ChatGPT vs. neurologists: a cross-sectional study investigating preference, satisfaction ratings and perceived empathy in responses among people living with multiple sclerosis.

BACKGROUND: ChatGPT is an open-source natural language processing software that replies to users' queries. We conducted a cross-sectional study to assess people living with Multiple Sclerosis' (PwMS) preferences, satisfaction, and empathy toward two alternate responses to four frequently-asked questions, one authored by a group of neurologists, the other by ChatGPT. METHODS: An online form was sent through digital communication platforms. PwMS were blind to the author of each response and were asked to express their preference for each alternate response to the four questions. The overall satisfaction was assessed using a Likert scale (1-5); the Consultation and Relational Empathy scale was employed to assess perceived empathy. RESULTS: We included 1133 PwMS (age, 45.26 ± 11.50 years; females, 68.49%). ChatGPT's responses showed significantly higher empathy scores (Coeff = 1.38; 95% CI = 0.65, 2.11; p > z < 0.01), when compared with neurologists' responses. No association was found between ChatGPT' responses and mean satisfaction (Coeff = 0.03; 95% CI = - 0.01, 0.07; p = 0.157). College graduate, when compared with high school education responder, had significantly lower likelihood to prefer ChatGPT response (IRR = 0.87; 95% CI = 0.79, 0.95; p < 0.01). CONCLUSIONS: ChatGPT-authored responses provided higher empathy than neurologists. Although AI holds potential, physicians should prepare to interact with increasingly digitized patients and guide them on responsible AI use. Future development should consider tailoring AIs' responses to individual characteristics. Within the progressive digitalization of the population, ChatGPT could emerge as a helpful support in healthcare management rather than an alternative.

A Review on the Feasibility and Efficacy of Home-Based Cognitive Remediation in People with Multiple Sclerosis.

Cognitive impairment affects 34-65% of People with Multiple Sclerosis (PwMS), significantly impacting their quality of life. Clinicians routinely address cognitive deficits with in-clinic neuro-behavioural interventions, but accessibility issues exist. Given these challenges, coupled with the lifelong need for continuous assistance in PwMS, researchers have underscored the advantageous role of telerehabilitation in addressing these requirements. Nonetheless, the feasibility and efficacy of home-based cognitive remediation remain to be firmly established. In this narrative review, we aimed to investigate the feasibility and efficacy of digital telerehabilitation for cognition in PwMS. Thirteen relevant studies were identified and carefully assessed. Regarding the feasibility of cognitive telerehabilitation, evidence shows adherence rates are generally good, although, surprisingly, not all studies reported measures of compliance with the cognitive training explored. Considering the efficacy of rehabilitative techniques on cognitive performance in PwMS, findings are generally inconsistent, with only one study reporting uniformly positive results. A range of methodological limitations are reported as potential factors contributing to the variable results. Future research must address these challenges, as more rigorous studies are required to draw definitive conclusions regarding the efficacy of home-based cognitive remediation in PwMS. Researchers must prioritise identifying optimal intervention approaches and exploring the long-term effects of telerehabilitation.

The consequences of the new European reclassification of non-invasive brain stimulation devices and the medical device regulations pose an existential threat to research and treatment: An invited opinion paper.

A significant amount of European basic and clinical neuroscience research includes the use of transcranial magnetic stimulation (TMS) and low intensity transcranial electrical stimulation (tES), mainly transcranial direct current stimulation (tDCS). Two recent changes in the EU regulations, the introduction of the Medical Device Regulation (MDR) (2017/745) and the Annex XVI have caused significant problems and confusions in the brain stimulation field. The negative consequences of the MDR for non-invasive brain stimulation (NIBS) have been largely overlooked and until today, have not been consequently addressed by National Competent Authorities, local ethical committees, politicians and by the scientific communities. In addition, a rushed bureaucratic decision led to seemingly wrong classification of NIBS products without an intended medical purpose into the same risk group III as invasive stimulators. Overregulation is detrimental for any research and for future developments, therefore researchers, clinicians, industry, patient representatives and an ethicist were invited to contribute to this document with the aim of starting a constructive dialogue and enacting positive changes in the regulatory environment.

Managing multiple sclerosis in individuals aged 55 and above: a comprehensive review.

Multiple Sclerosis (MS) management in individuals aged 55 and above presents unique challenges due to the complex interaction between aging, comorbidities, immunosenescence, and MS pathophysiology. This comprehensive review explores the evolving landscape of MS in older adults, including the increased incidence and prevalence of MS in this age group, the shift in disease phenotypes from relapsing-remitting to progressive forms, and the presence of multimorbidity and polypharmacy. We aim to provide an updated review of the available evidence of disease-modifying treatments (DMTs) in older patients, including the efficacy and safety of existing therapies, emerging treatments such as Bruton tyrosine kinase (BTKs) inhibitors and those targeting remyelination and neuroprotection, and the critical decisions surrounding the initiation, de-escalation, and discontinuation of DMTs. Non-pharmacologic approaches, including physical therapy, neuromodulation therapies, cognitive rehabilitation, and psychotherapy, are also examined for their role in holistic care. The importance of MS Care Units and advance care planning are explored as a cornerstone in providing patient-centric care, ensuring alignment with patient preferences in the disease trajectory. Finally, the review emphasizes the need for personalized management and continuous monitoring of MS patients, alongside advocating for inclusive study designs in clinical research to improve the management of this growing patient demographic.

Optical coherence tomography with voxel-based morphometry: a new tool to unveil focal retinal neurodegeneration in multiple sclerosis.

Neurodegeneration is the main contributor to disability accumulation in multiple sclerosis. Previous studies in neuro-ophthalmology have revealed that neurodegeneration in multiple sclerosis also affects the neuro-retina. Optical coherence tomography has been used to measure thinning of retinal layers, which correlates with several other markers for axonal/neuronal loss in multiple sclerosis. However, the existing analytical tools have limitations in terms of sensitivity and do not provide topographical information. In this study, we aim to evaluate whether voxel-based morphometry can increase sensitivity in detecting neuroaxonal degeneration in the retina and offer topographical information. A total of 131 people with multiple sclerosis (41 clinically isolated syndrome, 53 relapsing-remitting and 37 progressive multiple sclerosis) and 50 healthy subjects were included. Only eyes with normal global peripapillary retinal nerve fibre layer thickness and no history of optic neuritis were considered. Voxel-based morphometry and voxel-wise statistical comparisons were performed on the following: (i) patients at different disease stages and 2) patients who experienced the first demyelination attack without subclinical optic neuritis, assessed by visual evoked potentials. Standard parameters failed to discern any differences; however, voxel-based morphometry-optical coherence tomography successfully detected focal macular atrophy of retinal nerve fibre layer and ganglion cell/inner plexiform layer, along with thickening of inner nuclear layer in patients who experienced the first demyelination attack (disease duration = 4.2 months). Notably, the atrophy pattern of the ganglion cell/inner plexiform layer was comparable across disease phenotypes. In contrast, the retinal nerve fibre layer atrophy spread from the optic nerve head to the fovea as the disease evolved towards the progressive phase. Furthermore, for patients who experienced the first neurological episode, the severity of retinal nerve fibre layer atrophy at entry could predict a second attack. Our results demonstrate that voxel-based morphometry-optical coherence tomography exhibits greater sensitivity than standard parameters in detecting focal retinal atrophy, even at clinical presentation, in eyes with no history of optic neuritis and with normal latency of visual evoked potentials. Thinning of the ganglion cell/inner plexiform layer primarily concentrated in nasal perifovea in all disease phenotypes, indicating selective vulnerability of retinal ganglion cells and their perifoveal axons. Conversely, the degree of retinal nerve fibre layer thinning seems to be related to the clinical course of multiple sclerosis. The findings suggest bidirectional neurodegeneration in the visual pathway. Voxel-based morphometry-optical coherence tomography shows potential as a valuable tool for monitoring neurodegeneration on a patient level and evaluating the efficacy of novel neuroprotective treatments.

A wearable device perspective on the standard definitions of disability progression in multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is a leading cause of disability among young adults, but standard clinical scales may not accurately detect subtle changes in disability occurring between visits. This study aims to explore whether wearable device data provides more granular and objective measures of disability progression in MS. METHODS: Remote Assessment of Disease and Relapse in Central Nervous System Disorders (RADAR-CNS) is a longitudinal multicenter observational study in which 400 MS patients have been recruited since June 2018 and prospectively followed up for 24 months. Monitoring of patients included standard clinical visits with assessment of disability through use of the Expanded Disability Status Scale (EDSS), 6-minute walking test (6MWT) and timed 25-foot walk (T25FW), as well as remote monitoring through the use of a Fitbit. RESULTS: Among the 306 patients who completed the study (mean age, 45.6 years; females 67%), confirmed disability progression defined by the EDSS was observed in 74 patients, who had approximately 1392 fewer daily steps than patients without disability progression. However, the decrease in the number of steps experienced over time by patients with EDSS progression and stable patients was not significantly different. Similar results were obtained with disability progression defined by the 6MWT and the T25FW. CONCLUSION: The use of continuous activity monitoring holds great promise as a sensitive and ecologically valid measure of disability progression in MS.

An Internet- and Kinect-Based Multiple Sclerosis Fitness Intervention Training With Pilates Exercises: Development and Usability Study.

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.

Topical Nerve Growth Factor (NGF) restores electrophysiological alterations in the Ins2Akita mouse model of diabetic retinopathy.

People suffering from diabetes mellitus commonly have to face diabetic retinopathy (DR), an eye disease characterized by early retinal neurodegeneration and microvascular damage, progressively leading to sight loss. The Ins2Akita (Akita) diabetic mouse presents the characteristics of DR and experimental drugs can be tested on this model to check their efficacy before going to the clinic. Topical administration of Nerve Growth Factor (NGF) has been recently demonstrated to prevent DR in the Akita mouse, reverting the thinning of retinal layers and protecting the retinal ganglion cells (RGCs) from death. In this study, we characterize the effects of topical NGF on neuroretina function, quantified with the electroretinogram (ERG). In particular, we show that NGF can ameliorate RGC conduction in the retina of Akita mice, which correlates with a recovery of retinal nerve fiber plus ganglion cell layer (RNFL-GCL) structure. Overall, our preclinical results highlight that topical administration of NGF could be a promising therapeutic approach for DR, being capable of exerting a beneficial impact on retinal functionality.

Mobilizing Patient and Public Involvement in the Development of Real-World Digital Technology Solutions: Tutorial.

Although the value of patient and public involvement and engagement (PPIE) activities in the development of new interventions and tools is well known, little guidance exists on how to perform these activities in a meaningful way. This is particularly true within large research consortia that target multiple objectives, include multiple patient groups, and work across many countries. Without clear guidance, there is a risk that PPIE may not capture patient opinions and needs correctly, thereby reducing the usefulness and effectiveness of new tools. Mobilise-D is an example of a large research consortium that aims to develop new digital outcome measures for real-world walking in 4 patient cohorts. Mobility is an important indicator of physical health. As such, there is potential clinical value in being able to accurately measure a person's mobility in their daily life environment to help researchers and clinicians better track changes and patterns in a person's daily life and activities. To achieve this, there is a need to create new ways of measuring walking. Recent advancements in digital technology help researchers meet this need. However, before any new measure can be used, researchers, health care professionals, and regulators need to know that the digital method is accurate and both accepted by and produces meaningful outcomes for patients and clinicians. Therefore, this paper outlines how PPIE structures were developed in the Mobilise-D consortium, providing details about the steps taken to implement PPIE, the experiences PPIE contributors had within this process, the lessons learned from the experiences, and recommendations for others who may want to do similar work in the future. The work outlined in this paper provided the Mobilise-D consortium with a foundation from which future PPIE tasks can be created and managed with clearly defined collaboration between researchers and patient representatives across Europe. This paper provides guidance on the work required to set up PPIE structures within a large consortium to promote and support the creation of meaningful and efficient PPIE related to the development of digital mobility outcomes.

Automatic Assessment of the 2-Minute Walk Distance for Remote Monitoring of People with Multiple Sclerosis.

The aim of this study was to investigate the feasibility of automatically assessing the 2-Minute Walk Distance (2MWD) for monitoring people with multiple sclerosis (pwMS). For 154 pwMS, MS-related clinical outcomes as well as the 2MWDs as evaluated by clinicians and derived from accelerometer data were collected from a total of 323 periodic clinical visits. Accelerometer data from a wearable device during 100 home-based 2MWD assessments were also acquired. The error in estimating the 2MWD was validated for walk tests performed at hospital, and then the correlation (r) between clinical outcomes and home-based 2MWD assessments was evaluated. Robust performance in estimating the 2MWD from the wearable device was obtained, yielding an error of less than 10% in about two-thirds of clinical visits. Correlation analysis showed that there is a strong association between the actual and the estimated 2MWD obtained either at hospital (r = 0.71) or at home (r = 0.58). Furthermore, the estimated 2MWD exhibits moderate-to-strong correlation with various MS-related clinical outcomes, including disability and fatigue severity scores. Automatic assessment of the 2MWD in pwMS is feasible with the usage of a consumer-friendly wearable device in clinical and non-clinical settings. Wearable devices can also enhance the assessment of MS-related clinical outcomes.

Visual evoked potentials waveform analysis to measure intracortical damage in a preclinical model of multiple sclerosis.

Introduction: Visual evoked potentials (VEPs) are a non-invasive technique routinely used in clinical and preclinical practice. Discussion about inclusion of VEPs in McDonald criteria, used for Multiple Sclerosis (MS) diagnosis, increased the importance of VEP in MS preclinical models. While the interpretation of the N1 peak is recognized, less is known about the first and second positive VEP peaks, P1 and P2, and the implicit time of the different segments. Our hypothesis is that P2 latency delay describes intracortical neurophysiological dysfunction from the visual cortex to the other cortical areas. Methods: In this work, we analyzed VEP traces that were included in our two recently published papers on Experimental Autoimmune Encephalomyelitis (EAE) mouse model. Compared with these previous publications other VEP peaks, P1 and P2, and the implicit time of components P1-N1, N1-P2 and P1-P2, were analyzed in blind. Results: Latencies of P2, P1-P2, P1-N1 and N1-P2 were increased in all EAE mice, including group without N1 latency change delay at early time points. In particular, at 7 dpi the P2 latency delay change was significantly higher compared with N1 latency change delay. Moreover, new analysis of these VEP components under the influence of neurostimulation revealed a decrease in P2 delay in stimulated animals. Discussion: P2 latency delay, P1-P2, P1-N1, and N1-P2 latency changes which reflect intracortical dysfunction, were consistently detected across all EAE groups before N1 change. Results underline the importance of analyzing all VEP components for a complete overview of the neurophysiological visual pathway dysfunction and treatment efficacy.

Autonomic response to walk tests is useful for assessing outcome measures in people with multiple sclerosis.

Objective: The aim of this study was to evaluate the association between changes in the autonomic control of cardiorespiratory system induced by walk tests and outcome measures in people with Multiple Sclerosis (pwMS). Methods: Electrocardiogram (ECG) recordings of 148 people with Relapsing-Remitting MS (RRMS) and 58 with Secondary Progressive MS (SPMS) were acquired using a wearable device before, during, and after walk test performance from a total of 386 periodical clinical visits. A subset of 90 participants repeated a walk test at home. Various MS-related symptoms, including fatigue, disability, and walking capacity were evaluated at each clinical visit, while heart rate variability (HRV) and ECG-derived respiration (EDR) were analyzed to assess autonomic nervous system (ANS) function. Statistical tests were conducted to assess differences in ANS control between pwMS grouped based on the phenotype or the severity of MS-related symptoms. Furthermore, correlation coefficients (r) were calculated to assess the association between the most significant ANS parameters and MS-outcome measures. Results: People with SPMS, compared to RRMS, reached higher mean heart rate (HRM) values during walk test, and larger sympathovagal balance after test performance. Furthermore, pwMS who were able to adjust their HRM and ventilatory values, such as respiratory rate and standard deviation of the ECG-derived respiration, were associated with better clinical outcomes. Correlation analyses showed weak associations between ANS parameters and clinical outcomes when the Multiple Sclerosis phenotype is not taken into account. Blunted autonomic response, in particular HRM reactivity, was related with worse walking capacity, yielding r = 0.36 r = 0.29 (RRMS) and r > 0.5 (SPMS). A positive strong correlation r > 0.7 r > 0.65 between cardiorespiratory parameters derived at hospital and at home was also found. Conclusion: Autonomic function, as measured by HRV, differs according to MS phenotype. Autonomic response to walk tests may be useful for assessing clinical outcomes, mainly in the progressive stage of MS. Participants with larger changes in HRM are able to walk longer distance, while reduced ventilatory function during and after walk test performance is associated with higher fatigue and disability severity scores. Monitoring of disorder severity could also be feasible using ECG-derived cardiac and respiratory parameters recorded with a wearable device at home.

Impact of treatment with dimethyl fumarate on sleep quality in patients with relapsing-remitting multiple sclerosis: A multicentre Italian wearable tracker study.

Background: Sleep disorders are common in patients with multiple sclerosis and have a bidirectional interplay with fatigue and depression. Objective: To evaluate the effect of treatment with oral dimethyl fumarate on the quality of sleep in relapsing-remitting multiple sclerosis. Methods: This was a multicentre observational study with 223 relapsing-remitting multiple sclerosis subjects starting treatment with dimethyl fumarate (n=177) or beta interferon (n=46). All patients underwent subjective (Pittsburgh Sleep Quality Index) and objective (wearable tracker) measurements of quality of sleep. Fatigue, depression, and quality of life were also investigated and physical activity was monitored. Results: Patients treated with dimethyl fumarate had significant improvement in the quality of sleep as measured with the Pittsburgh Sleep Quality Index (p<0.001). At all-time points, no significant changes in Pittsburgh Sleep Quality Index score were observed in the interferon group. Total and deep sleep measured by wearable tracker decreased at week 12 with both treatments, then remained stable for the total study duration. Depression significantly improved in patients treated with dimethyl fumarate. No significant changes were observed in mobility, fatigue and quality of life. Conclusion: In patients with relapsing-remitting multiple sclerosis, the treatment with dimethyl fumarate was associated with improvements in patient-reported quality of sleep. Further randomised clinical trials are needed to confirm the benefits of long-term treatment with dimethyl fumarate.

Diagnostic value of intereye difference metrics for optic neuritis in aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorders.

BACKGROUND: The novel optic neuritis (ON) diagnostic criteria include intereye differences (IED) of optical coherence tomography (OCT) parameters. IED has proven valuable for ON diagnosis in multiple sclerosis but has not been evaluated in aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorders (AQP4+NMOSD). We evaluated the diagnostic accuracy of intereye absolute (IEAD) and percentage difference (IEPD) in AQP4+NMOSD after unilateral ON >6 months before OCT as compared with healthy controls (HC). METHODS: Twenty-eight AQP4+NMOSD after unilateral ON (NMOSD-ON), 62 HC and 45 AQP4+NMOSD without ON history (NMOSD-NON) were recruited by 13 centres as part of the international Collaborative Retrospective Study on retinal OCT in Neuromyelitis Optica study. Mean thickness of peripapillary retinal nerve fibre layer (pRNFL) and macular ganglion cell and inner plexiform layer (GCIPL) were quantified by Spectralis spectral domain OCT. Threshold values of the ON diagnostic criteria (pRNFL: IEAD 5 µm, IEPD 5%; GCIPL: IEAD: 4 µm, IEPD: 4%) were evaluated using receiver operating characteristics and area under the curve (AUC) metrics. RESULTS: The discriminative power was high for NMOSD-ON versus HC for IEAD (pRNFL: AUC 0.95, specificity 82%, sensitivity 86%; GCIPL: AUC 0.93, specificity 98%, sensitivity 75%) and IEPD (pRNFL: AUC 0.96, specificity 87%, sensitivity 89%; GCIPL: AUC 0.94, specificity 96%, sensitivity 82%). The discriminative power was high/moderate for NMOSD-ON versus NMOSD-NON for IEAD (pRNFL: AUC 0.92, specificity 77%, sensitivity 86%; GCIP: AUC 0.87, specificity 85%, sensitivity 75%) and for IEPD (pRNFL: AUC 0.94, specificity 82%, sensitivity 89%; GCIP: AUC 0.88, specificity 82%, sensitivity 82%). CONCLUSIONS: Results support the validation of the IED metrics as OCT parameters of the novel diagnostic ON criteria in AQP4+NMOSD.

MCT1-dependent energetic failure and neuroinflammation underlie optic nerve degeneration in Wolfram syndrome mice.

Wolfram syndrome 1 (WS1) is a rare genetic disorder caused by mutations in the WFS1 gene leading to a wide spectrum of clinical dysfunctions, among which blindness, diabetes, and neurological deficits are the most prominent. WFS1 encodes for the endoplasmic reticulum (ER) resident transmembrane protein wolframin with multiple functions in ER processes. However, the WFS1-dependent etiopathology in retinal cells is unknown. Herein, we showed that Wfs1 mutant mice developed early retinal electrophysiological impairments followed by marked visual loss. Interestingly, axons and myelin disruption in the optic nerve preceded the degeneration of the retinal ganglion cell bodies in the retina. Transcriptomics at pre-degenerative stage revealed the STAT3-dependent activation of proinflammatory glial markers with reduction of the homeostatic and pro-survival factors glutamine synthetase and BDNF. Furthermore, label-free comparative proteomics identified a significant reduction of the monocarboxylate transport isoform 1 (MCT1) and its partner basigin that are highly enriched on retinal glia and myelin-forming oligodendrocytes in optic nerve together with wolframin. Loss of MCT1 caused a failure in lactate transfer from glial to neuronal cell bodies and axons leading to a chronic hypometabolic state. Thus, this bioenergetic impairment is occurring concurrently both within the axonal regions and cell bodies of the retinal ganglion cells, selectively endangering their survival while impacting less on other retinal cells. This metabolic dysfunction occurs months before the frank RGC degeneration suggesting an extended time-window for intervening with new therapeutic strategies focused on boosting retinal and optic nerve bioenergetics in WS1.

Neural stem cell transplantation in patients with progressive multiple sclerosis: an open-label, phase 1 study.

Innovative pro-regenerative treatment strategies for progressive multiple sclerosis (PMS), combining neuroprotection and immunomodulation, represent an unmet need. Neural precursor cells (NPCs) transplanted in animal models of multiple sclerosis have shown preclinical efficacy by promoting neuroprotection and remyelination by releasing molecules sustaining trophic support and neural plasticity. Here we present the results of STEMS, a prospective, therapeutic exploratory, non-randomized, open-label, single-dose-finding phase 1 clinical trial ( NCT03269071 , EudraCT 2016-002020-86), performed at San Raffaele Hospital in Milan, Italy, evaluating the feasibility, safety and tolerability of intrathecally transplanted human fetal NPCs (hfNPCs) in 12 patients with PMS (with evidence of disease progression, Expanded Disability Status Scale ≥6.5, age 18-55 years, disease duration 2-20 years, without any alternative approved therapy). The safety primary outcome was reached, with no severe adverse reactions related to hfNPCs at 2-year follow-up, clearly demonstrating that hfNPC therapy in PMS is feasible, safe and tolerable. Exploratory secondary analyses showed a lower rate of brain atrophy in patients receiving the highest dosage of hfNPCs and increased cerebrospinal fluid levels of anti-inflammatory and neuroprotective molecules. Although preliminary, these results support the rationale and value of future clinical studies with the highest dose of hfNPCs in a larger cohort of patients.

Specific Patterns of Immune Cell Dynamics May Explain the Early Onset and Prolonged Efficacy of Cladribine Tablets: A MAGNIFY-MS Substudy.

BACKGROUND AND OBJECTIVES: Cladribine tablets cause a reduction in lymphocytes with a predominant effect on B-cell and T-cell counts. The MAGNIFY-MS substudy reports the dynamic changes on multiple peripheral blood mononuclear cell (PBMC) subtypes and immunoglobulin (Ig) levels over 12 months after the first course of cladribine tablets in patients with highly active relapsing multiple sclerosis (MS). METHODS: Immunophenotyping was performed at baseline (predose) and at the end of months 1, 2, 3, 6, and 12 after initiating treatment with cladribine tablets. Assessments included lymphocyte subtype counts of CD19+ B cells, CD4+ and CD8+ T cells, CD16+ natural killer cells, plasmablasts, and Igs. Immune cell subtypes were analyzed by flow cytometry, and serum IgG and IgM were analyzed by nephelometric assay. Absolute cell counts and percentage change from baseline were assessed. RESULTS: The full analysis set included 57 patients. Rapid reductions in median CD19+, CD20+, memory, activated, and naive B-cell counts were detected, reaching nadir by month 2. Thereafter, total CD19+, CD20+, and naive B-cell counts subsequently reconstituted, but memory B cells remained reduced by 93%-87% for the remainder of the study. The decrease in plasmablasts was slower, reaching nadir at month 3. Decrease in T-cell subtypes was also slower and more moderate compared with B-cell subtypes, reaching nadir between months 3 and 6. IgG and IgM levels remained within the normal range over the 12-month study period. DISCUSSION: Cladribine tablets induce a specific pattern of early and sustained PBMC subtype dynamics in the absence of relevant Ig changes: While total B cells were reduced dramatically, T cells were affected significantly less. Naive B cells recovered toward baseline, naive CD4 and CD8 T cells did not, and memory B cells remained reduced. The results help to explain the unique immune depletion and repopulation architecture regarding onset of action and durability of effects of cladribine tablets while largely maintaining immune competence. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03364036. Date registered: December 06, 2017.

Biopsychosocial Response to the COVID-19 Lockdown in People with Major Depressive Disorder and Multiple Sclerosis.

BACKGROUND: Changes in lifestyle, finances and work status during COVID-19 lockdowns may have led to biopsychosocial changes in people with pre-existing vulnerabilities such as Major Depressive Disorders (MDDs) and Multiple Sclerosis (MS). METHODS: Data were collected as a part of the RADAR-CNS (Remote Assessment of Disease and Relapse-Central Nervous System) program. We analyzed the following data from long-term participants in a decentralized multinational study: symptoms of depression, heart rate (HR) during the day and night; social activity; sedentary state, steps and physical activity of varying intensity. Linear mixed-effects regression analyses with repeated measures were fitted to assess the changes among three time periods (pre, during and post-lockdown) across the groups, adjusting for depression severity before the pandemic and gender. RESULTS: Participants with MDDs (N = 255) and MS (N = 214) were included in the analyses. Overall, depressive symptoms remained stable across the three periods in both groups. A lower mean HR and HR variation were observed between pre and during lockdown during the day for MDDs and during the night for MS. HR variation during rest periods also decreased between pre- and post-lockdown in both clinical conditions. We observed a reduction in physical activity for MDDs and MS upon the introduction of lockdowns. The group with MDDs exhibited a net increase in social interaction via social network apps over the three periods. CONCLUSIONS: Behavioral responses to the lockdown measured by social activity, physical activity and HR may reflect changes in stress in people with MDDs and MS. Remote technology monitoring might promptly activate an early warning of physical and social alterations in these stressful situations. Future studies must explore how stress does or does not impact depression severity.