Progression is independent of relapse activity in early multiple sclerosis: a real-life cohort study.

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.

Pregnancy in multiple sclerosis women with relapses in the year before conception increases the risk of long-term disability worsening.

BACKGROUND: The influence of pregnancy on long-term disability in multiple sclerosis (MS) is still controversial. OBJECTIVE: To assess the risk of long-term disability worsening after pregnancy in MS women as compared with a propensity-score (PS) matched group of MS women without pregnancy. METHODS: In the setting of the Italian Pregnancy Dataset, MS patients with (pregnancy group (PG)) and without pregnancy (control group (CG)) were recruited. Time to disability worsening on the Expanded Disability Status Scale (EDSS) was assessed through a multivariable Cox regression model. RESULTS: The PS-matching retained 230 PG and 102 CG patients. After a follow-up of 6.5 +/- 3.1 years, disability worsening occurred in 87 (26.2%) women. In the multivariable analysis, disability worsening was associated with pregnancy in women with relapses in the year before conception (adjusted hazard ratio (aHR) = 1.74; 95% confidence interval (CI) 1.06-2.84; p = 0.027), higher EDSS (aHR = 1.39; 95% CI 1.12-1.74; p = 0.003), younger age (aHR = 0.95; 95% CI 0.91-0.99; p = 0.022) and shorter DMD exposure over the follow-up (p < 0.008). CONCLUSION: Pregnancy in MS women with relapses in the year before conception increases the risk of long-term disability worsening. Our findings underscore the importance of counselling in MS women facing a pregnancy that should be planned after a period of clinical stability, favouring treatment optimization in patients with recent disease activity.

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.

Cost-utility analysis of teriflunomide in naïve vs. previously treated patients with relapsing-remitting multiple sclerosis in Italy.

BACKGROUND: Multiple sclerosis (MS) accounts for 176 cases per 100,000 inhabitants (female/male ratio = 2:1) in Italy. For most of the patients (67%), the disease course is relapsing-remitting MS (RRMS). OBJECTIVE: To compare the costs and quality-adjusted life years (QALYs) of teriflunomide in RRMS naïve patients vs. RRMS patients previously treated (experienced) with other disease-modifying therapies in Italy. METHODS: A four health states Markov model-supported cost-utility analysis (CUA) covering a 7-year timespan through annual cycles was developed, following the healthcare sector and the societal viewpoints. Part of the parameters that populated the Markov model was obtained from a questionnaire administered to four primary Italian MS centres. Costs of healthcare and non-healthcare resources, expressed in euro (€) 2019, and QALYs were discounted at 3% real social discount rate. One-way, scenario and probabilistic sensitivity analyses tested the uncertainty of the baseline findings. RESULTS: Baseline CUA shows that teriflunomide in RRMS naïve patients is strongly dominant vs. experienced patients (healthcare sector perspective: - €1042.68 and + 0.480 QALYs; societal perspective: - €6782.81 and + 0.480 QALYs). Sensitivity analyses confirmed the robustness of the baseline results. CONCLUSION: Teriflunomide in RRMS naïve vs. experienced patients is cost-effective and possibly strongly dominant from both the healthcare sector and the society viewpoints in Italy. Our findings need further confirmation from real-world studies.

Defining the course of tumefactive multiple sclerosis: A large retrospective multicentre study.

BACKGROUND AND PURPOSE: Tumefactive multiple sclerosis (TuMS) (i.e., MS onset presenting with tumefactive demyelinating lesions [TDLs]) is a diagnostic and therapeutic challenge. We performed a multicentre retrospective study to describe the clinical characteristics and the prognostic factors of TuMS. METHODS: One hundred two TuMS patients were included in this retrospective study. Demographic, clinical, magnetic resonance imaging (MRI), laboratory data and treatment choices were collected. RESULTS: TuMS was found to affect women more than men (female:male: 2.4), with a young adulthood onset (median age: 29.5 years, range: 11-68 years, interquartile range [IQR]: 38 years). At onset, 52% of TuMS patients presented with the involvement of more than one functional system and 24.5% of them with multiple TDLs. TDLs most frequently presented with an infiltrative MRI pattern (38.7%). Cerebrospinal fluid immunoglobulin G oligoclonal bands were often demonstrated (76.6%). In 25.3% of the cases, more than one acute-phase treatment was administered, and almost one-half of the patients (46.6%) were treated with high-efficacy treatments. After a median follow-up of 2.3 years (range: 0.1-10.7 years, IQR: 3.4 years), the median Expanded Disability Status Scale (EDSS) score was 1.5 (range: 0-7, IQR: 2). Independent risk factors for reaching an EDSS score ≥3 were a higher age at onset (odds ratio [OR]: 1.08, 95% confidence interval [CI]: 1.03-1.14, p < 0.01), a higher number of TDLs (OR: 1.67, 95% CI: 1.02-2.74, p < 0.05) and the presence of infiltrative TDLs (OR: 3.34, 95% CI: 1.18-9.5, p < 0.001) at baseline. CONCLUSIONS: The management of TuMS might be challenging because of its peculiar characteristics. Large prospective studies could help to define the clinical characteristics and the best treatment algorithms for people with TuMS.

Disease-modifying drugs can reduce disability progression in relapsing multiple sclerosis.

An ever-expanding number of disease-modifying drugs for multiple sclerosis have become available in recent years, after demonstrating efficacy in clinical trials. In the real-world setting, however, disease-modifying drugs are prescribed in patient populations that differ from those included in pivotal studies, where extreme age patients are usually excluded or under-represented. In this multicentre, observational, retrospective Italian cohort study, we evaluated treatment exposure in three cohorts of patients with relapsing-remitting multiple sclerosis defined by age at onset: paediatric-onset (≤18 years), adult-onset (18-49 years) and late-onset multiple sclerosis (≥50 years). We included patients with a relapsing-remitting phenotype, ≥5 years follow-up, ≥3 Expanded Disability Status Scale (EDSS) evaluations and a first neurological evaluation within 3 years from the first demyelinating event. Multivariate Cox regression models (adjusted hazard ratio with 95% confidence intervals) were used to assess the risk of reaching a first 12-month confirmed disability worsening and the risk of reaching a sustained EDSS of 4.0. The effect of disease-modifying drugs was assessed as quartiles of time exposure. We found that disease-modifying drugs reduced the risk of 12-month confirmed disability worsening, with a progressive risk reduction in different quartiles of exposure in paediatric-onset and adult-onset patients [adjusted hazard ratios in non-exposed versus exposed >62% of the follow-up time: 8.0 (3.5-17.9) for paediatric-onset and 6.3 (4.9-8.0) for adult-onset, P < 0.0001] showing a trend in late-onset patients [adjusted hazard ratio = 1.9 (0.9-4.1), P = 0.07]. These results were confirmed for a sustained EDSS score of 4.0. We also found that relapses were a risk factor for 12-month confirmed disability worsening in all three cohorts, and female sex exerted a protective role in the late-onset cohort. This study provides evidence that sustained exposure to disease-modifying drugs decreases the risk of disability accumulation, seemingly in a dose-dependent manner. It confirms that the effectiveness of disease-modifying drugs is lower in late-onset patients, although still detectable.

Natalizumab is associated with early improvement of working ability in relapsing-remitting multiple sclerosis patients: WANT observational study results.

BACKGROUND: The Work Ability in Natalizumab-Treated MS Patients (WANT) study assessed work ability, quality of life, and cognitive processing speed during natalizumab treatment. METHODS: WANT was a 1-year, prospective, multicenter observational study conducted in Italy. Inclusion criteria included relapsing-remitting multiple sclerosis (MS), natalizumab treatment, full-time worker status, and loss of working hours due to MS as measured by the Work Productivity and Activity Impairment Questionnaire for MS (WPAI:MS). The primary endpoint was change in WPAI:MS domain scores after 1 year on natalizumab. Secondary endpoints included change in annualized relapse rate (ARR), Multiple Sclerosis Impact Scale (MSIS-29) score, and Symbol Digit Modalities Test (SDMT) score. RESULTS: At enrollment, the 91 patients had a mean age of 38.3 (standard deviation [SD], 9.0) years and a mean ARR of 1.5 (SD, 0.8). After 1 year, improvements were observed in all WPAI:MS domains, with significant reductions in Absenteeism (-4.2 [SD, 26.0], p = 0.0190) and Work Productivity Loss (-7.2 [SD, 28.6]; p = 0.0456). These changes were accompanied by a low ARR (0.1), and 87.9% of patients were relapse free. Significant improvement was observed in MSIS-29 physical and psychological domains (reductions of 2.8 [SD, 11.6; p = 0.0295] and 6.3 [SD, 15.6; p = 0.0007], respectively) and SDMT score (increase of 2.4 [SD, 7.9; p = 0.0006]). Adverse events were reported in 32 of 104 patients (30.8%). CONCLUSIONS: The reductions in Absenteeism and Work Productivity Loss and the improved physical and psychological functioning reported after 1 year of natalizumab treatment in real-world settings extend our understanding of natalizumab's effects on patient-centric and health economics outcomes.

Occurrence and long-term outcome of tumefactive demyelinating lesions in multiple sclerosis.

Although tumefactive multiple sclerosis is a well recognized variant of multiple sclerosis, prognostic uncertainty still exists about long term prognosis. The aim of this study was to estimate the occurrence and long term outcome of tumefactive demyelinating lesions (TDLs) in a cohort of multiple sclerosis patients. We reviewed brain MRI of 443 patients referred to our MS clinic. All patients meeting the McDonald criteria for multiple sclerosis and showing at least one TDL were included. Kaplan-Meier estimates of disease-free survival in patient cohort were compared with control group without TDLs using a log-rank test. Seven cases with TDLs were identified (occurrence 1.58 %). Tumefactive demyelinating lesion recurrence was 16.6 %. Cumulative proportion of patients free from clinical relapse and from new T2 lesions was lower in the control group although not reaching statistical significance (30 vs 50 %; P = 0.666 and 21.7 vs 33.3 %; P = 0.761, respectively). Disability progression analysis showed a not significant trend towards lower probability of remaining progression free for TDL patients (50 vs 61 %; P = 0.295). Occurrence of tumefactive demyelinating lesions in our cohort was higher than those reported in other studies. Overall, TDLs were not predictive of poor outcome in terms of disability progression.

Multiple sclerosis--new treatment modalities.

Ever since the introduction of the first disease modifying therapies, the concept of multiple sclerosis treatment algorithms developed ceaselessly. The increasing number of available drugs is paralleled by impelling issue of ensuring the most appropriate treatment to the right patient at the right time. The purpose of this review is to describe novel agents recently approved for multiple sclerosis treatment, namely teriflunomide, alemtuzumab and dimethylfumarate, focusing on mechanism of action, efficacy data in experimental setting, safety and tolerability. The place in therapy of newer treatment implies careful balancing of risk-benefit profile as well as accurate patient selection. Hence the widening of therapeutic arsenal provides greater opportunity for personalized therapy but also entails a complex trade-off between efficacy, tolerability, safety and eventually patient preference.

Postpartum relapses increase the risk of disability progression in multiple sclerosis: the role of disease modifying drugs.

OBJECTIVE: To assess relapses, disability progression and the role of disease modifying drugs (DMDs) in the year after delivery in women with multiple sclerosis (MS). METHODS: We prospectively followed-up pregnancies occurring between 2002 and 2008 in women with MS, recruited from 21 Italian MS centres. The risk of relapses and disability progression in the year after delivery was assessed using time-dependent Cox regression analysis. RESULTS: 350 out of 423 pregnancies were assessed (pregnancies not resulting in live birth and with a postpartum follow-up period shorter than 1 year were excluded from the analysis). 148 patients (42.3%) had at least one relapse in the year after delivery. An Expanded Disability Status Scale (EDSS) score at conception ≥2.0 (HR=1.4; 95% CI 1.1 to 2.0; p=0.046) and a higher number of relapses before (HR=1.5; 95% CI 1.2 to 1.8; p<0.001) and during pregnancy (HR=2.3; 95% CI 1.6 to 3.4; p<0.001) were related to a higher risk of postpartum relapses. On the contrary, early DMD resumption after delivery marginally reduced the risk of postpartum relapses (HR=0.7, 95% CI 0.4 to 1.0; p=0.079). Moreover, 44/338 women progressed by at least one point on the EDSS. Disability progression was associated with a higher number of relapses before (HR=1.4, 95% CI 1.1 to 1.9; p=0.047) and after delivery (HR=2.7, 95% CI 1.4 to 5.2; p=0.002). CONCLUSIONS: Our findings show an increased risk of postpartum relapses and disability accrual in women with higher disease activity before and during pregnancy. Since it may reduce the risk of postpartum relapses, early DMD resumption should be encouraged, particularly in patients with more active disease.

Paternal therapy with disease modifying drugs in multiple sclerosis and pregnancy outcomes: a prospective observational multicentric study.

BACKGROUND: Most of Multiple Sclerosis (MS) patients undergo disease modifying drug (DMD) therapy at childbearing age. The objective of this prospective, collaborative study, was to assess outcomes of pregnancies fathered by MS patients undergoing DMD. METHODS: Structured interviews on pregnancies fathered by MS patients gathered in the Italian Pregnancy Dataset were collected; pregnancies were divided according to father exposure or unexposure to DMD at time of procreation. Treatment were compared with multivariable logistic and linear models. RESULTS: Seventy-eight pregnancies fathered by MS patients were tracked. Forty-five patients were taking DMD at time of conception (39 beta-interferons, 6 glatiramer acetate), while 33 pregnancies were unexposed to DMD. Seventy-five pregnancies ended in live-births, 44 in the exposed and 31 in the unexposed group. No significant differences between the two groups were found in the risk of spontaneous abortion or malformations (p > 0.454), mean gestational age (p = 0.513), frequency of cesarean delivery (p = 0.644), birth weight (p = 0.821) and birth length (p = 0.649). In comparison with data of the Italian general population, the proportion of spontaneous abortion and caesarean delivery in exposed pregnancies fell within the estimates, while the proportion of pre-term delivery in the exposed group was higher than expected. CONCLUSIONS: Our data indicate no association between paternal DMD exposure at time of conception and risk of spontaneous abortion, adverse fetal outcomes and congenital malformations. Further studies clarifying the role of DMD fathers intake prior and during pregnancy are desirable, to supply guidelines for clinical practice.

Network analysis of negative emotions in patients with episodic migraine: need for a multidisciplinary perspective.

Background: Episodic migraine (EM) is the second most prevalent neurological disorder worldwide and is responsible for more disability than all other neurological disorders combined. Triggers for the development of migraine include, stress, emotional burden, low blood sugar levels, tobacco, skipped meals, anxious and depressive feelings. Migraine affects both children and adults, occurring three times more frequently in women than in men. Objective: The aim of this study was to evaluate the psychological profile of EM patients and the relationship among negative emotions in EM patients, analyzing self-efficacy measures in pain management. Design: We performed an observational study in 60 outpatients aged 18-55 years (mean age 33.8; SD ±10.4) with EM. Methods: All patients have been enrolled at the Headache Center of the San Salvatore Hospital of L'Aquila. The assessment comprised five standardized psychological self-assessments investigating relevant emotional dimensions and pain self-efficacy, along with two questionnaires assessing migraine-related disability. A network analysis of negative emotions was performed to evaluate which emotional traits and relationships play a crucial role in pain coping and management. Results: Our findings indicate that migraine significantly impairs the quality of life of patients in their daily lives. Over half of the patients reported experiencing severe disability, with negative emotions significantly influencing their ability to cope with pain and maintain productivity during migraine attacks. Dysphoric variables (irritability, interpersonal resentment, and surrender) were correlated with difficulties in emotion regulation ability and with the capacity of engaging in goal-directed behaviors despite experiencing pain. The ability to regulate one's emotions and manage dysphoria were positively correlated with pain self-efficacy, whereas positive mental health was associated with individuals' confidence in performing activities despite experiencing pain. Conclusion: Negative emotions had a negative correlation with positive mental health and were linked to a lower capacity to carry out daily activities despite experiencing migraine pain. This suggests that psychological interventions could improve mental health and potentially surpassing the effects of pharmacological interventions alone in migraine management. An integrated, patient-centered approach may represent an effective paradigm to address and reduce the burden of migraine, leading to a reduction in healthcare costs.

Staged magnetic resonance-guided focused ultrasound thalamotomy for the treatment of bilateral essential tremor and Parkinson's disease related tremor: a systematic review and critical appraisal of current knowledge.

Introduction: Essential tremor (ET) and Parkinson's Disease (PD) are debilitating neurodegenerative disorders characterized by tremor as a predominant symptom, significantly impacting patients' quality of life. Magnetic Resonance-guided Focused Ultrasound (MRgFUS) Thalamotomy is an innovative therapeutic option for the treatment of unilateral medically refractory tremor with fewer adverse effects compared to traditional surgical interventions. A recent CE approval allows appropriate patients to have their second side treated. Objective: The objective of this systematic review was to analyze available current knowledge about the use of MRgFUS for the treatment of bilateral ET and PD related tremor, to identify the effectiveness and the risks associated with bilateral treatment. Methods: Eligible studies were identified by searching published studies in PubMed and Scopus databases from May 2014 to January 2024 and by identifying ongoing studies registered on the clinicaltrials.gov website. Data were summarized by considering the following information topics: the number of patients involved, the selected lesion target, the assessment tool used to evaluate clinical changes, the observed improvement, the reported side effects, and the time interval between the two treatments. The study was registered in PROSPERO (ID: CRD42024513178). Results: Nine studies were eligible for this review, 7 for ET and 2 for PD. The involved population included a variable number of patients, ranging from 1 to 11 subjects for ET and from 10 to 15 subjects for PD. The main lesional targets were the ventral intermediate nucleus of the thalamus, the pallidothalamic tract and the cerebellothalamic tract bilaterally. All studies investigated the tremor relief through the Clinical Rating Scale for Tremor (CRST) in patients with ET, and through the Unified Parkinson's Disease Rating Scale (UPDRS) in patients with PD. A variable degree of improvement was observed, with all patients expressing overall satisfaction with the bilateral treatment. Adverse events were mild and transient, primarily involving gait disturbances, dysarthria, and ataxia. A standardized protocol for administering the two consecutive treatments was not identifiable; typically, the timing of the second treatment was delayed by at least 6 months. Conclusion: Available evidence supports the effectiveness and safety of staged bilateral MRgFUS treatments for ET and PD-related tremor.

Intravenous or subcutaneous natalizumab in patients with relapsing-remitting multiple sclerosis: investigation on efficiency and savings-the EASIER study.

INTRODUCTION: EASIER is a multicenter, observational, cross-sectional study investigating the consumption of healthcare resources, including healthcare professional (HCP) active working time, the costs associated with the current natalizumab intravenous (IV) administration, and the potential impact of the adoption of subcutaneous (SC) route. METHODS: The EASIER study has three parts: (1) time and motion study to measure healthcare resources and working time needed for natalizumab IV administration using a digital data collection tool operated directly by HCPs; (2) HCP structured questionnaire-based estimation of the potential impact of natalizumab SC vs. IV administration; and (3) patient survey on the burden of natalizumab administration. RESULTS: Nine Italian multiple sclerosis (MS) centers measured 404 IV natalizumab administration procedures and administered 26 HCP questionnaires and 297 patient questionnaires. Patients had a mean of 52 (range 1-176) previous IV administrations and spent a mean (median, IQR) of 152 (130, 94-184) minutes in the center per each IV procedure, with IV infusion covering 50% of the total. Including patient travel time, an average of 5 h was dedicated to each IV administration. Active working time by HCP amounted to 29 min per IV administration procedure, 70% of which by nursing staff. With adoption of the SC route, HCPs estimated a 50% reduction in patient procedure time and 55% lower HCP active working time. This translated into a 63% cost reduction for the MS center per natalizumab administration procedure. CONCLUSIONS: SC natalizumab administration will consistently reduce consumption of patient and HCP times per procedure and associated costs.

Cognitive safety of focused ultrasound thalamotomy for tremor: 1-year follow-up results of the COGNIFUS part 2 study.

Introduction: In the COGNitive in Focused UltraSound (COGNIFUS) study, we examined the 6-month cognitive outcomes of patients undergoing MRgFUS thalamotomy. This study endorsed the safety profile of the procedure in terms of cognitive functions that cannot be evaluated in real-time during the procedure unlike other aspects. The aim of the COGNIFUS Part 2 study was to investigate the cognitive trajectory of MRgFUS patients over a 1-year period, in order to confirm long-term safety and satisfaction. Methods: We prospectively evaluated the cognitive and neurobehavioral profile of patients with essential tremor (ET) or Parkinson's Disease (PD) related tremor undergoing MRgFUS thalamotomy at 1 year-follow-up following the treatment. Results: The sample consists of 50 patients (male 76%; mean age ± SD 69.0 ± 8.56; mean disease duration ± SD 12.13 ± 12.59; ET 28, PD 22 patients). A significant improvement was detected at the 1 year-follow-up assessment in anxiety and mood feelings (Hamilton Anxiety rating scale 5.66 ± 5.02 vs. 2.69 ± 3.76, p ≤ <0.001; Beck depression Inventory II score 3.74 ± 3.80 vs. 1.80 ± 2.78, p = 0.001), memory domains (Rey Auditory Verbal Learning Test, immediate recall 31.76 ± 7.60 vs. 35.38 ± 7.72, p = 0.001 and delayed recall scores 5.57 ± 2 0.75 vs. 6.41 ± 2.48), frontal functions (Frontal Assessment Battery score 14.24 ± 3.04 vs. 15.16 ± 2.74) and in quality of life (Quality of life in Essential Tremor Questionnaire 35.00 ± 12.08 vs. 9.03 ± 10.64, p ≤ 0.001 and PD Questionnaire -8 7.86 ± 3.10 vs. 3.09 ± 2.29, p ≤ 0.001). Conclusion: Our study supports the long-term efficacy and cognitive safety of MRgFUS treatment for ET and PD.

Effects of fingolimod on focal and diffuse damage in patients with relapsing-remitting multiple sclerosis - The "EVOLUTION" study.

BACKGROUND AND OBJECTIVES: In multiple sclerosis (MS), MRI markers can measure the potential neuroprotective effects of fingolimod beyond its anti-inflammatory activity. In this study we aimed to comprehensively explore, in the real-word setting, whether fingolimod not only reduces clinical/MRI inflammatory activity, but also influences the progression of irreversible focal and whole brain damage in relapsing-remitting [RR] MS patients. METHODS: The "EVOLUTION" study, a 24-month observational, prospective, single-arm, multicenter study, enrolled 261 RRMS patients who started fingolimod at 32 Italian MS centers and underwent biannual neurological assessments and annual MRI evaluations. Study outcomes included the proportions of evaluable RRMS patients achieving at 24 months: (1) no new/enlarging T2-hyperintense white matter (WM) lesions and/or clinical relapses; (2) a modified classification of "No Evidence of Disease Activity 4" ("modified NEDA-4") defined as no new/enlarging T2-hyperintense WM lesions, clinical relapses, and 6-month confirmed disability progression, and a yearly percentage lateral ventricular volume change on T2-FLAIR images < 2%; (3) less than 40% of active lesions at baseline and month 12 evolving to permanent black holes (PBHs). RESULTS: At month 24, 76/160 (47.5%; 95% confidence interval [CI] = 39.8%;55.2%) RRMS patients had no clinical/MRI activity. Thirty-nine of 170 RRMS patients (22.9%; 95% CI = 16.6%;29.3%) achieved "modified NEDA-4" status. Forty-four of 72 RRMS patients (61.1%; 95% CI = 49.8%;72.4%) had less than 40% of active WM lesions evolving to PBHs. The study confirmed the established safety and tolerability profile of fingolimod. DISCUSSION: By comparing our results with those from the literature, the EVOLUTION study seems to indicate a neuroprotective effect of fingolimod, limiting inflammatory activity, brain atrophy and PBH development.

Active and non-active secondary progressive multiple sclerosis patients exhibit similar disability progression: results of an Italian MS registry study (ASPERA).

'Active' and 'non-active' secondary progressive MS (SPMS) have distinct pathophysiological mechanisms and clinical characteristics, but there is still no consensus regarding the frequency of these MS forms in the real-world setting. We aimed to evaluate the frequency of 'active' and 'non-active' SPMS in a large cohort of Italian MS patients and the differences in terms of clinical and MRI characteristics and disease progression. This multicenter study collected data about MS patients who have transitioned to the SP form in the period between 1st January 2014 and 31st December 2019 and followed by the MS centers contributing to the Italian MS Registry. Patients were divided into 'active SPMS' and 'non-active SPMS', based on both reported MRI data and relapse activity in the year before conversion to SPMS. Out of 68,621, 8,316 (12.1%) patients were diagnosed with SPMS. Out of them, 872 (10.5%) were classified into patients with either 'active' or 'non-active' SPMS. A total of 237 were classified into patients with 'active SPMS' (27.2%) and 635 as 'non-active SPMS' (72.8%). 'Non-active SPMS' patients were older, with a longer disease duration compared to those with 'active SPMS'. The percentages of patients showing progression independent of relapse activity (PIRA) at 24 months were similar between 'active' and 'non-active' SPMS patients (67 [27.4%] vs 188 [29.6%]; p = 0.60). In the 'active' group, 36 (15.2%) patients showed relapse-associated worsening (RAW). Comparison of the survival curves to EDSS 6 and 7 according to disease activity did not show significant differences (p = 0.68 and p = 0.71). 'Active' and 'non-active' SPMS patients had a similar risk of achieving disability milestones, suggesting that progression is primarily attributed to PIRA and only to a small extent to disease activity.

Multiple Sclerosis Progression and Relapse Activity in Children.

Importance: Although up to 20% of patients with multiple sclerosis (MS) experience onset before 18 years of age, it has been suggested that people with pediatric-onset MS (POMS) are protected against disability because of greater capacity for repair. Objective: To assess the incidence of and factors associated with progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW) in POMS compared with typical adult-onset MS (AOMS) and late-onset MS (LOMS). Design, Setting, and Participants: This cohort study on prospectively acquired data from the Italian MS Register was performed from June 1, 2000, to September 30, 2021. At the time of data extraction, longitudinal data from 73 564 patients from 120 MS centers were available in the register. Main Outcomes and Measures: The main outcomes included age-related cumulative incidence and adjusted hazard ratios (HRs) for PIRA and RAW and associated factors. Exposures: Clinical and magnetic resonance imaging features, time receiving disease-modifying therapy (DMT), and time to first DMT. Results: After applying the inclusion and exclusion criteria, the study assessed 16 130 patients with MS (median [IQR] age at onset, 28.7 [22.8-36.2 years]; 68.3% female). Compared with AOMS and LOMS, patients with POMS had less disability, exhibited more active disease, and were exposed to DMT for a longer period. A first 48-week-confirmed PIRA occurred in 7176 patients (44.5%): 558 patients with POMS (40.4%), 6258 patients with AOMS (44.3%), and 360 patients with LOMS (56.8%) (P < .001). Factors associated with PIRA were older age at onset (AOMS vs POMS HR, 1.42; 95% CI, 1.30-1.55; LOMS vs POMS HR, 2.98; 95% CI, 2.60-3.41; P < .001), longer disease duration (HR, 1.04; 95% CI, 1.04-1.05; P < .001), and shorter DMT exposure (HR, 0.69; 95% CI, 0.64-0.74; P < .001). The incidence of PIRA was 1.3% at 20 years of age, but it rapidly increased approximately 7 times between 21 and 30 years of age (9.0%) and nearly doubled for each age decade from 40 to 70 years (21.6% at 40 years, 39.0% at 50 years, 61.0% at 60 years, and 78.7% at 70 years). The cumulative incidence of RAW events followed a similar trend from 20 to 60 years (0.5% at 20 years, 3.5% at 30 years, 7.8% at 40 years, 14.4% at 50 years, and 24.1% at 60 years); no further increase was found at 70 years (27.7%). Delayed DMT initiation was associated with higher risk of PIRA (HR, 1.16; 95% CI, 1.00-1.34; P = .04) and RAW (HR, 1.75; 95% CI, 1.28-2.39; P = .001). Conclusions and Relevance: PIRA can occur at any age, and although pediatric onset is not fully protective against progression, this study's findings suggest that patients with pediatric onset are less likely to exhibit PIRA over a decade of follow-up. However, these data also reinforce the benefit for DMT initiation in patients with POMS, as treatment was associated with reduced occurrence of both PIRA and RAW regardless of age at onset.

Long-term effectiveness of natalizumab in secondary progressive multiple sclerosis: A propensity-matched study.

Treatment options for secondary progressive MS (SPMS) are limited, especially considering that the new drugs recently approved are licensed for actively relapsing patients. We aimed to compare the disability progression in a real-world cohort of SPMS patients treated with natalizumab (NTZ) or interferon beta-1b (IFNb-1b). This multicenter retrospective enrolled patients with a diagnosis of SPMS according to 2014 Lublin criteria, who received NTZ or IFNb-1b for at least 48 months between the 1st June 2012 and the 15th May 2018 â€‹at 33 Italian MS centers contributing to the Italian MS Registry NTZ or IFNb-1b. Confirmed Expanded Disability Status Scale worsening (CEW) and progression independent of relapse (PIRA) were evaluated. In order to correct for non-randomization, a propensity score matching of the groups was performed. Out of 5206 MS patients identified at the time of data extraction, 421 SPMS patients treated with NTZ (224 [53.2%] females, mean age 45.3 â€‹± â€‹25.4 years) and 353 with IFNb-1b (133 [37.8%] females, mean age 48.5 â€‹± â€‹19.8 years) were enrolled. After applying the matching procedure, 102 patients were retained in the NTZ group and 98 in the IFNb-2b group. The proportion of patients who reached the 48-month 1-point CEW was significantly higher in IFNb-1b compared to NTZ group (58.2% versus 30.4%, p â€‹= â€‹0.01). The proportion of patients who developed PIRA at 48 months were significantly higher in IFNb-1b compared to NTZ (72.4% versus 40.2%, p â€‹= â€‹0.01). EDSS before treatment initiation and SPMS duration were risk factors for disability progression in terms of PIRA (HR 2.54, 25%CI 1.67-5.7; p â€‹= â€‹0.006 and HR 2.04, 25%CI 1.22-3.35; p â€‹= â€‹0.01, respectively). Patients treated with IFNb-1b were 1.64 times more to likely to develop PIRA (HR 1.64, 25%CI 1.04-4.87; p â€‹= â€‹0.001). Treatment with NTZ in SPMS patients showed more favorable disability outcomes compared to IFNb-1b with beneficial effects over 48 months.

Progression independent of relapse activity in relapsing multiple sclerosis: impact and relationship with secondary progression.

OBJECTIVES: We investigated the occurrence and relative contribution of relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA) to confirmed disability accrual (CDA) and transition to secondary progression (SP) in relapsing multiple sclerosis (MS). METHODS: Relapsing-onset MS patients with follow-up > / = 5 years (16,130) were extracted from the Italian MS Registry. CDA was a 6-month confirmed increase in Expanded Disability Status Scale (EDSS) score. Sustained disability accumulation (SDA) was a CDA with no EDSS improvement in all subsequent visits. Predictors of PIRA and RAW and the association between final EDSS score and type of CDA were assessed using logistic multivariable regression and multivariable ordinal regression models, respectively. RESULTS: Over 11.8 ± 5.4 years, 16,731 CDA events occurred in 8998 (55.8%) patients. PIRA (12,175) accounted for 72.3% of CDA. SDA occurred in 8912 (73.2%) PIRA and 2583 (56.7%) RAW (p < 0.001). 4453 (27.6%) patients transitioned to SPMS, 4010 (73.2%) out of 5476 patients with sustained PIRA and 443 (24.8%) out of 1790 patients with non-sustained PIRA. In the multivariable ordinal regression analysis, higher final EDSS score was associated with PIRA (estimated coefficient 0.349, 95% CI 0.120-0.577, p = 0.003). DISCUSSION: In this real-world relapsing-onset MS cohort, PIRA was the main driver of disability accumulation and was associated with higher disability in the long term. Sustained PIRA was linked to transition to SP and could represent a more accurate PIRA definition and a criterion to mark the putative onset of the progressive phase.