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.

Age-related blood transcriptional regulators affect disease progression in pediatric multiple sclerosis.

BACKGROUND: Pediatric onset multiple sclerosis patients (POMS) are defined as multiple sclerosis with an onset before the age of 18 years. Compared to adult onset multiple sclerosis (AOMS), POMS has more severe disease activity at onset, but better recovery. Little is known about the molecular mechanism responsible for the differences in the clinical presentations. METHODS: Peripheral Blood Mononuclear Cells samples were taken from 22 POMS patients (mean age 14.1 ± 2.4 years, 15 females, 7 male), and 16 AOMS patients, (mean age 30.8 ± 6.1 years,10 females, 6 males), and gene-expression were analyzed using Affymetrix Inc. HU-133-A2 microarrays. Differentially Expressed Genes (DEGs) that significantly distinguished between POMS and AOMS with pvalue <0.05 after false discovery rate correction were evaluated using Partek software. Twenty-one matched age and gender control was applied to clarify age-related changes. Clinical assessment was performed by analysis of expanded disability status scale (EDSS) and brain MRI lesion loads. Gene functional analysis was performed by Ingenuity Pathway Analysis software. RESULTS: Compared to AOMS, POMS had higher EDSS (3.0 IQR 2.0-3.0 and 2.0 IQR 2.0-3.0, p = 0.005), volume of T1 (2.72 mm3, IQR 0.44-8.39 mm3 and 0.5 mm3 IQR 0-1.29 mm3 respectively, p = 0.04) and T2 (3.70 mm3, IQR 1.3-9.6 and 0.96 mm3, IQR 0.24-4.63 respectively, p = 0.02) brain MRI lesions. The POMS transcriptional profile was characterized by 551 DEGs, enriched by cell cycling, B lymphocyte signaling and senescent pathways (p < 0.02). Of these, 183 DEGs significantly correlated with T2 lesions volume. The POMS MRI correlated DEGs (n = 183) and their upstream regulators (n = 718) has overlapped with age related DEGs obtained from healthy subjects (n = 497). This evaluated common DEGs (n = 29) defined as POMS age-related regulators, suggesting to promote effect on disease severity. CONCLUSION: Our finding of higher transcriptional levels of genes involved in cell cycle, cell migration and B cell proliferation that promoted by transcriptional level of age-associated genes and transcription factors allows better understanding of the more aggressive clinical course that defines the POMS.

[TUMOR-LIKE EFFECT AS INITIAL PRESENTATION OF PEDIATRIC MULTIPLE SCLEROSIS].

INTRODUCTION: In both children and adults, magnetic resonance imaging of the brain in cases of multiple sclerosis (MS) has typical indications, where one of the key points for differentiating between demyelinating processes and place-taking processes is the fact that most of the lesions that appear in multiple sclerosis do not cause a mass effect or much edema around them. There are several uncommon subtypes of multiple sclerosis that can appear specifically in adolescents, presenting with a stormy clinical course and accompanied by brain lesions that resemble space-occupying lesions. These include Marburg disease, Balò's concentric sclerosis, and tumefactive MS. These unusual presentations raise the question regarding the ability to distinguish between neoplastic and demyelinating processes. In this article we present two case studies that illustrate this diagnostic dilemma and an accompanying literature review.

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.

VPS53 gene is associated with a new phenotype of complicated hereditary spastic paraparesis.

Hereditary spastic paraparesis (HSP) is a progressive neurodegenerative disorder, characterized by progressive lower limb weakness and spasticity. Multiple genes are associated with both the pure and complicated HSP types. Our study is aimed at seeking for novel genetic basis of HSP in a family with two affected siblings. Genetic analysis using whole exome sequencing was conducted in a family quartet with two female siblings, who presented with complicated HSP featuring slowly progressive paraparesis, mild-moderate intellectual disability, normal head circumference (HC), and normal magnetic resonance imaging (MRI). A homozygous pathogenic variant was identified in both siblings in the VPS53 gene (c.2084A>G: c.2084A>G, p.Gln695Arg). This gene acts as a component of the Golgi-associated retrograde protein (GARP) complex that is involved, among others, in intracellular cholesterol transport and sphingolipid homeostasis in lysosomes and was previously associated with progressive cerebello-cerebral atrophy (PCCA) type 2. This is the first description of the VPS53 gene as a cause of autosomal recessive complicated HSP. Lysosomal dysfunction as a result of impaired cholesterol trafficking can explain the neurodegenerative processes responsible for the HSP. Our finding expands the phenotype of VPS53-related disease and warrants the addition of VPS53 analysis to the genetic investigation in patients with autosomal recessive HSP. The exact role of GARP complex in neurodegenerative processes should be further elucidated.

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.

Physical activity participation according to the pyramidal, sensory, and cerebellar functional systems in multiple sclerosis.

The objective of the study was to examine the differences in physical activity participation with the pyramidal, cerebellar, and sensory functional systems in people with multiple sclerosis (PwMS). This cross-sectional study included 289 PwMS with a median EDSS of 2.0 (range 0-6.5) and a mean disease duration of 6.8 (SD = 8.4) years. The Godin leisure-time exercise questionnaire (GLTEQ) assessed physical activity participation. The sample was divided into seven groups according to the pyramidal, cerebellar, and sensory functional system scores derived from the EDSS data. Additionally, PwMS were divided into three physical activity subgroups (active, moderately active, and insufficiently active). Furthermore, PwMS were categorized into four levels of disability based on their global Expanded Disability Status Scale (EDSS) score [very mild (0-1.5), mild (2.0-3.5), moderate (4.0-5.5), and severe (6.0-6.5)]. In the physical activity subgroups, 159 (55.0%) were classified as insufficiently active, 59 (20.4%) as moderately active, and 71 (24.6%) as active. Pyramidal, cerebellar, and sensory impairments were demonstrated in 134 (46.4%), 73 (25.3%), and 85 (29.4%) patients, respectively. No differences were found for the GLTEQ scores for all seven functional system groups (P value = 0.168). As for the EDSS disability subgroups, the percentage of active patients (moderately at least) were 60%, 45.8%, 36.5%, and 15.4%, for the very mild, mild, moderate, and severe subgroups, respectively. This study found that participation in leisure-time physical activity is independent from the pyramidal, cerebellar, and sensory functional systems in PwMS.

RSRC1 mutation affects intellect and behaviour through aberrant splicing and transcription, downregulating IGFBP3.

RSRC1, whose polymorphism is associated with altered brain function in schizophrenia, is a member of the serine and arginine rich-related protein family. Through homozygosity mapping and whole exome sequencing we show that RSRC1 mutation causes an autosomal recessive syndrome of intellectual disability, aberrant behaviour, hypotonia and mild facial dysmorphism with normal brain MRI. Further, we show that RSRC1 is ubiquitously expressed, and that the RSRC1 mutation triggers nonsense-mediated mRNA decay of the RSRC1 transcript in patients' fibroblasts. Short hairpin RNA (shRNA)-mediated lentiviral silencing and overexpression of RSRC1 in SH-SY5Y cells demonstrated that RSRC1 has a role in alternative splicing and transcription regulation. Transcriptome profiling of RSRC1-silenced cells unravelled specific differentially expressed genes previously associated with intellectual disability, hypotonia and schizophrenia, relevant to the disease phenotype. Protein-protein interaction network modelling suggested possible intermediate interactions by which RSRC1 affects gene-specific differential expression. Patient-derived induced pluripotent stem cells, differentiated into neural progenitor cells, showed expression dynamics similar to the RSRC1-silenced SH-SY5Y model. Notably, patient neural progenitor cells had 9.6-fold downregulated expression of IGFBP3, whose brain expression is affected by MECP2, aberrant in Rett syndrome. Interestingly, Igfbp3-null mice have behavioural impairment, abnormal synaptic function and monoaminergic neurotransmission, likely correlating with the disease phenotype.

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.

Focal cortical thinning in patients with stable relapsing-remitting multiple sclerosis: cross-sectional-based novel estimation of gray matter kinetics.

PURPOSE: The aim of our study is to identify radiological patterns of cortical gray matter atrophy (CGMA) that correlate with disease duration in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: RRMS patients were randomly selected from the Sheba Multiple Sclerosis (MS) center computerized data registry based on stratification of disease duration up to 10 years. Patients were scanned by 3.0 T (Signa, GE) MRI, using a T1 weighted 3D high resolution, FSPGR, MS protocol. Neurological disability was assessed by the Expanded Disability Status Scale (EDSS). FreeSurfer was used to obtain brain volumetric segmentation and to perform cortical thickness surface-based analysis. Clusters of change in cortical thickness with correlation to disease duration were produced. RESULTS: Two hundred seventy-one RRMS patients, mean ± SD age 33.0 ± 7.0 years, EDSS 1.6 ± 1.2, disease duration 5.0 ± 3.4 years. Cortical thickness analysis demonstrated focal areas of cerebral thinning that correlated with disease duration. Seven clusters accounting for 11.7% of the left hemisphere surface and eight clusters accounting for 10.6% of the right hemisphere surface were identified, with cluster-wise probability of p < 0.002 and p < 0.02, respectively.The clusters included bilateral involvement of areas within the cingulate, precentral, postcentral, paracentral, superior-parietal, superior-frontal gyri and insular cortex. Mean and cluster-wise cortical thickness negatively correlated with EDSS score, p < 0.001, with stronger Spearman rho for cluster-wise measurements. CONCLUSIONS: We identified CGMA patterns in sensitive brain regions which give insight and better understanding of the progression of cortical gray matter loss in relation to dissemination in space and time. These patterns may serve as markers to modulate therapeutic interventions to improve the management of MS patients.

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.

Unveiling the Psychological Consequences of Illness Perception in Pediatric Multiple Sclerosis: A Parent-Child Study.

BACKGROUND: Previous research has emphasized the significant role of illness perception in chronic diseases, including Multiple Sclerosis. Limited research has been conducted on exploring illness perception in Pediatric Onset Multiple Sclerosis (POMS), parental illness perception, and the impact of differences in their illness perceptions on the emotional well-being of the child. METHOD: This study included 65 dyads of children aged 10-17 and their parents, divided into the following two groups: (I) 32 dyads of children with POMS and their parents; and (II) 33 dyads of healthy children and their parents. RESULTS: Overall, 73.1% and 43.8% of the children with POMS met the criteria for probable anxiety and depression, respectively, compared to 27.3% and 0% of the healthy children. Differences were found between the dimensions of illness perception in the POMS children and their parents, in the areas of consequences, personal control, identity, and control factors. Multinomial Logistic Regression indicated that differences in child-parent illness perception increased the likelihood of comorbid anxiety and depression by 37%. DISCUSSION: These findings underscore the importance of alignment between children with POMS and their parents in illness perception. Healthcare providers should prioritize interventions that address illness perceptions and be mindful of the potential impact on depression and anxiety comorbidity.

The association of fear of falling and falls with sedentary behavior in people with multiple sclerosis.

OBJECTIVE: Sedentary behavior, falls, and fear of falling (FoF) are specific concerns for people with MS (pwMS). Considering the relatively high incidence and potential linkage, it is surprising that this triple relationship has as yet not been extensively investigated in pwMS. Thus, the present study aimed to examine the correlates of sedentary behavior with FoF and falls in pwMS. METHODS: Fifty pwMS, 30 women, were admitted to this cross-sectional study. Primary outcome measures included physical activity and sedentary behavior metrics measured by accelerometry, fall status, and FoF. Additional measures included mobility clinical tests, cognition, perceived fatigue, depression, and anxiety. The sample was divided into two subgroups according to the daily Metabolic Equivalent of Task (MET) rate scores; <1.5 was defined as sedentary, ≥1.5 were defined as non-sedentary. Multivariate analysis of variance and linear regression analyses assessed the relationships by using an alpha of 0.05. RESULTS: Sixty-four percent of the sample were classified as sedentary. The sedentary subgroup reported more FoF than the non-sedentary subgroup (32.5 (S·D. = 11.3) vs. 29.9 (S.D. = 9.5); however, no differences were found in fall status between the subgroups. No differences were found for depression, anxiety, cognition, and perceived fatigue between the subgroups. Furthermore, according to the linear regression analysis, FoF explained 23.9% of the variance pertaining to the daily MET rate when controlling for age, gender, disease duration, and disability. CONCLUSIONS: Clinicians are encouraged to incorporate the issue of FoF during standard management, which may represent an opportunity to improve care and reduce sedentary behavior in pwMS.

Range of motion abnormalities in the lower limb joints during gait in youth with multiple sclerosis.

BACKGROUND: The major objective of this study was to examine whether differences occur in the joint angles of the major lower limb joints while walking in youth with multiple sclerosis (YwMS) compared to age-gender-matched healthy youngsters. METHODS: Gait analysis was collected using a six-camera Cartesian Optoelectronic Dynamic Anthropometer (CODA) 3D motion analysis system. To determine the gait normality in the YwMS group, we compared our results to reference gait data from normal youngsters. Gait data was divided according to gender and age subgroups (8-14, 15-18 years old). RESULTS: The total sample included 26 YwMS (12 girls, 14 boys), 11 in the 8-14 age subgroup, and 15 in the 15-18 age subgroup. The mean expanded disability status scale score was 1.3 (S.D=1.0), indicating minimal disability. The total range of hip motion was significantly less in the YwMS group aged 15-18 (both genders) compared with the normative values. Additionally, the maximum flexion in the knee joint during gait was significantly less in boys in the 15 to 18 age subgroup (p<0.001). No differences were found in the hip and knee joint angles in the 8-14 age subgroup. CONCLUSIONS: YwMS experience modifications in their gait pattern compared with age-gender-matched healthy youngsters. The MS teenagers demonstrated less range of movement in the hip joints and walked slower at a decreased pace than the healthy teenagers. By tracking gait patterns, healthcare providers can identify subtle changes that might facilitate timely interventions to prevent further mobility impairment in this young population.

Attention Deficit/Hyperactivity Disorder in Children with Multiple Sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a chronic neurological autoimmune disease; pediatric-onset multiple sclerosis (POMS) represents 5% to 10% of total MS population. Children with POMS may experience attention difficulties due to the disease's impact on the central nervous system. However, little is known regarding Attention Deficit Hyperactivity Disorder (ADHD) in POMS, and its relation to cognitive performance. METHODS: A retrospective case review was conducted using medical records of 66 children and adolescent patients diagnosed with POMS between 2012 and 2021 in a MS center of a tertiary medical center. All patients had undergone routine clinical neurological examinations and had been assessed for a diagnosis of ADHD by a department pediatric neurologist. In addition, sociodemographic data, disease-related variables, and cognitive performance were collected. RESULTS: Of the 66 patients, 31 (47%) had a diagnosis of ADHD; 29 (44%) had cognitive impairment. Moreover, we identified four different profiles of POMS: those with only ADHD (17, 26%); only cognitive impairment (15, 23%), ADHD and cognitive impairment (14, 21%), and only POMS (20, 30%). A significant difference in disease duration was found among the four profiles [F(3,65) = 8.17, p < .001, η² = 0.29], indicating that patients with ADHD and cognitive impairment were characterized by longer disease duration. CONCLUSIONS: ADHD may be prominently involved in POMS, even during the early stages of the disease and early diagnosis is crucial in order to provide appropriate interventions and support.

No immediate change in systemic cytokines following an eccentric muscle training session in people with multiple sclerosis.

Background: Eccentric muscle contractions elicit distinct physiological responses, including modulation of the cytokine profile. Although relevant for rehabilitation, the effect of eccentric muscle training on the immune system has never been investigated in multiple sclerosis (MS). Objectives: Examine the immediate cytokine response of interleukin-4 (IL-4), IL-6, IL-10, IL-17a, interferon-gamma, and tumor necrosis factor-alpha after a moderate eccentric training session in individuals with MS. Additionally, further investigate the association between systemic cytokine levels at rest and clinical measures of mobility and lower limb functional strength. Design: Observational study. Methods: The first session included blood sampling for baseline cytokine measures. Subsequently, the participant completed a battery of clinical assessments related to mobility and lower limb strength, that is, the Timed-Up-and-Go Test, Five-Repetition-Sit-to-Stand-Test (5STS), Four-Square-Step-Test, and Two-Minute-Walk-Test. The second session included the eccentric exercise training session, followed by a second blood sampling to assess the acute cytokine response to the eccentric training bout. This session comprised 10 exercises concentrating on the strength of the trunk and lower extremities. Results: Twenty-seven people with MS (pwMS), with a mean age of 40.1 years, participated in the study. No difference was demonstrated in the cytokine concentration values between baseline and immediately after the eccentric training session. The 5STS explained 30.3% of the variance associated with interferon-gamma, 14.8% with IL-4, and 13.8% with IL-10. Conclusion: An eccentric training bout does not impact cytokine concentration in the blood and, consequently, does not boost a pro-inflammatory response, thus, it can be performed on pwMS in a rehabilitation setting.

A strength-lengthening exercise session doesn't affect inflammation markers in people with multiple sclerosis The article explores how a specific type of exercise, called eccentric muscle training, affects people with multiple sclerosis (MS). Eccentric muscle training involves exercises where the muscle lengthens under tension, like when you slowly lower a heavy object. This type of exercise is known for causing unique physical responses, including changes in certain proteins in the blood that help control the immune system and inflammation. The main goal of the study was to see if a session of eccentric muscle training would change the levels of these proteins, called cytokines, in the blood of people with MS immediately after exercise. The cytokines studied included IL-4, IL-6, IL-10, IL-17a, INF-γ, and TNF-α. These proteins are important because they help regulate inflammation and immune responses. The researchers also wanted to know if there was any connection between the levels of these proteins at rest and measures of mobility and leg strength. Twenty-seven people with MS took part in the study. Their average age was 40.1 years. In the first session, blood samples were taken to measure the baseline levels of these proteins, and various tests were conducted to assess mobility and leg strength. In the second session, participants completed an eccentric training session, and another blood sample was taken immediately after to see if there were any immediate changes in the protein levels. The results showed no significant differences in the protein levels before and after the exercise session. This suggests that a single session of eccentric muscle training does not cause an immediate inflammatory response in the blood. Therefore, this type of exercise can be safely included in rehabilitation programs for people with MS without the risk of causing harmful inflammation. Overall, the study supports the safety of eccentric muscle training for people with MS and provides valuable insights into its immediate effects on the immune system.

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.

The Israeli retrospective multicenter open-label study evaluating vagus nerve stimulation efficacy in children and adults.

BACKGROUND: The management of intractable epilepsy in children and adults is challenging. For patients who do not respond to anti-epileptic drugs and are not suitable candidates for epilepsy surgery, vagal nerve stimulation (VNS) is a viable alternative for reducing seizure frequency. METHODS: In this retrospective multicenter open-label study we examined the efficacy and tolerability of VNS in patients in five adult and pediatric epilepsy centers in Israel. All patients had drug-resistant epilepsy and after VNS implantation in 2006-2007 were followed for a minimum of 18 months. Patients were divided into two age groups: < 21 and > 21 years old. RESULTS: Fifty-six adults and children had a stimulator implanted in 2006-2007. At 18 months post-VNS implantation, none of the patients was seizure-free, 24.3% reported a reduction in seizures of > or = 75%, 19% reported a 50-75% reduction, and 10.8% a 25-50% reduction. The best response rate occurred in patients with complex partial seizures. Among these patients, 7 reported a > or = 75% reduction, 5 patients a 50-75% reduction, 3 patients a 25-50% reduction, and 8 patients a < 25% reduction. A comparison of the two age groups showed that the older group (< 21 years old) had fewer seizures than the younger group. CONCLUSIONS: VNS is a relatively effective and safe palliative method for treating refractory epilepsy in both adults and children. It is an alternative treatment for patients with drug-resistant epilepsy, even after a relatively long disease duration, who are not candidates for localized epilepsy surgery.