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.

Central Neuropathic Pain in Multiple Sclerosis Is Associated with Impaired Innocuous Thermal Pathways and Neuronal Hyperexcitability.

OBJECTIVE: About one-third of patients with multiple sclerosis (MS) suffers from chronic and excruciating central neuropathic pain (CNP). The mechanism underlying CNP in MS is not clear, since previous studies are scarce and their results are inconsistent. Our aim was to determine whether CNP in MS is associated with impairment of the spinothalamic-thalamocortical pathways (STTCs) and/or increased excitability of the pain system. DESIGN: The study was cross-sectional. SETTING: The study was conducted at a general hospital. PARTICIPANTS: Participants were 47 MS patients with CNP, 42 MS patients without CNP and 32 healthy controls. METHODS: Sensory testing included the measurement of temperature, pain, and touch thresholds and the thermal grill illusion for evaluating STTCs function and hyperpathia and allodynia as indicators of hyperexcitability. CNP was characterized using interviews and questionnaires. RESULTS: The CNP group had higher cold and warm thresholds (P < 0.01), as well as higher thermal grill illusion perception thresholds (P < 0.05), especially in painful body regions compared with controls, whereas touch and pain thresholds values were normal. The CNP group also had a significantly greater prevalence of hyperpathia and allodynia. Regression analysis revealed that whereas presence of CNP was associated with a higher cold threshold, CNP intensity and the number of painful body regions were associated with allodynia and hyperpathia, respectively. CONCLUSIONS: CNP in MS is characterized by a specific impairment of STTC function, the innocuous thermal pathways, and by pain hyperexcitability. Whereas CNP presence is associated with STTC impairment, its severity and extent are associated with pain hyperexcitability. Interventions that reduce excitability level may therefore mitigate CNP severity.

Reproducibility and Convergent Validity of the Sitting-Rising Test in People With Multiple Sclerosis.

OBJECTIVE: To evaluate the test-retest reproducibility and convergent validity of the sitting-rising test (SRT) in people with multiple sclerosis (PwMS). DESIGN: Observational study comprising a test-retest design. SETTING: Multiple Sclerosis Center, Rehabilitation Hospital at Sheba Medical Center, Tel-Hashomer, Israel. PARTICIPANTS: A total of 50 PwMS (32 women, 18 men, N=50), mean age 44.8±7.6 years and mean disease duration of 13.8±8.5 years since diagnosis, were enrolled in the study. The median Expanded Disability Status Scale score was 4.5, indicating a mild-moderate neurologic disability. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: SRT, posturography measures, 10-repetion sit-to-stand test (10STS), timed Up and Go (TUG) test, hand grip strength, strength of hip flexion/extension/abduction, knee flexion/extension, and Fall Status Questionnaire. RESULTS: The intraclass correlation coefficient value for the intrarater test-retest reproducibility (7- to 10-day interval between tests) of the SRT test, was 0.931 (95% confidence interval, 0.796-0.977). Strong correlations were found between the SRT, TUG test (ρ=-0.709), and 10STS (ρ=-0.719), and moderate correlations were found between the SRT and postural control measures (ρ∼0.4). Moderate correlations were found between the SRT and the hip and knee strength (combined) of the weaker limb (ρ=0.344). No differences were found in the SRT score between fallers and nonfallers. CONCLUSIONS: The current study supports the convergent validity and test-retest reproducibility of the SRT in PwMS.

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.

The relationship between gait variability and cognitive functions differs between fallers and non-fallers in MS.

The objective of the study was to determine if cognitive function is associated with step time variability in people with multiple sclerosis (PwMS). The study included 355 PwMS (218 women), average age 41.1 (SD = 13.5), disease duration 5.9 (SD = 7.3) years, and a median expanded disability status scale score of 2.5. We separately analyzed the sample group of fallers and non-fallers based on their fall history. Gait variability was measured by an electronic walkway and all participants completed a computerized cognitive test battery designed to evaluate multiple cognitive domains. Fallers (43.7%) demonstrated elevated step time variability (%CV), 5.0 (SD = 3.4) vs. 3.5 (SD = 1.6), P < 0.001 compared to the non-faller subjects. According to the regression analysis in the non-fallers' group, step time variability was found significantly associated with the global cognitive score (P = 0.001), executive function subcategory (P = 0.038), and motor skills subcategory (P < 0.001). No relationship between step time variability and any cognitive domain was demonstrated in the faller group. This study illustrated that the association between gait variability and cognition occurs only in PwMS without a fall history. From a clinical standpoint, these findings might help medical professionals to create improved assessment tests and rehabilitation strategies in the MS population.

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.

Faster progression to multiple sclerosis disability is linked to neuronal pathways associated with neurodegeneration: An ethnicity study.

Although the causes of multiple sclerosis are largely unknown, genetic and environmental components play an important role. Geographic distribution, varying with latitude, reflects both genetic and environmental influences. We conducted a retrospective exploratory observational study to characterize the disability progression of 2396 Jewish patients with relapsing-remitting multiple sclerosis, followed at the Sheba Multiple Sclerosis Center, Tel-Aviv, Israel; 188 patients who originated in Iraq and 2207 patients who originated in northern Europe. Peripheral blood microarray gene expression analysis was performed in a subgroup of patients to identify molecular pathways associated with faster disability progression. During a follow-up period of 18.8 and 19.8 years, respectively, 51.6% of patients with an Iraqi origin progressed to moderate disability defined as expanded disability status scale (EDSS) score of 3.0 to 5.5, compared to 44.2% of patients with a northern European origin (odds ratio 1.347, 95% CI 1.0-1.815, p = 0.049). An Iraqi origin was associated with increased risk of progression to moderate disability adjusted for sex, disease duration, age at onset, and treatment with immunomodulatory drugs (hazard ratio 1.323; 95% CI, 1.049-1.668, p = 0.02), but not to severe disability defined as EDSS score > = 6.0 (i.e., walking aids are required for a distance of 100 meters, (hazard ratio 1.311; 95% CI, 0.918-1.874, p = 0.136). Gene expression analysis disclosed 98 differentially expressed genes (79 over-expressed and 19 under-expressed) between relapsing-remitting multiple sclerosis patients of Iraqi origin (N = 17) and northern European (N = 34) origin. Interestingly, this gene expression was enriched with genes related to neuronal pathways associated with morphology of axons, branching of neurites, proliferation of neocortical neurons, and formation of myelin sheath, suggesting an augmented process of neurodegeneration in relapsing-remitting multiple sclerosis patients with an Iraqi origin. The study results suggest that relapsing-remitting multiple sclerosis patients with an Iraqi origin progress faster to disability possibly due to an enhanced process of neurodegeneration.

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.

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.

The month of birth and the incidence of multiple sclerosis in the Israeli population.

BACKGROUND: Recent studies on date of birth of multiple sclerosis (MS) patients showed a spring peak and an autumn nadir. We examined the effect of date of birth in a large group of MS patients and non-MS patients, compared to the general population in Israel. METHODS: A retrospective analysis was performed in a large cohort of MS patients and patients with other neurological disorders. The date of birth, gender, and country of birth were identified for each patient. The results were compared to a national database. RESULTS: There were 2,264 MS patients and 1,758 patients with other diagnoses. No significant peak or nadir in the date of birth was identified in either group, both in patients born in Israel or in immigrants. No difference was found compared to the national birth rate. When we controlled for the country of birth, there was no difference. CONCLUSION: An increased frequency of MS patients born in the months of April and May was considered as a proof of maternal influence. The results of our study show that this finding is not consistent worldwide. The month of birth was not found to be a significant factor in Israeli MS patients.

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.

Unique features of central neuropathic pain in multiple sclerosis: Results of a cluster analysis.

BACKGROUND: Central neuropathic pain (CNP) is an excruciating condition, prevalent in up to a third of patients with multiple sclerosis (MS). Identifying CNP among MS patients is particularly challenging considering the ample comorbid chronic pain conditions and sensory disturbances entailed by the disease. The aim was to identify sensory features unique to CNP beyond those of chronic pain and MS. METHODS: Participants were 112 MS patients: 44 with a diagnosis of CNP, 28 with a diagnosis of chronic musculoskeletal pain (MSP), and 40 pain free. Participants underwent testing of thermal and mechanical thresholds, thermal grill illusion (TGI), pain adaptation (PA), and offset analgesia (OA), and chronic pain was characterized. A two-step cluster analysis was performed, and the association between the cluster membership and the clinical group membership (CNP, MSP, pain free) was evaluated. RESULTS: The CNP and MSP groups were similar in most of the chronic pain variables (e.g., severity, location and quality) and MS-related variables (e.g., type, severity and medication intake). The three created clusters had unique sensory features: (1) 'Hyposensitivity' (increased thermal and touch thresholds) characterized the CNP group; (2) 'Poor inhibition and hyperalgesia' (worst PA and OA and decreased TGI threshold) characterized the MSP group; and (3) 'Efficient inhibition' (best PA and OA, smallest sensory loss) characterized the pain-free group. CONCLUSIONS: The unique sensory features of CNP and MSP provide insight into their pathophysiology, and evaluating them may increase the ability to provide individually based interventions. Efficient inhibition may protect MS patients from chronic pain. SIGNIFICANCE: Cluster analysis among patients with multiple sclerosis (MS) revealed that while central neuropathic pain is associated with thermal and mechanical hypoesthesia, musculoskeletal pain is involved with reduced pain inhibition and hyperalgesia; sensory profiles that provide insights into the mechanisms of these conditions and may promote an individually based pain management.

Motoric cognitive risk syndrome in people with multiple sclerosis: prevalence and correlations with disease-related factors.

Background: The motoric cognitive risk (MCR) syndrome, defined as the coexistence of slow gait and subjective cognitive complaints, has as yet not been researched in people with multiple sclerosis (pwMS). Objective: To examine the prevalence of the MCR syndrome in pwMS and its association with disability, disease duration, perceived fatigue, and fear of falling. Methods: The study comprised 618 pwMS [43.7 (SD = 12.6) years, 61.7% females]. Gait speed was measured by the GAITRite™ electronic walkway (CIR Systems, Inc. Haverton, PA, USA). Cognitive status was defined according to the global cognitive score computed by the NeuroTrax™ cognitive battery (NeuroTrax Corporation, Medina, NY, USA). The sample was divided into four main groups: 'normal', 'cognitively impaired', 'gait impaired' or 'MCR'. Perceived fatigue was assessed by the Modified Fatigue Impact Scale; fear of falling by the Falls Efficacy Scale International. Results: Sixty-three (10.2%) patients were diagnosed with MCR. The percentage of subjects categorized as MCR was 26.0% in severely disabled pwMS compared with 10.9%, 6.0%, and 4.6% in moderately, mildly and very mildly disabled pwMS, respectively. Subjects in the MCR group presented with elevated fatigue compared with patients classified as normal [49.7 (SD = 23.3) vs 26.5 (SD = 19.2), p < 0.001]. Fear of falling was significantly higher in the MCR and gait impairment groups compared with the cognitively impaired and normal groups. Conclusions: The current study corroborates the presence of MCR in pwMS. Nevertheless, future longitudinal research is warranted to better understand its application.

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.