Paolo Gallo

Background: Physical activity (PA) has been recommended in multiple sclerosis (MS) to maintain good physical fitness and mental health, reduce the severity of symptoms and risk of relapse, and improve quality of life. Pilates has been suggested as an ideal PA to manage physical, cognitive, and psychological symptoms of MS and a useful method to maintain and improve balance and gait. Objective: This paper presents the protocol for a study that aims to evaluate the efficacy on the physical domain (specifically balance and gait) of a home-based, self-managed PA intervention delivered through the MS-FIT exergame (HELAGLOBE Società a responsabilità limitata). In addition, measures of cognitive performance, quality of life, and well-being will be considered. Methods: This is a 2-arm, multicenter, randomized controlled trial with 3 assessment points (baseline, 12 weeks postintervention, and 6 weeks follow-up). People with MS with mild disability, low risk of falling, preserved cognitive functions, and low anxiety and depression are potential eligible participants. The experimental group (MS-FIT) will self-administer the MS-FIT exergame at home in addition to their leisure-time physical activities. MS-FIT is an internet- and Pilates-based tool that uses the Microsoft Kinect Sensor V2. Participants in the control group will only have access to their leisure-time physical activities. Participants in the MS-FIT group will train at home with MS-FIT for 12 weeks and will be required to perform the exercises for a total of 30 minutes/day for at least 3 days/week. The primary outcome is the Timed Up and Go, a test designed to assess walking. We will also administer additional tests for motor function (visual analog scale 0-10, Timed 25-Foot Walk, Ambulation Index, 2-minute walk test, Twelve Item Multiple Sclerosis Walking Scale, Nine-Hole Peg Test), cognition (Brief International Cognitive Assessment for Multiple Sclerosis), fatigue (Modified Fatigue Impact Scale), quality of life (Multiple Sclerosis Quality of Life-54), well-being (Psychological Well-Being Scales), and PA (International Physical Activity Questionnaire and Minnesota Leisure Time Physical Activity Questionnaire). Acceptance and satisfaction with the intervention received (Client Satisfaction Questionnaire and an adapted version of the Tele-healthcare Satisfaction Questionnaire – Wearable Technology) and subjective impressions of changes in performance (Patients’ Global Impression of Change) will also be assessed. Results: Recruitment for the trial started on March 16, 2022, and the first participant was randomized the same day. Data analysis and results are expected to be published in 2025. Conclusions: Pilates has proven beneficial in several neurological diseases such as MS. With this study, we will provide evidence for the use in clinical practice of a digital tool for self-administered Pilates exercises at home as a complement to rehabilitation and for the continuity of care in MS. Trial Registration: ClinicalTrials.gov NCT04011579; https://tinyurl.com/2p9n4d2t International Registered Report Identifier (IRRID): DERR1-10.2196/58026

Although pediatric-onset multiple sclerosis (POMS) is characterized by a more rapid accumulation of CNS inflammation than adult-onset MS (AOMS), the therapeutic algorithms applied in POMS are usually based on AOMS therapeutic outcomes. To define a high-efficacy treatment (HET)-based strategy to treat POMS, we designed an observational retrospective study aimed at evaluating the efficacy and safety of natalizumab (NTZ) in naïve POMS and AOMS. Starting from 160 patients, we applied a 2:1 (adult:pediatric) matching on propensity scores and obtained 32 patients with NTZ-treated POMS and 64 with AOMS, estimated from a multivariable logistic regression model. All patients were clinically and radiologically followed up every 6 months for a mean period of 46.0 ± 26.9 months. Following re-baseline at month 6, no difference (log-rank test: p = 0.924) in new and enlarging T2 white matter lesions, postcontrast T1 lesions, and relapse rate were observed between POMS and AOMS throughout the study. Progression independent of relapse activity (PIRA) was never observed in POMS, while 9 of 64 patients with AOMS (12.5%) had PIRA events during the follow-up (40.0 ± 25.9 months; log-rank p value 0.0156). JCV seroconversion rate during NTZ infusion did not differ between POMS and AOMS (log-rank test p = 0.3231). Finally, no serious adverse event was observed in both POMS and AOMS. The favorable outcomes observed on clinical, especially in PIRA, and radiologic parameters strongly support the use of NTZ as a first-choice HET in POMS.

BACKGROUND Physical activity (PA) has been recommended in multiple sclerosis (MS) to maintain good physical fitness and mental health, reduce the severity of symptoms and risk of relapse, and improve quality of life. Pilates has been suggested as an ideal PA to manage physical, cognitive, and psychological symptoms of MS and a useful method to maintain and improve balance and gait. OBJECTIVE This paper presents the protocol for a study that aims to evaluate the efficacy on the physical domain (specifically balance and gait) of a home-based, self-managed PA intervention delivered through the MS-FIT exergame (HELAGLOBE Società a responsabilità limitata). In addition, measures of cognitive performance, quality of life, and well-being will be considered. METHODS This is a 2-arm, multicenter, randomized controlled trial with 3 assessment points (baseline, 12 weeks postintervention, and 6 weeks follow-up). People with MS with mild disability, low risk of falling, preserved cognitive functions, and low anxiety and depression are potential eligible participants. The experimental group (MS-FIT) will self-administer the MS-FIT exergame at home in addition to their leisure-time physical activities. MS-FIT is an internet- and Pilates-based tool that uses the Microsoft Kinect Sensor V2. Participants in the control group will only have access to their leisure-time physical activities. Participants in the MS-FIT group will train at home with MS-FIT for 12 weeks and will be required to perform the exercises for a total of 30 minutes/day for at least 3 days/week. The primary outcome is the Timed Up and Go, a test designed to assess walking. We will also administer additional tests for motor function (visual analog scale 0-10, Timed 25-Foot Walk, Ambulation Index, 2-minute walk test, Twelve Item Multiple Sclerosis Walking Scale, Nine-Hole Peg Test), cognition (Brief International Cognitive Assessment for Multiple Sclerosis), fatigue (Modified Fatigue Impact Scale), quality of life (Multiple Sclerosis Quality of Life-54), well-being (Psychological Well-Being Scales), and PA (International Physical Activity Questionnaire and Minnesota Leisure Time Physical Activity Questionnaire). Acceptance and satisfaction with the intervention received (Client Satisfaction Questionnaire and an adapted version of the Tele-healthcare Satisfaction Questionnaire – Wearable Technology) and subjective impressions of changes in performance (Patients’ Global Impression of Change) will also be assessed. RESULTS Recruitment for the trial started on March 16, 2022, and the first participant was randomized the same day. Data analysis and results are expected to be published in 2025. CONCLUSIONS Pilates has proven beneficial in several neurological diseases such as MS. With this study, we will provide evidence for the use in clinical practice of a digital tool for self-administered Pilates exercises at home as a complement to rehabilitation and for the continuity of care in MS. CLINICALTRIAL ClinicalTrials.gov NCT04011579; https://tinyurl.com/2p9n4d2t INTERNATIONAL REGISTERED REPORT DERR1-10.2196/58026

Background: Balance impairments are common in people with multiple sclerosis (MS), with reduced ability to maintain position and delayed responses to postural adjustments. Pilates is a popular alternative method for balance training that may reduce the rapid worsening of symptoms and the increased risk of secondary conditions (eg, depression) that are frequently associated with physical inactivity. Objective: In this paper, we aimed to describe the design, development, and usability testing of MS Fitness Intervention Training (MS-FIT), a Kinect-based tool implementing Pilates exercises customized for MS. Methods: MS-FIT has been developed using a user-centered design approach (design, prototype, user feedback, and analysis) to gain the target user’s perspective. A team composed of 1 physical therapist, 2 game programmers, and 1 game designer developed the first version of MS-FIT that integrated the knowledge and experience of the team with MS literature findings related to Pilates exercises and balance interventions based on exergames. MS-FIT, developed by using the Unity 3D (Unity Technologies) game engine software with Kinect Sensor V2 for Windows, implements exercises for breathing, posture, and balance. Feedback from an Italian panel of experts in MS rehabilitation (neurologists, physiatrists, physical therapists, 1 statistician, and 1 bioengineer) and people with MS was collected to customize the tool for use in MS. The context of MS-FIT is traveling around the world to visit some of the most important cities to learn the aspects of their culture through pictures and stories. At each stay of the travel, the avatar of a Pilates teacher shows the user the exercises to be performed. Overall, 9 people with MS (n=4, 44% women; mean age 42.89, SD 11.97 years; mean disease duration 10.19, SD 9.18 years; Expanded Disability Status Scale score 3.17, SD 0.75) were involved in 3 outpatient user test sessions of 30 minutes; MS-FIT’s usability was assessed through an ad hoc questionnaire (maximum value=5; higher the score, higher the usability) evaluating easiness to use, playability, enjoyment, satisfaction, and acceptance. Results: A user-centered design approach was used to develop an accessible and challenging tool for balance training. All people with MS (9/9, 100%) completed the user test sessions and answered the ad hoc questionnaire. The average score on each item ranged from 3.78 (SD 0.67) to 4.33 (SD 1.00), which indicated a high usability level. The feedback and suggestions provided by 64% (9/14) of people with MS and 36% (5/14) of therapists involved in the user test were implemented to refine the first prototype to release MS-FIT 2.0. Conclusions: The participants reported that MS-FIT was a usable tool. It is a promising system for enhancing the motivation and engagement of people with MS in performing exercise with the aim of improving their physical status.

(i) Background: Cognitive impairment in people with multiple sclerosis (MS) has been studied in relation to certain clinical variables (e.g., motor disability and disease duration) and lifestyle factors such as cognitive reserve (CR). However, only very few studies have considered the interaction of clinical variables and cognitive reserve in preserving the integrity of the neuropsychological profile. In this paper, we hypothesised that a higher level of CR might predict good cognitive efficiency by modulating the clinical outcome of the disease. (ii) Methods: A sample of 100 participants with MS (age range 30–74), was recruited and assessed remotely with a questionnaire to measure CR and a cognitive screening test. Data were analysed through generalized additive models. (iii) Results: We found that the model analysing the interaction between CR and disease duration, and between CR and motor disability, was able to explain a significant percentage of cognitive performance. In particular, higher levels of CR predicted a better cognitive performance despite a long disease duration, unless the motor disability was severe. (iv) Conclusion: This study highlights the crucial role of CR in modulating cognitive efficiency in people with MS.

(1) Background. Cognitive impairment in people with Multiple Sclerosis (MS) has been studied in relation to some clinical variables (e.g., motor disability and disease duration) and lifestyle fac-tors such as Cognitive Reserve (CR). However, only very few studies have considered the interac-tion of clinical variables and cognitive reserve in preserving the integrity of the neuropsychologi-cal profile. In this paper, we hypothesised that a higher level of CR might predict good cognitive efficiency by modulating the clinical outcome of the disease. (2) Methods. A sample of 100 partic-ipants with MS (age range 30-74), was recruited and assessed remotely with a questionnaire to measure CR and a cognitive screening test. Data were analysed through Generalized Additive Models. (3) Results. We found that the model analysing the interaction between CR and disease duration, and between CR and motor disability was able to explain a significant percentage of cognitive performance. In particular, higher levels of CR predicted better cognitive performance despite long disease duration, unless the motor disability was severe. (4) Conclusion. This study highlights the crucial role of CR in modulating cognitive efficiency in people with MS.

Cognitive impairment and sexual dysfunction are common symptoms in persons with Multiple Sclerosis (MS). The present study focuses on the relationship between these two dimensions by means of a specific assessment commonly used in clinical practice with this population. Fifty-five persons with a diagnosis of MS underwent specific cognitive tests and answered clinical questionnaires. Two cognitive tests, one for memory (the Selective Reminding Test), and one for attention (the Symbol Digit Modalities Test), were administered together with two tests for executive functions (the D-KEFS Sorting Test and Stroop Test). Two self-report questionnaires to investigate clinical, psychological and sexual features (the Beck Depression Inventory-II and Self-perception of Cognition in Multiple Sclerosis and Multiple Sclerosis Intimacy and Sexuality Questionnaire-19), were also administered. The main result highlights that sexual difficulties are associated with cognitive deficits, particularly with executive disorders, but not with memory and attention. Furthermore, sexual difficulties are better explained when depression symptoms are also taken into account. This study disentangles the interaction between sexual dysfunction, cognitive impairment and depression in persons with MS by emphasising the role of very high cognitive processing (i.e., executive functioning) in determining human behaviour.

Background and objectives: alemtuzumab is a monoclonal anti-CD52 antibody acting on B and T cells in highly active multiple sclerosis (MS). We analyzed changes in lymphocyte subsets after alemtuzumab administration in relation to disease activity and autoimmune adverse events. Methods: lymphocyte subset counts were assessed longitudinally using linear mixed models. Subset counts at baseline and during follow-up were correlated with relapse rate, adverse events, or magnetic resonance (MRI) activity. Results: we recruited 150 patients followed for a median of 2.7 years (IQR: 1.9–3.7). Total lymphocytes, CD4, CD8, and CD20 significantly decreased in all patients over 2 years (p < 0.001). Previous treatment with fingolimod increased the risk of disease activity and adverse events (p = 0.029). We found a higher probability of disease reactivation in males and in patients with over three active lesions at baseline. Higher EDSS scores at baseline and longer disease duration predicted the switch to other treatments after alemtuzumab. Discussion and conclusions: Our real-world study supports data from clinical trials in which lymphocyte subsets were not useful for predicting disease activity or autoimmune disease during treatment. The early use of an induction therapy such as alemtuzumab in patients with a lower EDSS score and short history of disease could mitigate the risk of treatment failure.

BACKGROUND Balance impairments are common in people with multiple sclerosis (MS), with reduced ability to maintain position and delayed responses to postural adjustments. Pilates is a popular alternative method for balance training that may reduce the rapid worsening of symptoms and the increased risk of secondary conditions (eg, depression) that are frequently associated with physical inactivity. OBJECTIVE In this paper, we aimed to describe the design, development, and usability testing of MS Fitness Intervention Training (MS-FIT), a Kinect-based tool implementing Pilates exercises customized for MS. METHODS MS-FIT has been developed using a user-centered design approach (design, prototype, user feedback, and analysis) to gain the target user’s perspective. A team composed of 1 physical therapist, 2 game programmers, and 1 game designer developed the first version of MS-FIT that integrated the knowledge and experience of the team with MS literature findings related to Pilates exercises and balance interventions based on exergames. MS-FIT, developed by using the Unity 3D (Unity Technologies) game engine software with Kinect Sensor V2 for Windows, implements exercises for breathing, posture, and balance. Feedback from an Italian panel of experts in MS rehabilitation (neurologists, physiatrists, physical therapists, 1 statistician, and 1 bioengineer) and people with MS was collected to customize the tool for use in MS. The context of MS-FIT is traveling around the world to visit some of the most important cities to learn the aspects of their culture through pictures and stories. At each stay of the travel, the avatar of a Pilates teacher shows the user the exercises to be performed. Overall, 9 people with MS (n=4, 44% women; mean age 42.89, SD 11.97 years; mean disease duration 10.19, SD 9.18 years; Expanded Disability Status Scale score 3.17, SD 0.75) were involved in 3 outpatient user test sessions of 30 minutes; MS-FIT’s usability was assessed through an ad hoc questionnaire (maximum value=5; higher the score, higher the usability) evaluating easiness to use, playability, enjoyment, satisfaction, and acceptance. RESULTS A user-centered design approach was used to develop an accessible and challenging tool for balance training. All people with MS (9/9, 100%) completed the user test sessions and answered the ad hoc questionnaire. The average score on each item ranged from 3.78 (SD 0.67) to 4.33 (SD 1.00), which indicated a high usability level. The feedback and suggestions provided by 64% (9/14) of people with MS and 36% (5/14) of therapists involved in the user test were implemented to refine the first prototype to release MS-FIT 2.0. CONCLUSIONS The participants reported that MS-FIT was a usable tool. It is a promising system for enhancing the motivation and engagement of people with MS in performing exercise with the aim of improving their physical status.

Background and Objectives Microglia, the resident immune cell of the brain and retina, is widespread activated in the white and gray matter (GM) in multiple sclerosis (MS). The objective of this study is to evaluate the presence and number of hyperreflecting foci (HRF), considered clusters of activated and proliferating retinal microglia, and their association with clinical and radiologic disease parameters in relapsing-remitting MS (RRMS). Methods At baseline, 80 patients with RRMS underwent optical coherence tomography (OCT) and 3T-MRI (including 3-dimensional T1, fluid-attenuated inversion recovery, and double inversion recovery sequences), closed to their disease onset (6.3 ± 5.1 months). These patients were then clinically and radiologically followed up for a mean of 43 months, evaluating the no evidence of disease activity (NEDA) condition, further divided into clinical (cNEDA) and radiologic (rNEDA). Patients with a clinical history or MRI/OCT findings suggestive of optic neuritis (ON) were excluded from the study. Results Compared with healthy controls, the HRF number was significantly higher in the inner nuclear layer (INL) of patients with RRMS (19.55 ± 5.65 vs 13.84 ± 2.57, p < 0.001) and associated with INL volume (β: 1.21, p < 0.001). GM lesion volume significantly correlated with the INL HRF count (p = 0.008). Survival analysis revealed a significant association between INL HRF and both cNEDA (p = 0.017) and rNEDA (p = 0.002). Discussion We found a strong association between retinal microglial proliferation and cortical pathology in RRMS, a finding suggesting a possible underlying common immunopathologic mechanism. Furthermore, microglial activation at baseline was observed to predict subsequent inflammatory events, indicating that HRF might be a candidate prognostic biomarker worthy of further investigation. Classification of Evidence This study provides Class II evidence that in patients with early RRMS but without ON, the number of HRF on OCT of the retinal inner nuclear layer is associated with cNEDA and rNEDA.