Pediatric-onset multiple sclerosis (MS) has a highly active and aggressive course, which can have a devastating effect on the physical and cognitive functioning of a child if not treated ...appropriately with effective disease-modifying drugs. The optimal treatment strategy of pediatric MS is currently unknown and debate continues as to whether treatment escalation or initiation of a highly active therapy provides a better outcome. Here, we present the case of a 16-year-old female diagnosed with highly active relapsing-remitting MS (age at onset: 14 years) who received first-line treatment with fingolimod within 1 year of the first recorded symptom. Since starting fingolimod, the course of the disease has essentially been stable. No new or active lesions were observed in magnetic resonance imaging scans performed at 3 and 12 months after starting fingolimod, and treatment was well tolerated. These data suggest that, in this case, early treatment with first-line fingolimod was able to slow disease progression.
Mindfulness interventions have been shown to treat depressive symptoms and improve quality of life in patients with several chronic diseases, including multiple sclerosis, but to date most evaluation ...of the effectiveness of mindfulness interventions in multiple sclerosis have used patients receiving standard care as the control group. Hence we decided to evaluate the effectiveness of a group-based body-affective mindfulness intervention by comparing it with a psycho-educational intervention, by means of a randomized controlled clinical trial. The outcome variables (i.e., depression, anxiety, perceived stress, illness perception, fatigue and quality of life) were evaluated at the end of the interventions (T1) and after a further 6 months (T2).
Of 90 multiple sclerosis patients with depressive symptoms (Beck Depression Inventory-II score greater than 13) who were randomized, 71 completed the intervention (mindfulness group
36; psycho-educational group
35). The data were analyzed with GLM repeated-measures ANOVA followed by pairwise comparisons.
Per-protocol analysis revealed a time by group interaction on Beck Depression Inventory-II score, with the mindfulness intervention producing a greater reduction in score than the psycho-educational intervention, both at T1 and at T2. Furthermore, the mindfulness intervention improved patients' quality of life and illness perception at T1 relative to the baseline and these improvements were maintained at the follow-up assessment (T2). Lastly, both interventions were similarly effective in reducing anxiety and perceived stress; these reductions were maintained at T2. A whole-sample intention-to-treat (ITT) analysis broadly confirmed the effectiveness of the mindfulness intervention.
In conclusion, these results provide methodologically robust evidence that in multiple sclerosis patients with depressive symptoms mindfulness interventions improve symptoms of depression and anxiety and perceived stress, modulate illness representation and enhance quality of life and that the benefits are maintained for at least 6 months.
the study was registered in the ClinicalTrials.gov registry (NCT02611401).
To investigate the presence and the nature of cognitive impairment in a large sample of patients with Multiple Sclerosis (MS), and to identify clinical and demographic determinants of cognitive ...impairment in MS.
303 patients with MS and 279 healthy controls were administered the Brief Repeatable Battery of Neuropsychological tests (BRB-N); measures of pre-morbid verbal competence and neuropsychiatric measures were also administered.
Patients and healthy controls were matched for age, gender, education and pre-morbid verbal Intelligence Quotient. Patients presenting with cognitive impairment were 108/303 (35.6%). In the overall group of participants, the significant predictors of the most sensitive BRB-N scores were: presence of MS, age, education, and Vocabulary. The significant predictors when considering MS patients only were: course of MS, age, education, vocabulary, and depression. Using logistic regression analyses, significant determinants of the presence of cognitive impairment in relapsing-remitting MS patients were: duration of illness (OR = 1.053, 95% CI = 1.010-1.097, p = 0.015), Expanded Disability Status Scale score (OR = 1.247, 95% CI = 1.024-1.517, p = 0.028), and vocabulary (OR = 0.960, 95% CI = 0.936-0.984, p = 0.001), while in the smaller group of progressive MS patients these predictors did not play a significant role in determining the cognitive outcome.
Our results corroborate the evidence about the presence and the nature of cognitive impairment in a large sample of patients with MS. Furthermore, our findings identify significant clinical and demographic determinants of cognitive impairment in a large sample of MS patients for the first time. Implications for further research and clinical practice were discussed.
Intertrial variability (ITV) of motor responses to peripheral (CMAP) and transcranial (MEP) stimulation prevents their use in follow-up studies. Our purpose was to develop strategies to reduce and ...measure CMAP and MEP ITV to guide long-term monitoring of conduction slowing and conduction failure of peripheral and central motor pathway in the individual patient.
Maximal compound muscle action potentials to High Voltage Electrical Stimulation (HVES) of lumbo-sacral nerve roots (r-CMAP) and activated, averaged motor evoked potentials (MEPs) to Transcranial Magnetic Stimulation (TMS) using double cone coil were recorded from 10 proximal and distal muscle districts of lower limbs. The procedure was repeated twice, 1-2 days apart, in 30 subjects, including healthy volunteers and clinically stable multiple sclerosis patients, using constant stimulating and recording sites and adopting a standardized procedure of voluntary activation. ITV for latency and area indexes and for the ratio between MEP and r-CMAP areas (a-Ratio) was expressed as Relative Intertrial Variation (RIV, 5th-95th percentile). As an inverse correlation between the size of area and ITV was found, raw ITV values were normalized as a function of area to make them comparable with one another.
All RIV values for latencies were significantly below the optimum threshold of ± 10%, with the exception of r-CMAP latencies recorded from Vastus Lateralis muscle. RIVs for a-Ratio, the most important index of central conduction failure, ranged from a maximum of -25.3% to +32.2% (Vastus Medialis) to a minimum of -15.0% to + 17.4% (Flexor Hallucis Brevis).
The described procedure represents an effort to lower as much as possible variability of motor responses in serial recording; the reported ITV normative values are the necessary premise to detect significant changes of motor conduction slowing and failure in the individual patient in follow-up studies.
Introduction
B-cell-depleting agents have been widely used for neuromyelitis optica spectrum disorder (NMOSD) and MOG-associated diseases (MOGAD), but no consensus exists on the optimal dose and ...frequency of treatment administration. The aim of our study was to evaluate the effect of a Rituximab (RTX) personalized treatment approach based on CD27-positive B-cell monitoring on efficacy, safety, and infusion rates.
Methods
This is a retrospective, uncontrolled, single-center study including patients with NMOSD and MOGAD treated with RTX at a tertiary multiple sclerosis center at the San Luigi University Hospital, Orbassano, Italy. All the patients were treated with RTX induction, followed by maintenance infusion at the dosage of 1000 mg according to cell repopulation: initially according to total CD19-positive B-cell monitoring (> 0.1% of lymphocytes), and subsequently according to CD27-positive B-cell repopulation (> 0.05% of lymphocytes for the first 2 years, and subsequently > 0.1%). NMOSD and MOGAD activity was assessed as clinical or MRI activity. All patients were screened of the occurrence of severe adverse events (AEs).
Results
A total of 19 patients were included in the analysis. Median follow-up was 7.64 years (range 3.09–16.25). The annualized relapse rate (ARR) 1 year before RTX start was 2.37 Standard deviation (SD), 1.34 and decreased to 0.08 (SD 0.11) in the subsequent years after RTX initiation. ARR did not differ before and after start of CD27 monitoring. Median inter-dose time was 8.80 (range 5.78–14.23) before CD27 monitoring and 15.93 months (range 8.56–35.37) after CD27 monitoring (
p
< 0.001). We observed no AEs.
Conclusion
Our findings suggest that in our cohort CD27-positive B-cell-based RTX reinfusion regimen was able to reduce the number of RTX reinfusions relative to CD19-positive B-cell monitoring, with comparable efficacy and safety profile. In order to achieve an even more individualized and effective treatment, the FCGR3A genetic polymorphisms could be evaluated when assessing RTX efficacy.
Pregnancy is associated with reduced activity of multiple sclerosis (MS). However, the biological mechanisms underlying this pregnancy-related decrease in disease activity are poorly understood.
We ...conducted a genome-wide transcription analysis in peripheral blood mononuclear cells (PBMCs) from 12 women (7 MS patients and 5 healthy controls) followed during their pregnancy. Samples were obtained before, during (i.e. at the third, sixth, and ninth month of gestation) and after pregnancy. A validation of the expression profiles has been conducted by using the same samples and an independent group of 25 MS patients and 11 healthy controls. Finally, considering the total group of 32 MS patients, we compared expression profiles of patients relapsing during pregnancy (n = 6) with those of relapse-free patients (n = 26).
Results showed an altered expression of 347 transcripts in non-pregnant MS patients with respect to non-pregnant healthy controls. Complementary changes in expression, occurring during pregnancy, reverted the previous imbalance particularly for seven inflammation-related transcripts, i.e. SOCS2, TNFAIP3, NR4A2, CXCR4, POLR2J, FAM49B, and STAG3L1. Longitudinal analysis showed that the overall deregulation of gene expression reverted to "normal" already within the third month of gestation, while in the post-partum gene expressions rebounded to pre-pregnancy levels. Six (18.7%) of the 32 MS patients had a relapse during pregnancy, mostly in the first trimester. The latter showed delayed expression profiles when compared to relapse-free patients: in these patients expression imbalance was reverted later in the pregnancy, i.e. at sixth month.
Specific changes in expression during pregnancy were associated with a decrease in disease activity assessed by occurrence of relapses during pregnancy. Findings might help in understanding the pathogenesis of MS and may provide basis for the development of novel therapeutic strategies.
Objective
This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID‐19) in people with multiple sclerosis ...(PwMS).
Methods
We retrospectively collected data of PwMS with suspected or confirmed COVID‐19. All the patients had complete follow‐up to death or recovery. Severe COVID‐19 was defined by a 3‐level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID‐19 by multivariate and propensity score (PS)‐weighted ordinal logistic models. Sensitivity analyses were run to confirm the results.
Results
Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID‐19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty‐eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized.
After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti‐CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio OR = 2.37, 95% confidence interval CI = 1.18–4.74, p = 0.015) with increased risk of severe COVID‐19. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20–12.53, p = 0.001). Results were confirmed by the PS‐weighted analysis and by all the sensitivity analyses.
Interpretation
This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID‐19 pandemic persists. ANN NEUROL 2021;89:780–789
Abstract Glatiramer acetate (GA) is a widely used treatment for multiple sclerosis (MS), with incompletely defined mechanism of action. Short-term studies suggested its involvement in the modulation ...of anti-inflammatory cytokines and regulatory T cells (Treg), while long-term effect is still unknown. To investigate this aspect, we analyzed by flow-cytometry peripheral-blood Treg, natural killer (NK), CD4 and CD8 T-cells and anti-inflammatory CD14+ CD163+ monocytes from 37 healthy donor and 90 RRMS patients divided in untreated, treated with GA for 12 months and from 34 to 192 months. While NK, CD4 and CD8 T-cells did not show any significant differences among groups over time, we demonstrated that GA increased the anti-inflammatory monocytes and restored the Treg level in both GA-treated groups. Both these effects are a characteristic of responder patients and are observed not just in short-term but even after as long as a decade of GA treatment.
The exclusion of other diseases that can mimic multiple sclerosis (MS) is the cornerstone of current diagnostic criteria. However, data on the frequency of MS mimics in real life are incomplete.
A ...total of 695 patients presenting with symptoms suggestive of MS in any of the 22 RIREMS centers underwent a detailed diagnostic workup, including a brain and spinal cord MRI scan, CSF and blood examinations, and a 3-year clinical and radiologic follow-up.
A total of 667 patients completed the study. Alternative diagnoses were formulated in 163 (24.4%) cases, the most frequent being nonspecific neurologic symptoms in association with atypical MRI lesions of suspected vascular origin (40 patients), migraine with atypical lesions (24 patients), and neuromyelitis optica (14 patients). MS was diagnosed in 401 (60.1%) patients according to the 2017 diagnostic criteria. The multivariate analysis revealed that the absence of CSF oligoclonal immunoglobulin G bands (IgG-OB) (odds ratio OR 18.113), the presence of atypical MRI lesions (OR 10.977), the absence of dissemination in space (DIS) of the lesions (OR 5.164), and normal visual evoked potentials (OR 3.550) were all independent predictors of an alternative diagnosis.
This observational, unsponsored, real-life study, based on clinical practice, showed that diseases that mimicked MS were many, but more than 45% were represented by nonspecific neurologic symptoms with atypical MRI lesions of suspected vascular origin, migraine, and neuromyelitis optica. The absence of IgG-OB and DIS, the presence of atypical MRI lesions, and normal visual evoked potentials should be considered suggestive of an alternative disease and red flags for the misdiagnosis of MS.
PDF
