.

BACKGROUND: Few data are available on very long-term follow-up of pediatric multiple sclerosis (MS) patients treated with disease modifying treatments (DMTs). OBJECTIVES: To present a long-term follow-up of a cohort of Pediatric-MS patients starting injectable first-line agents. METHODS: Data regarding treatments, annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS) score, and serious adverse event were collected. Baseline characteristics were tested in multivariate analysis to identify predictors of disease evolution. RESULTS: In total, 97 patients were followed for 12.5 ± 3.3 years. They started therapy at 13.9 ± 2.1 years, 88 with interferons and 9 with copaxone. During the whole follow-up, 82 patients changed therapy, switching to immunosuppressors/second-line treatment in 58% of cases. Compared to pre-treatment phase, the ARR was significantly reduced during the first treatment (from 3.2 ± 2.6 to 0.7 ± 1.5, p < 0.001), and it remained low during the whole follow-up (0.3 ± 0.2, p < 0.001). At last observation, 40% had disability worsening, but EDSS score remained <4 in 89%. One patient died at age of 23 years due to MS. One case of natalizumab-related progressive multifocal encephalopathy (PML) was recorded. Starting therapy before 12 years of age resulted in a better course of disease in multivariate analysis. CONCLUSION: Pediatric-MS patients benefited from interferons/copaxone, but the majority had to switch to more powerful drugs. Starting therapy before 12 years of age could lead to a more favorable outcome.

Determinants of therapy switch in multiple sclerosis treatment-naïve patients: A real-life study.

BACKGROUND: With many options now available, first therapy choice is challenging in multiple sclerosis (MS) and depends mainly on neurologist and patient preferences. OBJECTIVES: To identify prognostic factors for early switch after first therapy choice. METHODS: Newly diagnosed relapsing-remitting MS patients from 24 Italian centers were included. We evaluated the association of baseline demographics, clinical, and magnetic resonance imaging (MRI) data to the switch probability for lack of efficacy or intolerance/safety with a multivariate Cox analysis and estimated switch rates by competing risks models. RESULTS: We enrolled 3025 patients. The overall switch frequency was 48% after 3 years. Switch risk for lack of efficacy was lower with fingolimod (hazard ratio (HR) = 0.50; p = 0.009), natalizumab (HR = 0.13; p < 0.001), dimethyl-fumarate (HR = 0.60; p = 0.037), teriflunomide (HR = 0.21; p = 0.031) as compared to interferons. Younger age (HR = 0.96; p < 0.001), diagnosis delay (HR = 1.23; p = 0.021), higher baseline Expanded Disability Status Scale (HR = 1.17; p = 0.001), and spinal cord lesions (HR = 1.46; p = 0.001) were independently associated with higher inefficacy switch rates. We found lower switch for intolerance/safety with glatiramer acetate (HR = 0.61; p = 0.001), fingolimod (HR = 0.35; p = 0.002), and dimethyl-fumarate (HR = 0.57; p = 0.022) as compared to interferons, while it increased with natalizumab (HR = 1.43; p = 0.022). Comorbidities were associated with intolerance switch (HR = 1.28; p = 0.047). CONCLUSION: Several factors are associated with higher switch risk in patients starting a first-line therapy and could be integrated in the decision-making process of first treatment choice.

Assessing association of comorbidities with treatment choice and persistence in MS: A real-life multicenter study.

OBJECTIVE: To assess whether the presence of concomitant diseases at multiple sclerosis (MS) diagnosis is associated with the choice and the treatment persistence in an Italian MS cohort. METHODS: We included newly diagnosed patients (2010-2016) followed in 20 MS centers and collected demographic and clinical data. We evaluated baseline factors related to the presence of comorbidities and the association between comorbidities and the clinical course of MS and the time to the first treatment switch. RESULTS: The study cohort included 2,076 patients. Data on comorbidities were available for 1,877/2,076 patients (90.4%). A total of 449/1,877 (23.9%) patients had at least 1 comorbidity at MS diagnosis. Age at diagnosis (odds ratio 1.05, 95% confidence interval [CI] 1.04-1.06; p < 0.001) was the only baseline factor independently related to the presence of comorbidities. Comorbidities were not significantly associated with the choice of the first disease-modifying treatment, but were significantly associated with higher risk to switch from the first treatment due to intolerance (hazard ratio 1.42, CI 1.07-1.87; p = 0.014). Association of comorbidities with risk of switching for intolerance was significantly heterogeneous among treatments (interferon ß, glatiramer acetate, natalizumab, or fingolimod; interaction test, p = 0.04). CONCLUSIONS: Comorbidities at diagnosis should be taken into account at the first treatment choice because they are associated with lower persistence on treatment.

Weight gain after subthalamic nucleus deep brain stimulation in Parkinson's disease is influenced by dyskinesias' reduction and electrodes' position.

Parkinson's disease is a common neurodegenerative disease that can be treated with pharmacological or surgical therapy. Subthalamic nucleus (STN) deep brain stimulation is a commonly used surgical option. A reported side effect of STN-DBS is weight gain: the aim of our study was to find those factors that determine weight gain, through one year-long observation of 32 patients that underwent surgery in our centre. During the follow-up, we considered: anthropometric features, hormonal levels, motor outcome, neuropsychological and quality of life outcomes, therapeutic parameters and electrodes position. The majority (84%) of our patients gained weight (6.7 kg in 12 months); more than a half of the cohort became overweight. At 12th month, weight gain showed a correlation with dyskinesias reduction, electrodes voltage and distance on the lateral axis. In the multivariate regression analysis, the determinants of weight gain were dyskinesias reduction and electrodes position. In this study, we identified dyskinesias reduction and distance between the active electrodes and the third ventricle as determining factors of weight gain after STN-DBS implantation in PD patients. The first finding could be linked to a decrease in energy consumption, while the second one could be due to a lower stimulation of the lateral hypothalamic area, known for its important role in metabolism and body weight control. Weight gain is a common finding after STN-DBS implantation, and it should be carefully monitored given the potential harmful consequences of overweight.