Deciphering the shift from benign to active relapsing-remitting multiple sclerosis: Insights into T regulatory cell dysfunction and apoptosis regulation.

BACKGROUND: Relapsing-remitting multiple sclerosis (RRMS), a common demyelinating disease among young adults, follows a benign course in 10-15% of cases, where patients experience minimal neurological disability for a decade following disease onset. However, there is potential for these benign cases to transition into a clinically active, relapsing state. OBJECTIVE: To elucidate the biological mechanisms underlying the transition from benign to active RRMS using gene expression analysis. METHODS: We employed complementary-DNA microarrays to examine peripheral-blood gene expression patterns in patients with benign MS, defined as having a disease duration exceeding 10 years and an Expanded Disability Status Scale (EDSS) score of ≤3.0. We compared the gene expression pattern between patients who switched to active disease (Switching BMS) with those who maintained a benign state (Permanent-BMS) during an additional 5-year follow-up. RESULTS: We identified two primary mechanisms linked to the transition from benign MS to clinically active disease. The first involves the suppression of regulatory T cell activity, and the second pertains to the dysfunction of nuclear receptor 4 A family-dependent apoptosis. These mechanisms collectively contribute to an augmented autoimmune response and increased disease activity. CONCLUSIONS: The intricate gene regulatory networks that operate in switching-BMS are related to suppression of immune tolerance and aberrant apoptosis. These findings may lead to new therapeutic targets to prevent the escalation to active disease.

Radiological Disease Activity in Secondary Progressive Multiple Sclerosis.

INTRODUCTION: MRI activity is less frequent among secondary progressive multiple sclerosis (SPMS) patients. In the current study, we aimed to identify SPMS patients with higher radiological disease activity (RDA) and determine their clinical characteristics. METHODS: We evaluated the occurrence of RDA in SPMS patients followed at the Sheba Multiple Sclerosis Center between January 1, 2015, and December 31, 2020. All patients underwent brain and spinal cord MRI examinations as a routine follow-up unrelated to clinical disease activity. Patients were subdivided into RDA and non-RDA MRI groups based on the presence of active gadolinium-enhancing T1 lesions and/or new/enlarging T2 lesions. Demographic variables and disease-related data were compared. RESULTS: One hundred consecutive SPMS patients, 74 females, median age of 50 years, disease duration of 19.5 years, and neurological disability by the Expanded Disability Status Scale (EDSS) score of 6.0, were included in the study. The RDA group comprised 35 patients (35%), of them 65.7% (n = 23) exhibited only brain MRI activity, 22.8% (n = 8) only spinal cord MRI activity, and 11.4% (n = 4) had both. Patients in the RDA group were diagnosed at a younger mean (SD) age of 28.2 (8.9) versus 33.7 (10.1) years and were younger with a mean (SD) age of 47.8 (9.9) versus 53.4 (10.1) years, as compared with the non-RDA group. No significant differences were found in relation to disease duration, EDSS, exposure to immunomodulatory treatments, and duration of immunomodulatory treatments. CONCLUSIONS: RDA unrelated to clinical symptomatology was more frequent in a subgroup of young SPMS patients.

COVID-19 Alpha Variant (B.1.1.7): Humoral, memory B and T cells in COVID-19 pediatric convalescents.

BACKGROUND: Studies of anti-SARS-CoV-2 humoral and adaptive response in COVID-19 non-vaccinated pediatric convalescents are controversial and further evidence from the pediatric population are needed. OBJECTIVES: To elucidate SARS-CoV-2 humoral and memory B- and T-cells responses in pediatric convalescents as compared with the adult. METHODS: Blood samples were obtained from 80 non-vaccinated, IgG-positive, COVID-19 convalescents (age 8.0-61.0 years), 4.0 months from onset. Frequency of responders and magnitudes of SARS-COV-2 IgG, memory B-cells (MBC) and IFNg- and IL2-secreting memory T-cells (MTC) in response to immuno-dominant peptide pools in pediatric, young adults and middle-aged adults with onset age 8-18 years (N = 20), 19-39 years (N = 30) and 40-61 years (N = 30), respectively, were analyzed. SARS-CoV-2 IgG were detected by ELISA (Euroimmun, Germany). MBC, IFNg-, IL2- and IFNg+IL2-secreting MTC (IFNg-MTC, IL2-MTC and IFNg+IL2-MTC) were detected using FluoroSpot (Mabtech, Sweden). RESULTS: MBC level was lower in pediatric as compared with the middle-aged adults (median 12.75 interquartile range [IQR] 4.27-33.7 and 32.0 IQR 6.0-124.2, respectively, p = .003). MBC level in young adults was lower than in middle-aged adults (median 18.5 IQR 1.7-43.8 and 32.0 IQR 6.0-124.2, respectively, p = .006). The level of IL2-MTC was lower in the pediatric group as compared with middle aged-adults (median 2.1 IQR 0-16.9 and 28.6 IQR 11-49.6, respectively, p < .03) and in young adults lower than in middle-aged adults (median 1.45 IQR 0-18.6 and 28.6 IQR 11-49.6, respectively, p = .02). In addition, the level of IFNg-MTC was lower in pediatric as compared with young adults (median 4.25 IQR 0.0-15.0 and 20.9 IQR 0-75.2, respectively, p = .05). The level of IgG was comparable between pediatric and both young and middle-aged adult groups (4.82 ± 2.95, 3.70 ± 2.65 and 4.9 ± 2.94, respectively, p > .34). CONCLUSION: Non-vaccinated COVID-19 pediatric convalescents have lower adaptive immune responses than adults sustaining the recommendation for vaccination of the pediatric population.

COVID-19 vaccination in patients with multiple sclerosis: What we have learnt by February 2021.

BACKGROUND: Since vaccination against coronavirus disease 2019 (COVID-19) became available, risks related to vaccinating patients with multiple sclerosis (MS) need to be carefully assessed. OBJECTIVE: Characterize safety and occurrence of immediate relapses following COVID-19 vaccination in a large cohort of MS patients. METHODS: We assessed the safety of BNT162b2 COVID-19 vaccination in adult MS patients. RESULTS: Between 20 December 2020 and 25 January 2021, 555 MS patients received the first dose of BNT162b2 vaccine and 435 received the second dose. There were three cases of COVID-19 infection encountered after the first dose. Safety profile of COVID-19 vaccine was characterized by pain at the injection site, fatigue, and headache. No increased risk of relapse activity was noted over a median follow-up of 20 and 38 days after first and second vaccine doses, respectively. The rate of patients with acute relapse was 2.1% and 1.6% following the first and second doses, respectively, similar to the rate in non-vaccinating patients during the corresponding period. Mild increase in the rate of adverse events was noted in younger patients (18-55 years), among patients with lower disability (Expanded Disability Status Scale (EDSS) ⩽3.0), and in patients treated with immunomodulatory drugs. CONCLUSION: COVID-19 BNT162b2 vaccine proved safe for MS patients. No increased risk of relapse activity was noted.

Targeted cognitive game training enhances cognitive performance in multiple sclerosis patients treated with interferon beta 1-a.

BACKGROUND: Prevention of cognitive decline in Multiple Sclerosis (MS) is of major importance. We explored the effect of a 6 months computerized game training program on cognitive performance in MS patients with mild cognitive impairment. METHODS: This was a single-center, randomized prospective study. We enrolled in this study 100 eligible MS patients treated with Interferon-beta-1a (Rebif). All had mild cognitive impairment in either executive function or information processing speed. Patients were randomized 1:1 to either use the cognitive games platform by HappyNeuron (HN) or receive no intervention. Executive function and information processing speed scores were measured at 3 and 6 months from baseline to evaluate the effect of game training on cognitive scores. RESULTS: In both executive function and information processing speed, the game Training group showed significant improvement after 3 and 6 months. The Non-Training group showed mild deterioration in both domains at 3 months, and further deterioration that became significant at 6 months in executive function. Furthermore, at 6 months, the percent of patients in the Training group that improved or remained stable in both cognitive domains was significantly higher compared to the Non-Training group. CONCLUSIONS: Our findings suggest that cognitive game training has a beneficial effect on cognitive performance in MS patients suffering from mild cognitive impairment. While further evaluation is required to assess the longevity of that effect, we nonetheless recommend to MS patients to be engaged in cognitive gaming practice as part of a holistic approach to treating their condition.

Residual disability after severe relapse in people with multiple sclerosis treated with disease-modifying therapy.

BACKGROUND: The rate of post-relapse residual disability in patients with relapsing-remitting multiple sclerosis (RRMS) treated with disease-modifying drugs (DMD) has not been studied. OBJECTIVE: To assess relapse residual disability in DMD-treated RRMS patients. METHODS: We followed DMD-treated RRMS patients presenting with acute relapse who received high-dose steroids. Increases in Expanded Disability Status Scale (EDSS) of at least 2.0, 1.0-1.5 or 0.5 were defined as severe, moderate or mild relapses, respectively. The proportions of patients with post-relapse residual disability defined as the failure to regain pre-relapse neurological status at 1, 4 and 12 months were evaluated. RESULTS: Out of 1672 relapses in DMD-treated RRMS patients, 17% were severe. In patients who presented with a severe relapse, we observed post-relapse residual disability of at least 1.0 EDSS point in 60.1%, 55.9% and 48.2% of patients at 1, 2 and 12 months of follow-up, respectively. Post-relapse residual disability of at least 2.0 EDSS points was observed in 37.4%, 30.7% and 20.7% of patients after 1, 2 and 12 months, respectively. CONCLUSION: A high rate of incomplete recovery was seen 12 months following severe relapse among RRMS patients and may contribute to the accumulation of long-term disability.

Host cell virus entry mechanisms enhance anti-JCV-antibody switch in natalizumab-treated multiple sclerosis patients.

Estimating the individual risk for the development of progressive multifocal leukoencephalopathy (PML) in anti-John Cunningham virus (JCV) antibody-negative patients with multiple sclerosis (MS) treated with natalizumab is a major challenge. A serological conversion occurring under treatment from anti-JCV antibody-negative to positive status may significantly increase this risk. We investigated changes in peripheral blood cells' gene expression induced by natalizumab treatment in anti-JCV antibody-negative MS patients and tested blood transcriptional profile that characterizes patients predisposed to antibody switch under natalizumab treatment. After 3 years of natalizumab treatment, 24.6 % of anti-JCV antibody-negative MS patients switched to become anti-JCV antibody-positive (JCV switchers). Natalizumab induced 946 and 1186 significantly differentiating genes in JCV switchers and non-switchers, respectively. In JCV switchers, the signature was enriched by over-expression of genes associated with the first stages of viral entry to host cells including macropinocytosis (p = 1.82E-06), virus entry via endocytosis (p = 1.60E-06), clathrin-mediated endocytosis (p = 1.13E-04), and caveolar-mediated endocytosis (p = 4.50E-04) pathways. Further analysis to identify pre-existing transcriptional differences that characterize future JCV switchers prior to treatment initiation also demonstrated a transcriptional signature enriched by similar viral entry mechanisms. These findings, verified in an additional independent cohort of natalizumab-treated patients, could lead to future identification of patients that remain anti-JCV antibody-negative thus allowing safe continuation of treatment, as well as the development of future targeted therapeutic interventions to reduce the risk of PML.

Effect of Alfacalcidol on multiple sclerosis-related fatigue: A randomized, double-blind placebo-controlled study.

CONTEXT: Fatigue is one of the most common and disabling symptoms of multiple sclerosis (MS); however, there is no medication that has been approved specifically to treat MS-related fatigue. OBJECTIVE: We aimed to evaluate the effect of vitamin D analogue, Alfacalcidol, on MS-related fatigue. DESIGN, SETTINGS, PARTICIPANTS: This was a randomized, double-blind, parallel group, placebo-controlled trial in patients with clinically definite MS by McDonald criteria conducted in a single university-affiliated medical center in Israel. Randomly selected patients from the Sheba MS Registry computerized database (N=600) were assessed using the self-report Fatigue Severity Scale (FSS). Patients with clinically meaningful fatigue (N=259) were further assessed for trial eligibility, and MS patients with significant fatigue (N=158; 61%, 118 females, mean age 41.1 ± 9.2 years and mean disease duration of 6.2 ± 5.5 years) were included in the study and randomized to receive treatment or placebo. INTERVENTION: Alfacalcidol (1 mcg/d, N=80) or placebo (N=78) was administered for six consecutive months. MAIN OUTCOME MEASURE: The primary endpoint of the study was the change between Alfacalcidol and placebo-treated patients in the Fatigue Impact Scale (FIS) score; the cut-off point for improvement was defined as 30% decrease. All analyses followed the intention-to-treat principle and were performed for all participants based on the group they were randomly allocated regardless of whether or not they dropped out. RESULTS: Alfacalcidol decreased the mean relative FIS score as compared with placebo (-41.6% vs. -27.4%, p=0.007, respectively). This advantage was further emphasized when the modified FIS (MFIS) relative change was calculated. Quality of Life (QoL) improved in Alfacalcidol-treated patients as compared with placebo in the RAYS psychological (p=0.033) and social (p=0.043) sub-scales. The Alfacalcidol-treated group had reduced number of relapses (p=0.006) and higher proportion of relapse-free patients (p=0.007). Reduction of relapses by Alfacalcidol became significant at 4 months of treatment, was sustained at 6 months and decayed 2 months after drug discontinuation. Alfacalcidol treatment was safe and no serious adverse events were recorded. CONCLUSION: Alfacalcidol is a safe and effective treatment strategy to decrease fatigue and improve QoL in patients with MS.

Transcriptional response to interferon beta-1a treatment in patients with secondary progressive multiple sclerosis.

BACKGROUND: Interferon (IFN) beta-1a is an approved treatment for relapsing remitting multiple sclerosis (RRMS) and has been examined for use in secondary progressive multiple sclerosis (SPMS). However, no information regarding blood transcriptional changes induced by IFN treatment in SPMS patients is available. Our aim was to identify a subgroup of SPMS patients presenting a gene expression signature similar to that of RRMS patients who are clinical responders to IFN treatment. METHODS: SPMS patients (n = 50, 20 IFN treated and 30 untreated) were classified using unsupervised hierarchical clustering according to IFN inducible gene expression profile identified in RRMS clinical responders to treatment. IFN inducible gene expression profile was determined by finding differentially expressed genes (DEGs) between IFN treated (n = 10) and untreated (n = 25) RRMS patients. Validation was performed on an additional independent group of 27 SPMS IFN treated patients by qRT-PCR. RESULTS: One hundred and four DEGs, enriched by IFN signaling pathway (p = 7.4E-08), were identified in IFN treated RRMS patients. Classification of SPMS patients based on these DEGs yielded two patient groups: (1) IFN transcriptional responders (n = 12, 60% of SPMS treated patients) showing gene-expression profile similar to IFN treated RRMS patients; (2) IFN transcriptional non-responders (n = 8) showing expression profile similar to untreated patients. IFN transcriptional responders were characterized by a more active disease, as defined by higher EDSS progression and annual relapse rate. CONCLUSION: Within the IFN treated SPMS population, 60% of patients have a transcriptional response to IFN which is similar to that of RRMS patients who are IFN responders to treatment.

A personalized, intense physical rehabilitation program improves walking in people with multiple sclerosis presenting with different levels of disability: a retrospective cohort.

BACKGROUND: People with multiple sclerosis (PwMS) endure walking limitations. To address this restriction, various physical rehabilitation programs have been implemented with no consensus regarding their efficacy. Our objective was to report on the efficacy of an integrated tailored physical rehabilitation program on walking in people with multiple sclerosis categorized according to their level of neurological disability. METHODS: Retrospective data were examined and analyzed. Specifically, data obtained from all patients who participated in the Multiple Sclerosis Center's 3 week rehabilitation program were extracted for in depth exploration. The personalized rehabilitation program included three major components modified according to the patient's specific impairments and functional needs: (a) goal directed physical therapy (b) moderately intense aerobic exercise training on a bicycle ergometer and (c) aquatic therapy chiefly oriented to body structures appropriate to movement. Gait outcome measurements included the 10 meter, 20 meter, Timed up and go and 2 minute walking tests measured pre and post the rehabilitation program. Three hundred and twelve people with relapsing-remitting multiple sclerosis were included in the final analysis. Patients were categorized into mild (n = 87), moderate (n = 104) and severely (n = 121) disabled groups. RESULTS: All clinical walking outcome measurements demonstrated statistically significant improvements, however, only an increase in the 2 minute walking test was above the minimal clinical difference value. The moderate and severe groups considerably improved compared to the mild gait disability group. Mean change scores (%) of the pre-post intervention period of the 2 minute walking test were 19.0 (S.E. = 3.4) in the moderate group, 16.2 (S.E. = 5.4) in the severe group and 10.9 (S.E. = 2.3) in the mild gait disability group. CONCLUSIONS: We presented comprehensive evidence verifying the effects of an intense goal-directed physical rehabilitation program on ambulation in people with multiple sclerosis presenting with different neurological impairment levels.

Clinical correlation between disease progression and central vein sign in pediatric onset multiple sclerosis: A binational study.

BACKGROUND: The central vein sign (CVS) has been proposed as a novel MRI biomarker to improve diagnosis of pediatric-onset MS (POMS). However, the role of CVS in POMS progression has yet to be discovered. OBJECTIVES: To investigate the appearance of CVS and its correlation with POMS disease progression. METHODS: One hundred fifty-six POMS from two MS centers in Israel and Czech Republic MS centers were followed for five years. Patient assessment was performed by the Expanded Disability Status Scale (EDSS) and Annual Relapse Rate (ARR). Patients in whom at least 40 % of brain MRI lesions had CVS ("rule of 40") were determined as CVS-positive. RESULTS: The total group of POMS consisted of 96 CVS-negative (61.5 %), aged 14.6 ± 1.9 years, EDSS 2.0, 75 % Interquartile Range (IQR) 1.0-3.0, disease duration (DD) 6.28 ± 0.38 years, and 60 CVS-positive (38.5 %), aged 15.1 ± 0.3 years, EDSS 2.0, IQR 1.5-3.0, DD 5.62 ± 0.13 years, were analyzed. After a three and five-year follow-up, the CVS-positive patients had higher EDSS scores than those who were CVS-negative, 2.0, IQR 1.0-2.5, vs 1.0, IQR 1.0-2.0, (p = 0.009) and 2.0, IQR 1.0-3.25 vs 1.0, IQR 1.0-2.0, (p = 0.0003), respectively. Patients with CVS-positive POMS were characterized by a significantly higher ARR (0.78 ± 0.08 vs 0.57 ± 0.04, p = 0.002). These results were confirmed in subgroups of Disease Modifying Treatments (DMT) untreated and treated patients. CONCLUSION: CVS-positive POMS is characterized by higher disability progression than CVS-negative, indicating the importance of CVS in disease pathogenesis.

Intravenous immunoglobulin treatment during pregnancy and the post-partum period in women with multiple sclerosis: A prospective analysis.

Background: Relapsing-remitting multiple sclerosis (RRMS) affects predominantly young women within reproductive years. As an increased risk of relapses is known to occur during the post-partum period, it is important to consider treatment options. Aim: Evaluate the effects of intravenous immunoglobulins (IVIg) to prevent post-partum relapses. Methods: We prospectively followed 198 pregnant female RRMS patients, 67 treated with IVIg during pregnancy and the three months post-partum, and 131 untreated patients that served as controls. Results: During the pre-gestation year, 41.4% were treated with immunomodulatory drugs, and 28.3% experienced a relapse. During pregnancy and the post-partum period, the number of relapsing patients significantly decreased in the IVIg group (37.3%, 10.4%, 8.9%, respectively, p = 0.0003), while no significant change was observed in the untreated group (23.7%, 17.6%, and 22.1%). During the three-month post-partum period, there were only mild and moderate relapses in the IVIg group, while in the untreated group, there were also severe relapses. Stepwise logistic regression that assessed the relation between three-month post-partum relapse and explanatory variables demonstrated that untreated patients had increased risk for post-partum relapse (odds ratio = 4.6, 95% CI [1.69, 12.78], p = 0.033). Conclusions: IVIg treatment proved efficient to reduce the rate and severity of relapses during pregnancy and the three-month post-partum.

Practical recommendations on treatment of multiple sclerosis with Cladribine: an Israeli Experts Group Viewpoint.

Cladribine tablets (Mavenclad®) were approved by the European Union in 2017 as high-efficacy therapy for highly active relapsing-remitting multiple sclerosis. In Israel, Mavenclad® was approved in 2018. Real-life experience has confirmed the efficacy of cladribine tablets over at least 4 years from the initial course. During the last years, several questions were raised concerning the management of people with MS who show disease activity during years 3 and 4 post-cladribine initiation and what treatment decisions are needed beyond year 4. A few expert boards have tried to provide insight based on research data and to suggest recommendations on the therapeutic dilemmas and treatment decisions with cladribine. However, there is currently no widely accepted consensus about these issues. The vast clinical experience gained in Israel in the past 5 years in several MS centers across the country allows for a broad perspective of the outcomes with long-term cladribine use. This article summarizes previously published recent recommendations and describes the insights of Israeli neurology key opinion leaders that convened for an advisory board meeting on January 29th, 2023, with the aim of reaching a consensus regarding cladribine long-term treatment and follow-up.

In-depth characterization of long-term humoral and cellular immune responses to COVID-19m-RNA vaccination in multiple sclerosis patients treated with teriflunomide or alemtuzumab.

BACKGROUND: The impact of disease-modifying therapies on the efficacy to mount appropriate immune responses to COVID-19 vaccination in patients with multiple sclerosis (MS) is currently under investigation. OBJECTIVE: To characterize long-term humoral and cellular immunity in mRNA-COVID-19 MS vaccinees treated with teriflunomide or alemtuzumab. METHODS: We prospectively measured SARS-COV-2 IgG, memory B-cells specific for SARS-CoV-2 RBD, and memory T-cells secreting IFN-γ and/or IL-2, in MS patients vaccinated with BNT162b2-COVID-19 vaccine before, 1, 3 and 6 months after the second vaccine dose, and 3-6 months following vaccine booster. RESULTS: Patients were either untreated (N = 31, 21 females), under treatment with teriflunomide (N = 30, 23 females, median treatment duration 3.7 years, range 1.5-7.0 years), or under treatment with alemtuzumab (N = 12, 9 females, median time from last dosing 15.9 months, range 1.8-28.7 months). None of the patients had clinical SARS-CoV-2 or immune evidence for prior infection. Spike IgG titers were similar between untreated, teriflunomide and alemtuzumab treated MS patients both at 1 month (median 1320.7, 25-75 IQR 850.9-3152.8 vs. median 901.7, 25-75 IQR 618.5-1495.8, vs. median 1291.9, 25-75 IQR 590.8-2950.9, BAU/ml, respectively), at 3 months (median 1388.8, 25-75 1064.6-2347.6 vs. median 1164.3 25-75 IQR 726.4-1399.6, vs. median 837.2, 25-75 IQR 739.4-1868.5 BAU/ml, respectively), and at 6 months (median 437.0, 25-75 206.1-1161.3 vs. median 494.3, 25-75 IQR 214.6-716.5, vs. median 176.3, 25-75 IQR 72.3-328.8 BAU/ml, respectively) after the second vaccine dose. Specific SARS-CoV-2 memory B cells were detected in 41.9%, 40.0% and 41.7% of subjects at 1 month, in 32.3%, 43.3% and 25% at 3 months, and in 32.3%, 40.0%, 33.3% at 6 months following vaccination in untreated, teriflunomide treated and alemtuzumab treated MS patients, respectively. Specific SARS-CoV-2 memory T cells were found in 48.4%, 46.7% and 41.7 at 1 month, in 41.9%, 56.7% and 41.7% at 3 months, and in 38.7%, 50.0%, and 41.7% at 6 months, of untreated, teriflunomide-treated and alemtuzumab -treated MS patients, respectively. Administration of a third vaccine booster significantly increased both humoral and cellular responses in all patients. CONCLUSIONS: MS patients treated with teriflunomide or alemtuzumab achieved effective humoral and cellular immune responses up to 6 months following second COVID-19 vaccination. Immune responses were reinforced following the third vaccine booster.

Multiple sclerosis in Israeli children: incidence, an clinical, cerebrospinal fluid and magnetic resonance imaging findings.

BACKGROUND: Multiple sclerosis (MS) occurs in young adults and infrequently appears in childhood. OBJECTIVES: To determine the incidence of MS and describe the clinical, cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) findings at onset of MS in children in Israel. METHODS: Incidence and case-specific data were obtained through the MS Center Database and Israeli Health Statistics Census Data over 15 years, from 1995 to 2009, and compared between patients with childhood (< 12 years), juvenile (> or = 12 years, < or = 18 years) and adult (> 18 years) MS onset. RESULTS: Of 1129 eligible MS patients, we identified 10 (0.89%) with childhood-onset MS, 74 (6.55%) with juvenile-onset MS, and 1045 (92.56%) with adult-onset MS. There were 0 to 3 incident childhood cases/year, leading to an annual incidence of 0.1/100,000 among Israeli children; the incidence of juvenile and adult MS was 2.6 and 5.4/100,000, respectively. Neurological presentation among children with MS was optic neuritis, motor weakness or brainstem involvement. CSF oligoclonal immunoglobulin (IgG) were positive in 62.5%. The most frequent MRI finding was the occurrence of > or = 3 periventricular white matter lesions followed by corpus callosum lesions, with 71% co-occurrence. Cervical and thoracic lesions occurred in 33% and 43%, respectively. Time to second neurological event ranged from 0.3 to 4.2 years and none of the patients with childhood MS reached EDSS = 6.0 within a mean follow-up period of 8.4 years. CONCLUSIONS: Childhood-onset MS is rare, with an incidence of 0.1/100,000 Israeli children. Childhood MS does not differ significantly from juvenile and adult-onset MS in terms of clinical, laboratory and imaging findings.

Longitudinal relationships between disability and gait characteristics in people with MS.

Longitudinal data are vital in order to understand intra individual gait changes with the progression of multiple sclerosis (MS). Therefore, the primary aim of this study was to explore the relationship between changes in disability with changes in major spatio-temporal parameters of gait in people with MS (PwMS). PwMS (n = 83) completed two gait assessments performed at separate time points (M1, M2). For each individual, the absolute difference between the Expanded Disability Status Scale (EDSS) score, key spatio-temporal parameters of gait, Falls Efficacy Scale International (FES-I), and the 12-item Multiple Sclerosis Walking Scale (MSWS-12), were calculated. The mean time difference between M1 and M2 was 2.5 (SD = 1.7) years. At M2, PwMS presented with shorter strides, a wider base of support, increased perceived mobility difficulties and fear of falling compared with M1. According to the odds ratio (OR) analysis, the odds of experiencing an increase in the EDSS score was significantly higher once the MSWS-12 score increased at M2 compared with M1 (OR = 7.930, p = 0.004). This observation was highlighted specifically in people with mild-moderate MS (OR = 12.427, p < 0.001). The increase in the EDSS score was not associated with changes in key spatio-temporal parameters of gait. The present study provides a better understanding of gait and disease progression in PwMS, highlighting the significant role of the MSWS-12.

The Design, Development, and Testing of a Virtual Reality Device for Upper Limb Training in People With Multiple Sclerosis: Single-Center Feasibility Study.

BACKGROUND: Multiple sclerosis (MS) is a common nontraumatic, neurological, disabling disease that often presents with upper limb dysfunction. Exercise training has resulted in improvement for patients; however, there can be a lack of compliance due to access because of location and lack of MS experts. Virtual reality (VR) is a promising technology that can offer exercise therapy/rehabilitation at a distance. This type of remote training can be motivational and effective for patients with MS and can improve range of motion and muscle strength for those with upper limb dysfunction. OBJECTIVE: The aim of this study is to evaluate the safety and feasibility of the XRHealth software and the Oculus Rift Station for patients with MS with upper limb motor dysfunction. METHODS: A single-center, prospective, feasibility study was conducted with patients with MS who had upper limb motor dysfunction. Patients participated in a single 45-minute digital environment session with VR and completed a questionnaire about the quality of the training and fatigability. The clinician also completed a questionnaire to evaluate the suitability and safety of the training. RESULTS: Overall, 30 patients were enrolled between the ages of 20 and 81 years. Patients reported that the training sessions within the digital environment were helpful, challenging, fun, and simple to understand, and that they would be willing to repeat the sessions again. The physical therapist that oversaw the patients reported that the training was suitable for 87% (n=26) of the patients. Anticipated adverse events were fatigue, temporary dizziness, and temporary nausea. The operator complications included that the cable of the head-mounted display interrupted the training (n=2, 7%) and fatigue that caused cessation of the VR training session (n=2, 7%). No serious adverse events were reported. CONCLUSIONS: These preliminary results demonstrated that the use of the XRHealth software and Oculus Rift Station platform is feasible, safe, and engaging for patients, and has the potential to improve the functionality of the upper limbs in patients with MS. This study provides support for future studies of implementing a series of training sessions with virtual reality in a home-based environment.

Cladribine treatment for highly active multiple sclerosis: Real-world clinical outcomes for years 3 and 4.

INTRODUCTION: Cladribine is an effective immunomodulatory treatment used for relapsing forms of multiple sclerosis (MS). OBJECTIVES: To describe the clinical outcomes and rates of no evidence of disease activity (NEDA) in patients with highly-active disease treated with 2 years cumulative dose of cladribine, for years 3 and 4. METHODS: We used the Sheba Multiple Sclerosis computerized data registry to retrospectively evaluate year-3 and year-4 clinical outcomes and NEDA-2 rates in highly active RRMS patients who completed the 2-dose 2-year cladribine treatment protocol (3.5 mg/kg cumulative dose over 2 years). The first week of treatment in year 1 was considered as baseline. Data analyses were performed using Python (version 3.0) and SAS® (version 9.4 SAS Institute, Cary, NC). RESULTS: Among 128 patients with highly-active MS that received cladribine treatment, 61 patients, 43 females, were studied for year-3 clinical outcomes, and 35 patients, 23 females, also for year-4. At the initiation of cladribine treatment, the mean ± SD age was 39.6 ± 10.74 years (45.9% of the patients were between 18 and 40 years), disease duration 12.7 ± 9.08 years, Expanded Disability Status Scale (EDSS) 3.7 ± 1.86 (54% had EDSS score > 3.0), and the annual relapse rate was 1.6 ± 0.9. The annual relapse rate decreased to 0.36 in year-3 and was 0.17 in year-4; 68.9% (42/61) of the patients were relapse-free in year-3, and 82.9% (29/35) were relapse-free in year-4. Disability at year-3 was 3.1 ± 2.07; 83.6% (51/61) of the patients remained neurologically stable (33, 54.1%) or improved (18, 29.5%). In year-4, EDSS was 3.2 ± 1.91, and 85.7% (30/35) of the patients remained stable (20, 57.1%) or improved (10, 28.6%). NEDA-2 was achieved for 59.0% (36/61) of patients in year-3, and for 74.3% (26/35) in year-4 of cladribine treatment. CONCLUSIONS: In the real-world cladribine proved to be clinically effective in year-3 and year-4 of treatment in the majority of highly active RRMS patients.

Immune response to the third COVID-19 vaccine dose is related to lymphocyte count in multiple sclerosis patients treated with fingolimod.

BACKGROUND: The majority of multiple sclerosis [MS] patients treated with fingolimod fail to develop a protective level of IgG humoral and adaptive cellular immune responses following full BNT162b2 SARS-CoV-2 vaccination. OBJECTIVE: To compare the efficacy of the third COVID-19 vaccine dose in vaccine non-responders fingolimod-treated MS patients. STUDY DESIGN: This is a prospective 3-month, single-center, randomized clinical trial. METHODS: Twenty relapsing MS patients who had been on fingolimod therapy ≥ 12 months and failed to develop humoral IgG immune response to 2-dose Pfizer BNT162b2 COVID-19 vaccination were randomized into two groups: fingolimod-continuation group and fingolimod-discontinuation group. Humoral and memory cellular immune responses were assessed within 1 and 3 months following the third Pfizer BNT162b2 vaccine dose and compared between the groups. RESULTS: A higher rate of patients in the fingolimod-discontinuation group [n = 8/10] compared to fingolimod-continuation group [n = 2/10] developed positive SARS-COV-2 IgG. Median IgG titer 1 month following the third dose was 202.3 BAU/ml vs. 26.4 BAU/ml, respectively, p = 0.022. The development of IgG humoral response correlated with absolute lymphocyte count. Specific SARS-COV-2 memory B cell and T cell immune responses were not detected in both groups, either at 1 month or 3 months following the third COVID-19 vaccine dose. CONCLUSIONS: Short period of fingolimod treatment discontinuation was associated with the development of humoral protection but not with adaptive cellular immunity.

SARS-CoV-2 memory B and T cell profiles in mild COVID-19 convalescent patients.

OBJECTIVES: Antiviral adaptive immunity involves memory B cells (MBC) and memory T cells (MTC). The dynamics of MBC and MTC in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) convalescents warrant further investigation. METHODS: In this cross-sectional and longitudinal study, blood-derived MBC and MTC responses were evaluated in 68 anti-spike IgG-positive mild coronavirus disease 2019 (COVID-19) convalescents at visit 1, between 1 and 7 months (median 4.1 months) after disease onset. SARS-CoV-2 anti-spike IgG was determined by ELISA, MBC by SARS-CoV-2-specific receptor binding domain (RBD) ELISpot, and interferon gamma (IFN-γ)-, interleukin 2 (IL2)-, and IFN-γ+IL2-secreting MTC by IFN-γ and IL2 SARS-CoV-2 FluoroSpot. For 24 patients sampled at the first visit, the IgG, MBC, and MTC analyses were also performed 3 months later at the second visit. RESULTS: Seventy-two percent of convalescents were both MBC- and MTC-positive, 18% were MBC-positive and MTC-negative, and 10% were MTC-positive and MBC-negative. The peak MBC response level was detected at 3 months after COVID-19 onset and persisted up to 7 months post infection. Significant MTC levels were detected 1 month after onset in response to S1, S2_N, and SNMO peptide pools. The frequency and magnitude of the MTC response to SNMO was higher than those to S1 and S2_N. Longitudinal analysis demonstrated that even when specific humoral immunity declined, the cellular immunity persisted. CONCLUSIONS: The study findings demonstrate the durability of adaptive cellular immunity at least for 7 months after SARS-CoV-2 infection, suggesting long-lasting protection.