Hematopoietic stem cell transplantation for multiple sclerosis.

Over the past decades, several effective disease-modifying therapies have been approved for the treatment of multiple sclerosis (MS); however, achieving long-term disease remission remains challenging, particularly for patients with aggressive forms of MS. Intense immunosuppression followed by hematopoietic stem cell transplantation (HSCT) has been increasingly explored as a treatment strategy for aggressive MS. To date, more than 1800 MS patients have undergone HSCT worldwide. In this chapter, we provide a brief overview of the HSCT procedure, with a special focus on the unique considerations for transplanting MS patients (such as fertility preservation, prior therapy washout, and posttransplant monitoring). We also discuss the main evidence of efficacy and safety of the procedure in this context, as well as present preliminary data on the impact of HSCT on cerebrospinal fluid findings, magnetic resonance imaging metrics, and novel serum biomarkers of neurodegeneration and demyelination. In addition, we provide recommendations for patient selection from international guidelines.

HSCT for stiff person syndrome and myasthenia gravis.

Recent advances in neuroimmunology have shed light on the pathogenic mechanisms underlying rare neuroimmunologic conditions such as myasthenia gravis (MG) and stiff person syndrome (SPS). Despite the rarity of these conditions, their complex manifestations and potential for irreversible disability necessitate effective therapeutic strategies. This chapter reviews the current understanding of the safety and efficacy of hematopoietic stem cell transplantation (HSCT) in MG and SPS. Several case reports and retrospective studies have demonstrated promising outcomes following HSCT in refractory MG and SPS, with significant clinical improvement and even discontinuation of chronic immunomodulatory therapy in some cases. Furthermore, HSCT may offer insights into the underlying pathophysiologic mechanisms of these conditions, particularly the role of cellular immunity. Although more research is needed to fully understand the impact of HSCT on disease pathology and outcomes, current evidence suggests that HSCT could be a valuable therapeutic option for patients with refractory MG and SPS.

Introduction to HSCT for neurologic diseases.

The use of hematopoietic stem cell transplantation (HSCT) as a treatment option for severe autoimmune diseases originated from animal studies, with promising results in human patients reported through clinical responses seen in individuals who underwent HSCT for other reasons. Currently, over 3800 HSCT procedures have been performed specifically for autoimmune disorders and the procedure has become a standard of care for conditions such as multiple sclerosis and systemic sclerosis. Despite the growing interest among the neurology community in using HSCT to treat refractory autoimmune disorders, several obstacles must still be overcome for the procedure to become widely accepted. These include increasing the safety of the procedure, determining the most effective conditioning regimen, fostering collaboration between neurology and hematology teams, and providing robust phase III study data to demonstrate the superiority of HSCT over standard immunotherapy. This Handbook aims to provide a valuable resource for all those involved in the care of patients undergoing HSCT, and we hope it will contribute to the efforts to find the correct placement of HSCT in the therapeutic strategy of the treatment of autoimmune disorders of the nervous system.

Ongoing randomized clinical trials on HSCT in multiple sclerosis.

Autologous hematopoietic stem cell transplantation (AHSCT) is emerging as a potent treatment for highly active relapsing remitting multiple sclerosis (RRMS), potentially surpassing the efficacy of traditional disease-modifying therapies (DMTs). Phase II and III randomized controlled trials (RCTs) have demonstrated AHSCT's superiority in reducing relapse rates and delaying disability progression compared to standard DMTs. Despite the evolution of treatment guidelines, questions persist regarding patient selection criteria and optimal conditioning regimens. Notably, ongoing clinical trials in the United Kingdom, the United States, Italy, and Norway aim to address these uncertainties by evaluating the safety, efficacy, and long-term outcomes of AHSCT vs. high efficacy DMTs in both DMT-experienced and treatment-naïve patients with active RRMS or aggressive multiple sclerosis (MS). These trials promise to provide valuable insights into the positioning of AHSCT within the treatment landscape of MS.

Lesion phenotyping based on magnetic susceptibility in pediatric multiple sclerosis.

BACKGROUND AND PURPOSE: Pediatric multiple sclerosis (MS) displays different pathological features compared to adult MS, which can be studied in vivo by assessing tissue magnetic susceptibility with 3T-MRI. We aimed to assess different white matter lesions (WMLs) phenotypes in pediatric MS patients using quantitative susceptibility mapping (QSM) and susceptibility mapping weighted imaging (SMWI) over 12 months. METHODS: Eleven pediatric MS patients [female: 63.6%; mean ± standard deviation (SD) age and disease duration: 16.3 ± 2.2 and 2.4 ± 1.5; median (range) Expanded Disability Status Scale (EDSS) 1 (0-2)] underwent 3 Tesla-MRI exams and EDSS assessments at baseline and after 1 year. QSM and SMWI were obtained using 3-dimensional (3D)-segmented echo-planar-imaging with submillimetric spatial resolution. WMLs were classified according to their QSM appearance and SMWI was used to identify QSM hyperintensities ascribable to veins. Total brain volumes at baseline and follow-up were computed using high-resolution 3D T1-weighted images. RESULTS: Mean ± SD paramagnetic rim lesions (PRLs) prevalence was 7.0% ± 9.0. Fifty-four percent (6/11) of patients exhibited at least one PRL, with one patient exhibiting ≥ 4 PRLs. All patients showed QSM-iso-/hypo-intense lesions, which represented a mean ± SD of 65.8% ± 22.7 of total WMLs. QSM-hyperintense WMLs showed a positive correlation with total brain volume reduction at follow-up (r = 0.705; p =  .02). No lesion was classified as different between baseline and follow-up. CONCLUSION: Chronic compartmentalized inflammation seems to occur early in pediatric MS patients with short disease duration. A high prevalence of iso-/hypo-intense lesions was found, which could account for the higher remyelination potential in pediatric MS.

Multiparametric Characterization and Spatial Distribution of Different MS Lesion Phenotypes.

BACKGROUND AND PURPOSE: MS lesions exhibit varying degrees of axonal and myelin damage. A comprehensive description of lesion phenotypes could contribute to an improved radiologic evaluation of smoldering inflammation and remyelination processes. This study aimed to identify in vivo distinct MS lesion types using quantitative susceptibility mapping and susceptibility mapping-weighted imaging and to characterize them through T1-relaxometry, myelin mapping, and diffusion MR imaging. The spatial distribution of lesion phenotypes in relation to ventricular CSF was investigated. MATERIALS AND METHODS: MS lesions of 53 individuals were categorized into iso- or hypointense lesions, hyperintense lesions, and paramagnetic rim lesions, on the basis of their appearance on quantitative susceptibility mapping alone, according to published criteria, and with the additional support of susceptibility mapping-weighted imaging. Susceptibility values, T1-relaxation times, myelin and free water fractions, intracellular volume fraction, and the orientation dispersion index were compared among lesion phenotypes. The distance of the geometric center of each lesion from the ventricular CSF was calculated. RESULTS: Eight hundred ninety-six MS lesions underwent the categorization process using quantitative susceptibility mapping and susceptibility mapping-weighted imaging. The novel use of susceptibility mapping-weighted images, which revealed additional microvasculature details, led us to re-allocate several lesions to different categories, resulting in a 35.6% decrease in the number of paramagnetic rim lesions, a 22.5% decrease in hyperintense lesions, and a 17.2% increase in iso- or hypointense lesions, with respect to the categorization based on quantitative susceptibility mapping only. The outcome of the categorization based on the joint use of quantitative susceptibility mapping and susceptibility mapping-weighted imaging was that 44.4% of lesions were iso- or hypointense lesions, 47.9% were hyperintense lesions, and 7.7% were paramagnetic rim lesions. A worsening gradient was observed from iso- or hypointense lesions to hyperintense lesions to paramagnetic rim lesions in T1-relaxation times, myelin water fraction, free water fraction, and intracellular volume fraction. Paramagnetic rim lesions were located closer to ventricular CSF than iso- or hypointense lesions. The volume of hyperintense lesions was associated with a more severe disease course. CONCLUSIONS: Quantitative susceptibility mapping and susceptibility mapping-weighted imaging allow in vivo classification of MS lesions into different phenotypes, characterized by different levels of axonal and myelin loss and spatial distribution. Hyperintense lesions and paramagnetic rim lesions, which have the most severe microstructural damage, were more often observed in the periventricular WM and were associated with a more severe disease course.

Clinical and radiological correlates of apathy in multiple sclerosis.

BACKGROUND: Although apathy has been associated with fronto-striatal dysfunction in several neurological disorders, its clinical and magnetic resonance imaging (MRI) correlates have been poorly investigated in people with multiple sclerosis (PwMS). OBJECTIVES: To evaluate clinical variables and investigate microstructural integrity of fronto-striatal grey matter (GM) and white matter (WM) structures using diffusion tensor imaging (DTI). METHODS: A total of 123 PwMS (age: 40.25 ± 11.5; female: 60.9%; relapsing-remitting multiple sclerosis: 75.6%) were prospectively enrolled and underwent neurological and neuropsychological evaluation, including Expanded Disability Status Scale (EDSS), Apathy Evaluation Scale (AES-S), Hospital Anxiety and Depression Scale (HADS), Modified Fatigue Impact Scale (MFIS) and brain 3T-MRI volumes of whole brain, frontal/prefrontal cortex (PFC) and subcortical regions were calculated. DTI-derived metrics were evaluated in the same GM regions and in connecting WM tracts. RESULTS: Apathetic PwMS (32.5%) showed lower education levels, higher HADS, MFIS scores and WM lesions volume than nonapathetic PwMS. Significant differences in DTI metrics were found in middle frontal, anterior cingulate and superior frontal PFC subregions and in caudate nuclei. Significant alterations were found in the right cingulum and left striatal-frontorbital tracts. CONCLUSIONS: Apathy in PwMS is associated with higher levels of physical disability, depression, anxiety and fatigue together with lower educational backgrounds. Microstructural damage within frontal cortex, caudate and fronto-striatal WM bundles is a significant pathological substrate of apathy in multiple sclerosis (MS).

An aggressive form of MOGAD treated with aHSCT: A case report.

BACKGROUND: Although myelin-oligodendrocyte-glycoprotein (MOG)-antibody-associated disease (MOGAD) has been considered a more favorable demyelinating central nervous system disorder, recent data evidence that some patients might experience severe relapses and high disability. Actual treatment-options are acquired mostly from anti-aquaporin-4-antibody-positive neuromyelitis optica spectrum disorder and rely on clinical experience. Therefore, treatment of aggressive forms of MOGAD can be challenging. OBJECTIVES AND METHODS: To describe a patient with an aggressive MOGAD treated with autologous hematopoietic stem cell transplantation (aHSCT). RESULTS: A 56-year-old man was diagnosed with MOGAD in 2017 because of right optic-neuritis and anti-MOG-antibody positivity. In the following 2 years, he experienced two optic neuritis with good recovery after high-dose steroid. At the end of 2019, he presented sensory and motor impairment at lower limbs with evidence of several spinal, longitudinally extended, tumefactive inflammatory lesions. Despite sequential treatment with rituximab and tocilizumab alongside high-dose steroid, intravenous immunoglobulins and plasma-exchange, he experienced several clinical relapses and exhibited persistent magnetic resonance activity. He was finally addressed to intense immunosuppression with myeloablative conditioning regimen followed by autologous hematopoietic stem cell transplantation (aHSCT). After 2 years follow-up, he is free from disease-activity. CONCLUSIONS: In a patient affected by aggressive, treatment-refractory MOGAD, aHSCT resulted as safe and was able to suppress disease-activity for over 2 years.

In-vivo characterization of macro- and microstructural injury of the subventricular zone in relapsing-remitting and progressive multiple sclerosis.

Introduction: The subventricular zone (SVZ) represents one of the main adult brain neurogenesis niche. In-vivo imaging of SVZ is very challenging and little is known about MRI correlates of SVZ macro- and micro-structural injury in multiple sclerosis (MS) patients. Methods: The aim of the present study is to evaluate differences in terms of volume and microstructural changes [as assessed with the novel Spherical Mean Technique (SMT) model, evaluating: Neurite Signal fraction (INTRA); Extra-neurite transverse (EXTRATRANS) and mean diffusivity (EXTRAMD)] in SVZ between relapsing-remitting (RR) or progressive (P) MS patients and healthy controls (HC). We are also going to explore whether SVZ microstructural injury correlate with caudate (a nucleus that is in the vicinity of the SVZ) or thalamus (another well-defined grey matter area which is further from SVZ than caudate) volume and clinical disability. Clinical and brain MRI data were prospectively acquired from 20 HC, 101 RRMS, and 50 PMS patients. Structural and diffusion metrics inside the global SVZ, normal appearing (NA-) SVZ, caudate and thalamus were collected. Results: We found a statistically significant difference between groups in terms of NA-SVZ EXTRAMD (PMS>RRMS>HC; p = 0.002), EXTRATRANS (PMS>RRMS>HC; p<0.0001), and INTRA (HC>RRMS>PMS; p = 0.009). Multivariable models showed that NA-SVZ metrics significantly predicted caudate (R 2 = 0.21, p < 0.0001), but not thalamus, atrophy. A statistically significant correlation between EXTRAMD and EXTRATRANS of the NA-SVZ and EDSS (r=0.25, p=0.003 and r=0.24, p = 0.003, respectively) was found. These findings were confirmed in analyses restricted to RRMS, but not to PMS patients. Discussion: In conclusion, the microstructural damage we observed within the NA-SVZ of MS patients - reflecting higher free water content (higher EXTRAMD), cytoarchitecture disruption and astrogliosis (higher EXTRATRANS and lower INTRA) - was more evident in the progressive as compared to the relapsing phases of MS. These abnormalities were significantly associated with a more pronounced caudate atrophy and higher clinical disability scores. Our findings may support the neuroprotective role of SVZ in MS patients.

Positron Emission Tomography with [18 F]-DPA-714 Unveils a Smoldering Component in Most Multiple Sclerosis Lesions which Drives Disease Progression.

OBJECTIVE: To determine the prognostic value of persisting neuroinflammation in multiple sclerosis (MS) lesions, we developed a 18 kDa-translocator-protein-positron emission tomography (PET) -based classification of each lesion according to innate immune cell content and localization. We assessed the respective predictive value of lesion phenotype and diffuse inflammation on atrophy and disability progression over 2 years. METHODS: Thirty-six people with MS (disease duration 9 ± 6 years; 12 with relapsing-remitting, 13 with secondary-progressive, and 11 with primary-progressive) and 19 healthy controls (HCs) underwent a dynamic [18 F]-DPA-714-PET. At baseline and after 2 years, the patients also underwent a magnetic resonance imaging (MRI) and neurological examination. Based on a threshold of significant inflammation defined by a comparison of [18 F]-DPA-714 binding between patients with MS and HCs, white matter lesions were classified as homogeneously active (active center), rim-active (inactive center and active periphery), or nonactive. Longitudinal cortical atrophy was measured using Jacobian integration. RESULTS: Patients with MS had higher innate inflammation in normal-appearing white matter (NAWM) and cortex than HCs (respective standardized effect size = 1.15, 0.89, p = 0.003 and < 0.001). Out of 1,335 non-gadolinium-enhancing lesions, 53% were classified as homogeneously-active (median = 17 per patient with MS), 6% rim-active (median = 1 per patient with MS), and 41% non-active (median = 14 per patient with MS). The number of homogenously-active lesions was the strongest predictor of longitudinal changes, associating with cortical atrophy (ß = 0.49, p = 0.023) and Expanded Disability Status Scale (EDSS) changes (ß = 0.35, p = 0.023) over 2 years. NAWM and cortical binding were not associated to volumetric and clinical changes. INTERPRETATION: The [18 F]-DPA-714-PET revealed that an unexpectedly high proportion of MS lesions have a smoldering component, which predicts atrophy and clinical progression. This suggests that following the acute phase, most lesions develop a chronic inflammatory component, promoting neurodegeneration and clinical progression. ANN NEUROL 2023;94:366-383.

Central vein sign and diffusion MRI differentiate microstructural features within white matter lesions of multiple sclerosis patients with comorbidities.

Introduction: The Central Vein Sign (CVS) has been suggested as a potential biomarker to improve diagnostic specificity in multiple sclerosis (MS). Nevertheless, the impact of comorbidities on CVS performance has been poorly investigated so far. Despite the similar features shared by MS, migraine and Small Vessel Disease (SVD) at T2-weighted conventional MRI sequences, ex-vivo studies demonstrated their heterogeneous histopathological substrates. If in MS, inflammation, primitive demyelination and axonal loss coexist, in SVD demyelination is secondary to ischemic microangiopathy, while the contemporary presence of inflammatory and ischemic processes has been suggested in migraine. The aims of this study were to investigate the impact of comorbidities (risk factors for SVD and migraine) on the global and subregional assessment of the CVS in a large cohort of MS patients and to apply the Spherical Mean Technique (SMT) diffusion model to evaluate whether perivenular and non-perivenular lesions show distinctive microstructural features. Methods: 120 MS patients stratified into 4 Age Groups performed 3T brain MRI. WM lesions were classified in "perivenular" and "non-perivenular" by visual inspection of FLAIR* images; mean values of SMT metrics, indirect estimators of inflammation, demyelination and fiber disruption (EXTRAMD: extraneurite mean diffusivity, EXTRATRANS: extraneurite transverse diffusivity and INTRA: intraneurite signal fraction, respectively) were extracted. Results: Of the 5303 lesions selected for the CVS assessment, 68.7% were perivenular. Significant differences were found between perivenular and non-perivenular lesion volume in the whole brain (p < 0.001) and between perivenular and non-perivenular lesion volume and number in all the four subregions (p < 0.001 for all). The percentage of perivenular lesions decreased from youngest to oldest patients (79.7%-57.7%), with the deep/subcortical WM of oldest patients as the only subregion where the number of non-perivenular was higher than the number of perivenular lesions. Older age and migraine were independent predictors of a higher percentage of non-perivenular lesions (p < 0.001 and p = 0.013 respectively). Whole brain perivenular lesions showed higher inflammation, demyelination and fiber disruption than non perivenular lesions (p = 0.001, p = 0.001 and p = 0.02 for EXTRAMD, EXTRATRANS and INTRA respectively). Similar findings were found in the deep/subcortical WM (p = 0.001 for all). Compared to non-perivenular lesions, (i) perivenular lesions located in periventricular areas showed a more severe fiber disruption (p = 0.001), (ii) perivenular lesions located in juxtacortical and infratentorial regions exhibited a higher degree of inflammation (p = 0.01 and p = 0.05 respectively) and (iii) perivenular lesions located in infratentorial areas showed a higher degree of demyelination (p = 0.04). Discussion: Age and migraine have a relevant impact in reducing the percentage of perivenular lesions, particularly in the deep/subcortical WM. SMT may differentiate perivenular lesions, characterized by higher inflammation, demyelination and fiber disruption, from non perivenular lesions, where these pathological processes seemed to be less pronounced. The development of new non-perivenular lesions, especially in the deep/subcortical WM of older patients, should be considered a "red flag" for a different -other than MS- pathophysiology.

Hematopoietic Stem Cell Transplantation in People With Active Secondary Progressive Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Uncontrolled evidence suggests that autologous hematopoietic stem cell transplantation (AHSCT) can be effective in people with active secondary progressive multiple sclerosis (SPMS). In this study, we compared the effect of AHSCT with that of other anti-inflammatory disease-modifying therapies (DMTs) on long-term disability worsening in active SPMS. METHODS: We collected data from the Italian Bone Marrow Transplantation Study Group and the Italian Multiple Sclerosis Register. Patients were considered eligible if treatment had been started after the diagnosis of SPMS. Disability worsening was assessed by the cumulative proportion of patients with a 6-month confirmed disability progression (CDP) according to the Expanded Disability Status Scale (EDSS) score. Key secondary endpoints were the EDSS time trend after treatment start and the prevalence of disability improvement over time. Time to first CDP was assessed by means of proportional hazard Cox regression models. A linear mixed model with a time × treatment group interaction was used to assess the longitudinal EDSS time trends. Prevalence of improvement was estimated using a modified Kaplan-Meier estimator and compared between groups by bootstrapping the area under the curve. RESULTS: Seventy-nine AHSCT-treated patients and 1975 patients treated with other DMTs (beta interferons, azathioprine, glatiramer-acetate, mitoxantrone, fingolimod, natalizumab, methotrexate, teriflunomide, cyclophosphamide, dimethyl fumarate, and alemtuzumab) were matched to reduce treatment selection bias using propensity score and overlap weighting approaches. Time to first CDP was significantly longer in transplanted patients (hazard ratio [HR] = 0.50; 95% CI = 0.31-0.81; p = 0.005), with 61.7% of transplanted patients free from CPD at 5 years. Accordingly, EDSS time trend over 10 years was higher in patients treated with other DMTs than in AHSCT-treated patients (+0.157 EDSS points per year compared with -0.013 EDSS points per year; interaction p < 0.001). Patients who underwent AHSCT were more likely to experience a sustained disability improvement: 34.7% of patients maintained an improvement (a lower EDSS than baseline) 3 years after transplant vs 4.6% of patients treated by other DMTs (p < 0.001). DISCUSSION: The use of AHSCT in people with active SPMS is associated with a slowing of disability progression and a higher likelihood of disability improvement compared with standard immunotherapy. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that autologous hematopoietic stem cell transplants prolonged the time to CDP compared with other DMTs.

Vaccinations in patients with multiple sclerosis: a real-world, single-center experience.

Vaccines prevent infections in patients with multiple sclerosis (MS). Though recommendations regarding vaccinating patients with MS have been recently published, real-world data regarding vaccines' planning in patients receiving disease-modifying drugs (DMDs) for MS are missing. Our aim was, therefore, to describe vaccination coverage rates, timing-proposal and safety in real-life vaccinating patients with MS undergoing DMDs before the start of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination campaign. Patients followed at our MS-center were referred to individualized immunization-programs customized to Italian recommendations, patients' risks, immunity to exanthematic diseases, ongoing DMDs, or therapy-start urgency. Disease-activity stated the need for an essential immunization-cycle, whose core was composed by four vaccines: meningococcal-B, pneumococcal conjugated, Haemophilus influenzae B, and meningococcal-ACWY vaccines. Vaccines were administered prior to the planned DMD-start when possible, inactivated-vaccines >2 weeks and live-vaccines >4 weeks before treatment-start. Patients received a 6-months clinical-/radiological-follow-up after immunization. One-hundred and ninety-five patients were vaccinated between April 2017 and January 2021. 124/195 (63.6%) started a vaccination-program before therapy-start/-switch and 108/124 (87.1%) effectively completed immunization before new therapy-start without any delay. The time needed for immunization-conclusion reached a median of 27 (confidence interval 22) days in 2020. No increase in clinical-/radiological-activity 3-/6-months after immunization was noted. In conclusion, our study confirmed feasibility and safety of a vaccination-protocol in patients with MS whose duration resulted in a median of 27 days.

What happens after fingolimod discontinuation? A multicentre real-life experience.

OBJECTIVE: To analyse the course of multiple sclerosis (MS) after fingolimod withdrawal in a multicentre cohort. METHODS: Patients who discontinued fingolimod were included. Relapses, Expanded Disability Status Scale (EDSS), and new/gadolinium-enhancing lesions on magnetic resonance imaging (MRI) were assessed during the last year on fingolimod, and in the year after discontinuation. Wilcoxon test was used to analyse the difference in EDSS and relapses between the two periods, and to compare lymphocyte counts at discontinuation and 3 months later. Demographic and clinical variables were evaluated using univariable and multivariable logistic regression analyses. RESULTS: Patients were 230 (females 66.1%; mean age 38 years; median EDSS 3). Fingolimod was discontinued due to inefficacy in 57%, and 87.4% started another treatment. Relapse was observed in 33% of the patients in the year after discontinuation. Severe reactivation was observed in 15%. During the first 6 months after discontinuation, new/enhancing lesions were seen in 62/116 patients. Higher age at the fingolimod discontinuation was found to be associated with a lower probability of inflammatory activity (p = 0.001) and severe reactivation (p = 0.007) during the year after discontinuation. Lower lymphocyte count was a risk factor for clinical, radiological, and severe activity (p = 0.02, p = 0.002, p = 0.01, respectively). CONCLUSIONS: The main reason for the discontinuation of fingolimod was inefficacy. One-third of the patients had a relapse during the year after discontinuation, 15% experienced a severe reactivation, and approximately 50% of patients with available MRI scan had new/enhancing lesions. The risk factors for disease activity after discontinuation were low lymphocyte count and younger age.

Embracing resilience in multiple sclerosis: a new perspective from COVID-19 pandemic.

Coronavirus disease 2019 (COVID-19) resulted in several psychological consequences. Past epidemiological experiences already showed the deep albeit heterogeneous psychological repercussions of pandemics. Nevertheless, little is known about COVID-19 outbreak and the possible strategies for boosting resilience in patients with chronic diseases such as Multiple Sclerosis (MS). Therefore, we designed a study aiming to assess the changes in mental distress during COVID-19 outbreak in patients with MS and to identifyfactors contributing to resilience's development.We enrolled 106 patients (69 relapsing-remitting, 20 secondary-progressive, and 17 primary-progressive) whose neuropsychological assessment before the COVID-19 pandemic (1 January 2019-1 March 2020) was available. It consisted of Brief International Cognitive Assessment for MS (BICAMS), Hospital Anxiety and Depression Scale (HADS) and patient-reported MS Neuropsychological Screening Questionnaire (MSNQ-P). All patients were re-tested during Italian lockdown through an online survey, comprehensive of sociodemographic information, HADS self-rating Scale, MSNQ-P Questionnaire and finally Connor-Davidson Resilience self-rating Scale (CD-RISC 25), in order to evaluate resilience.No significant changes in HADS and MSNQ-P scores were detected during COVID-19 pandemic in our population. Though, pre-existing lower HADS and MSNQ-P scores but not demographic, disease- and treatment-related elements were found significantly (p < 0.0001) and independently associated with a better resilience attitude.

Predictors of Ocrelizumab Effectiveness in Patients with Multiple Sclerosis.

Data regarding effectiveness and safety of ocrelizumab in the post-marking setting are lacking. The aim of our study was to provide effectiveness and safety data of ocrelizumab treatment in patients with relapsing-remitting (RR-) and progressive multiple sclerosis (PMS) and to evaluate clinical and immunological predictors of early treatment response. In this single-center prospective observational study, we investigated effectiveness outcomes (time-to-confirmed disability worsening, time-to-first relapse, time-to-first evidence of MRI activity and time-to-first evidence of disease activity), clinical and immunological predictors of early treatment response, and incidence of adverse events (AEs). One hundred and fifty-three subjects were included (93 RRMS; 84 females). Median follow-up was 1.9 (1.3-2.7). At 2-year follow-up (FU), disability worsening-free survival were 90.5%, 64.7%, and 68.8% for RRMS, primary-progressive MS (PPMS), and secondary-progressive MS (SPMS) patients, respectively. At 2-year FU, 67.1%, 72.7%, and 81.3% of patients with RRMS, PPMS, and SPMS were free of MRI activity, with NEDA-3 percentages of 62.1%, 54.6%, and 55.1%, respectively. Lower baseline EDSS was independently associated with a reduced risk of disability worsening (HR(95%CI) = 1.45(1.05-2.00), p = 0.024) and previous treatment exposure was independently associated with increased probability of radiological activity (HR = 2.53(1.05-6.10), p = 0.039). At 6-month FU, CD8 + cell decrease was less pronounced in patients with inflammatory activity (p = 0.022). Six patients (3.9%) discontinued ocrelizumab due to severe AEs. Our findings suggest that ocrelizumab is an effective treatment in real-world patients with RRMS and PMS, with a manageable safety profile. Better outcomes were observed in treatment-naïve patients and in patients with a low baseline disability level. Depletion of CD8 + cells could underlie early therapeutic effects of ocrelizumab.

Physical Exercise Moderates the Effects of Disability on Depression in People with Multiple Sclerosis during the COVID-19 Outbreak.

Physical disability impacts psychosocial wellbeing in people with multiple sclerosis. However, the role of physical activity in this context is still debated. By taking advantage of a previous survey, conducted online from 22 April to 7 May 2020, we performed a post-hoc analysis with the aim to assess the associations between disability, physical exercise, and mental health in multiple sclerosis. We retrieved the following data: (i) sociodemographic information, (ii) changes in lifestyle (including exercise), (iii) physical disability, as measured with the Patient-Determined Disease Steps scale, and (iv) anxiety feelings and depressive symptoms assessed via the items included in the Quality of Life in Neurological Disorders measurement system. Examination of the interaction plot showed that the effect of disability on depression, but not on anxious symptoms, was significant for all levels of physical exercise (low: b = 1.22, 95% C.I. 0.85, 1.58, p < 0.001; moderate: b = 0.95, 95% C.I. 0.66, 1.24, p < 0.001; and high: b = 0.68, 95% C.I. 0.24, 1.13, p = 0.003). Based on these data, we can conclude that disability significantly impacted depression during the COVID-19 pandemic, with physical activity playing a moderating role. Our results suggest that favoring exercise in multiple sclerosis (MS) would ameliorate psychological wellbeing regardless of the level of physical disability.

Menstrual cycle resumption and female fertility after autologous hematopoietic stem cell transplantation for multiple sclerosis.

Data on fertility after autologous hematopoietic stem cell transplantation (aHSCT) in women with multiple sclerosis (MS) are inconclusive. This study aims to report on post-aHSCT menstrual resumption in a multi-center MS-women cohort. Out of 43 women, 30 (70%) recovered menses after a mean time of 6.8 months. Older age (odds ratio (OR) = 0.5, p < 0.0001) and previous pulsed cyclophosphamide (OR = 0.44, p = 0.005) were independently associated with a reduced menstrual recovery probability. Conditioning regimens' intensity resulted not associated with post-procedure amenorrhea. Our results highlight younger age as significantly associated with menses recovery; proper fertility counseling for MS women candidated to aHSCT both prior- and post-transplantation is therefore warranted.

Relationship Between Retinal Layer Thickness and Disability Worsening in Relapsing-Remitting and Progressive Multiple Sclerosis.

BACKGROUND: Data regarding the predictive value of optical coherence tomography (OCT)-derived measures are lacking, especially in progressive multiple sclerosis (PMS). Accordingly, we aimed at investigating whether a single OCT assessment can predict a disability risk in both relapsing-remitting MS (RRMS) and PMS. METHODS: One hundred one patients with RRMS and 79 patients with PMS underwent Spectral-Domain OCT, including intraretinal layer segmentation. All patients had at least 1 Expanded Disability Status Scale (EDSS) measurement during the subsequent follow-up (FU). Differences in terms of OCT metrics and their association with FU disability were assessed by analysis of covariance and linear regression models, respectively. RESULTS: The median FU was 2 years (range 1-5.5 years). The baseline peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell + inner plexiform layer (GCIPL) were thinner in PMS compared with RRMS (P = 0.02 and P = 0.003, respectively). In the RRMS population, multivariable models showed that the GCIPL significantly correlated with FU disability (0.04 increase in the EDSS for each 1-µm decrease in the baseline GCIPL, 95% confidence interval: 0.006-0.08; P = 0.02). The baseline GCIPL was thinner in patients with RRMS with FU-EDSS >4 compared with those with FU-EDSS ≤4, and individuals in the highest baseline GCIPL tertile had a significantly lower FU-EDSS score than those in the middle and lowest tertile (P = 0.01 and P = 0.001, respectively). These findings were not confirmed in analyses restricted to patients with PMS. CONCLUSIONS: Among OCT-derived metrics, GCIPL thickness had the strongest association with short-medium term disability in patients with RRMS. The predictive value of OCT metrics in the longer term will have to be further investigated, especially in PMS.

Long-Term Clinical Outcomes of Hematopoietic Stem Cell Transplantation in Multiple Sclerosis.

OBJECTIVE: To determine whether autologous hematopoietic stem cell transplantation (aHSCT) is able to induce durable disease remission in people with multiple sclerosis (MS), we analyzed the long-term outcomes after transplant in a large cohort of MS patients. METHODS: To be included, a minimum data set (consisting of age, MS phenotype, EDSS at baseline, information on transplant technology and at least 1 follow-up visit after transplant) was required. RESULTS: 210 patients were included [relapsing-remitting (RR)MS=122(58%)]. Median baseline EDSS was 6(1-9), mean follow-up was 6.2(±5.0) years. Among RRMS patients, disability worsening-free survival (95%CI) was 85.5%(76.9-94.1%) at 5 years and 71.3%(57.8-84.8%) at 10 years. In patients with progressive MS, disability worsening-free survival was 71.0%(59.4-82.6%) and 57.2%(41.8-72.7%) at 5 and 10 years, respectively. In RRMS patients, EDSS significantly reduced after aHSCT [p=0.001; mean EDSS change per year -0.09 (95%CI=-0.15 to -0.04%)]. In RRMS patients, the use of the BEAM+ATG conditioning protocol was independently associated with a reduced risk of NEDA-3 failure [HR=0.27(0.14-0.50), p<0.001]. Three patients died within 100-days from aHSCT (1.4%); no deaths occurred in patients transplanted after 2007. CONCLUSIONS: aHSCT prevents disability worsening in the majority of patients and induces durable improvement in disability in patients with RRMS. The BEAM+ATG conditioning protocol is associated with a more pronounced suppression of clinical relapses and MRI inflammatory activity. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for people with MS, aHSCT induces durable disease remission in most patients.