The Toronto Observational Study of Natalizumab in Multiple Sclerosis

The motor cortex (MC) receives an excitatory input from the cerebellum which is reduced in patients with cerebellar lesions. High-frequency repetitive transcranial magnetic stimulation (rTMS) induces cortical facilitation which can counteract the reduced cerebellar drive to the MC. Our study included 24 relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS) patients with dysmetria. The patients were divided into two groups: Group A received two sessions of real MC rTMS and Group B received one session of real rTMS and one session of sham rTMS. Ten healthy volunteers formed group C. Evaluation was carried out using the nine-hole pegboard task and the cerebellar functional system score (FSS) of the expanded disability status scale (EDSS). Group A patients showed a significant improvement in the time required to finish the pegboard task (P=0.002) and in their cerebellar FSS (P=0.000) directly after the second session and 1month later. The RRMS patients showed more improvement than the SPMS patients. Group B patients did not show any improvement in the pegboard task or the cerebellar FSS. These results indicate that MC rTMS can be a promising option in treating both RRMS or SPMS patients with cerebellar impairment and that its effect can be long-lasting.

Dysphagia is one of the most common symptoms in multiple sclerosis (MS) patients. It can reduce the quality of life and increase the risk of mortality by developing complications such as aspiration pneumonia. The present study was conducted to estimate the prevalence of dysphagia in MS patients and investigate the associations between dysphagia and disease characteristics. The Persian version of the DYMUS questionnaire was used to assess dysphagia in 865 patients with MS, including 738 (85.3%) relapsing-remitting MS (RRMS), 106 (12.3%) secondary progressive MS (SPMS), and 21 (2.4%) primary progressive MS (PPMS). Also, demographic and clinical data, including age, sex, smoking status, Expanded Disability Status Scale (EDSS) score, disease duration, disease-modifying therapies exposure, initial symptoms of MS, were recorded. The mean (SD) age was 37.95(9.25) years, and 83.1% of the participants were female. The prevalence of dysphagia was estimated to be 25.4% among all patients. According to the DYMUS questionnaire results, the prevalence of dysphagia in RRMS, SPMS, and PPMS patients was 22.2%, 44.3%, and 42.9%, respectively. After multivariate analysis the current EDSS score (OR = 1.197, CI: 1.062, 1.350, p = 0.003), cerebellar impairment (OR = 1.335, CI: 1.450, 4.716, p = 0.004) and motor dysfunction (OR = 1.651, CI: 1.004, 2.715, p = 0.048) emerged as the risk factors for dysphagia. Since dysphagia, as previously mentioned, is a common symptom in multiple sclerosis, particularly in SPMS and PPMS courses, active screening for this condition is recommended in all patients, particularly those with identified risk factors.

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.

ObjectivesTo evaluate white matter and grey matter T1-weighted (w)/T2w ratio (T1w/T2w ratio) in healthy controls and patients with multiple sclerosis, and its association with clinical disability.MethodsIn this cross-sectional study, 270...

The aim of this study was to investigate the shape differences in the corpus callosum (CC) and cerebellum of female relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS) patients compared with healthy controls. This study was conducted using the magnetic resonance imaging scans of 15 control subjects, 26 RRMS, and 14 SPMS patients. The data obtained from the landmark coordinates were analyzed with statistical shape analysis. The landmarks that were chosen to determine the shape differences of the CC and cerebellum have been identified and used in previous studies. In addition to these landmarks, constructed landmarks were determined and used to assess regional shape differences better. The shapes of the CC and cerebellum showed statistically significant differences from the controls when compared with both the RRMS and SPMS patients. It was found that the deformation observed from controls to SPMS was greater than the deformation from controls to RRMS, both for the CC and cerebellum. In conclusion, this study revealed CC and cerebellar shape change in RRMS and SPMS, and showed that deformations both in CC and cerebellum advances with the disease progression.

Magnetic resonance fingerprinting in multiple sclerosis

Mitoxantrone (MX) has been shown to be moderately effective in reducing the clinical outcome measures of disease activity in multiple sclerosis (MS) patients. The objective was to assess the efficacy and safety of MX in relapsing-remitting MS (RRMS), progressive relapsing MS (PRMS) and secondary progressive MS (SPMS). We searched the Cochrane MS Group Trials Register (searched April 2005), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2004), MEDLINE (Pub Med) (January 1966 to April 2005), EMBASE (January 1974 to April 2005), and reference lists of articles. We also undertook hand searching and contacting trialists and pharmaceutical companies. The trials were selected if double-blinded, placebo-controlled, randomised, irrespective of eventual additive therapy (such as steroids). Three reviewers independently selected articles for inclusion, assessed trials' quality and extracted data. Four trials involving 270 participants were included. MX was found to reduce the progression of disability at 2 years follow-up (proportion of participants with 6-months confirmed progression of disability: Odds Ratios (OR) 0.3, p = 0.05). Similar figures were found regarding the reduction in annualised relapse rate and the proportion of patients free from relapses at 1 and 2 years, as well as the number of patients with active MRI lesions at 6 months/ 1 year only. Side effects reported in the trials were more frequent in treated patients than in controls. Caution must be exercised in drawing conclusions from such data because of the heterogeneous quality and characteristics of the included trials, which are different in terms of treatment schedule and type of enrolled patients. More than half of the included patients came from a single study. Moreover, from the included trials, it was not possible to estimate the long-term efficacy and safety of MX, which may raise concerns about the risk of cardiotoxicity and therapy-related leukemias, which is increasingly reported in the literature. MX is moderately effective in reducing the disease progression and the frequency of relapses in patients affected by RR, PR and SP MS in the short-term follow-up (2 years), even if the results are based on trials heterogeneous in terms of drug dosage and inclusion criteria. No major neoplastic or symptomatic cardiotoxicity related to MX have been reported from the trials. However, longer follow-up studies are highly warranted to better explore the efficacy and safety of the drug, mainly as regards the long-term risk of therapy-related leukemias and cardiotoxicity. As a conclusion, MX has a partial efficacy, but, due to its unclear long-term safety profile, it should be used to treat patients with worsening RR and SP MS with evidence of worsening disability.

Objective: to study the effectiveness of art therapy methods in the complex treatment of neuropsychological disorders and quality of life improvement in patients with relapsing-remitting and secondary-progressive multiple sclerosis (MS).Patients and methods. A group of 42 patients (5 men and 37 women, mean age 32.9 years, mean EDSS severity 3.8 points) with MS underwent outpatient continuous active art therapy cycle. The mean group training cycle duration was six months. The comparison group included 15 age- and sex-adjusted individuals without neurological disorders. Tests on various drawing topics were carried out before and after a three-month therapy course. We used Hospital Anxiety and Depression Scale (HADS) to assess the severity of anxiety and depression and the SF-36 scale to evaluate the quality of life (QoL).Results and discussion. Before the art therapy start, light blue, yellow, pink, blue, and green colors prevailed in the drawings. There was no predominance of any color depending on MS severity or course. The green color predominated in this test in the control group, and the light blue color was significantly less represented. The art therapy course did not lead to a significant change in the severity of MS according to the Expanded Disability Status Scale (EDSS). After the art therapy course, the color scheme of the drawings was mainly represented by red, light blue, green, yellow, and blue colors. In addition, a red-orange color appeared in the drawings, which was completely absent before the course. Positive trends were noted according to HADS: a decrease in anxiety by 23% and depression by 19%. The physical component of QoL assessed by the SF-36 scale did not change substantially, but the psychological component significantly improved by 11%.Conclusion. The predominance of light blue color observed in MS is associated with damage to the nervous and musculoskeletal systems, and blue color – with psychological problems and depression. However, after a course of art therapy for MS, red, red-orange, yellow, and green colors representation increased significantly, which indicates an increase in positive attitude, a decrease in the level of depression, and an improvement in QoL.

In this multicenter study, a new semiautomatic method for segmenting the cervical cord from C2 to C5 was used to investigate the correlation between cord atrophy and clinical disability in a large sample of patients with multiple sclerosis (MS). T2 and 3-dimensional T1-weighted cervical cord scans and dual-echo brain scans were acquired from 143 healthy controls, 22 patients with clinically isolated syndromes (CIS), 101 patients with relapsing-remitting MS (RRMS), 79 patients with secondary progressive MS (SPMS), 58 patients with benign MS (BMS), and 75 patients with primary progressive MS (PPMS) in 3 European centers. Normalized cervical cord cross-sectional area (CSAn) was measured by an active surface cord model. Between-group comparisons were performed using linear mixed-effect models. A nonparametric kernel estimator was used to obtain smoothed plots of CSA along the cervical cord. Cord CSAn was significantly lower in PPMS vs healthy controls, BMS vs RRMS, SPMS vs BMS, and RRMS. From C2 to C5, a net separation and definition of the plots of patients with BMS, PPMS, and SPMS was seen with respect to those of the other study groups. CSAn was correlated with Expanded Disability Status Scale (r = -0.49, p < 0.0001), with a differential effect among disease clinical phenotypes: no association in either CIS or in BMS; association in RRMS (r = -0.30, p = 0.001), SPMS (r = -0.34, p = 0.001), and PPMS (r = -0.27, p = 0.01). Cervical cord atrophy provides a relevant and useful marker for the characterization of clinical heterogeneity of patients with MS. The stability of this measure among different centers supports its use as potential outcome measure to monitor disease progression in multicenter trials.

Vitamin B6 status is related to disease severity and modulated by endurance exercise in individuals with multiple sclerosis: a secondary analysis of a randomized controlled trial.

BackgroundAlemtuzumab is a humanized monoclonal antibody approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). Its efficacy and safety have been widely demonstrated in clinical trials, but experience from real-world cohorts is also needed to support its clinical use. Quality of life (QoL) outcomes are an important complement to the clinical benefits of treatment, offering a patient-centered perspective on how the drug contributes to general well-being. In this line we aimed to evaluate the QoL of patients treated with alemtuzumab in clinical practice.MethodsThis prospective 3-year multicenter study was carried out in adult patients diagnosed with RRMS who had started alemtuzumab according to clinical practice within 8 weeks before inclusion. The primary endpoint was the change in QoL over three years of treatment with alemtuzumab using the 29-item Multiple Sclerosis Impact Scale (MSIS-29). Secondary endpoints included changes from baseline in the 21-item Modified Fatigue Impact Scale (MFIS-21), Beck Depression Inventory (BDI-II), Symbol Digit Modalities Test (SDMT, oral version) and Work Productivity. Disability worsening was also assessed based on the Expanded Disability Status Scale (EDSS), along with the annualized relapse rate (ARR) and radiological activity.ResultsA cohort of 165 patients was analyzed (mean age 38.6 years, mean disease duration 8.5 years, mean EDSS score 3.3). MSIS-29 physical domain scores decreased significantly from baseline by a mean of 7.2 ± 1.8 points at year 1, 6.4 ± 2.2 at year 2 and 5.6 ± 2.3 at year 3 (p < 0.05 in all cases). Similarly, MSIS-29 psychological domain scores decreased significantly by a mean of 7.9 ± 2.4 points at year 1, 12.8 ± 2.9 at year 2 and 13.2 ± 3.0 at year 3 (p < 0.05 in all cases). Significant reductions from baseline were also evidenced in MFIS-21 and BDI-II scores, while SDMT scores remained unchanged. During the 3 years on alemtuzumab, the ARR was 0.15, representing an 83% reduction from the 2 years before initiation. At 3 years, 81.5% of patients were free from radiological activity and 87% were free from disability worsening.ConclusionsThese results indicate early and substantial improvements in patients’ perception of their QoL and functioning with alemtuzumab that were sustained over three years.

Activated microglia are thought to play a major role in cortical gray matter (GM) demyelination in multiple sclerosis (MS). Our objective was to evaluate microglial activation in cortical GM of patients with MS in vivo and to explore its relationship to measures of disability. Using PET and optimized modeling and segmentation procedures, we investigated cortical (11)C-PK11195 (PK11195) binding in patients with relapsing-remitting MS (RRMS), patients with secondary progressive MS (SPMS), and healthy controls. Disability was assessed with the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Impact Scale (MSIS-29). Patients with MS showed increased cortical GM PK11195 binding relative to controls, which was multifocal and highest in the postcentral, middle frontal, anterior orbital, fusiform, and parahippocampal gyri. Patients with SPMS also showed additional increases in precentral, superior parietal, lingual and anterior superior, medial and inferior temporal gyri. Total cortical GM PK11195 binding correlated with EDSS scores, with a stronger correlation for the subgroup of patients with SPMS. In patients with SPMS, PK11195 binding also correlated with MSIS-29 scores. No correlation with disability measures was seen for PK11195 binding in white matter. Higher EDSS scores correlated with higher levels of GM PK11195 binding in the postcentral gyrus for patients with RRMS and in precentral gyrus for those with SPMS. Microglial activation in cortical GM of patients with MS can be assessed in vivo. The distribution is not uniform and shows a relationship to clinical disability. We speculate that the increased PK11195 binding corresponds to enhanced microglial activation described in postmortem SPMS cortical GM.

The purpose of this work was to determine the extent of disease and disease severity in the conventional MR normal-appearing gray matter (NAGM) and white matter (NAWM) in patients with relapsing-remitting (RR) and secondary progressive (SP) multiple sclerosis (MS) utilizing quantitative magnetization transfer ratio (MTR) histogram analysis. Twenty-seven patients with MS (16 RR, 11 SP) and 16 healthy control subjects were studied. MTR was calculated in the totally segmented GM and WM without T2 lesions in each group. Each of the RR and SP MS patient groups had significantly smaller MTR histogram mean values in NAGM and NAWM than the healthy subjects (p </= 0.0015). SP MS patients had a significantly lower first quartile and MTR histogram peak height for NAGM only (p </= 0.004) when compared with both RR MS patients and healthy subjects. The T2 lesion load had a modest negative correlation with MTR values in both RR and SP MS, but only in NAGM. Separate analysis of GM and WM MTR histograms may allow better detection of subtle damage and better understanding of the natural history of MS disease and ultimately the response to therapeutics.

BackgroundMultiple sclerosis (MS) is a disease with profound heterogeneity in clinical course.ObjectiveTo analyze sources and levels of income among MS patients in relation to disease phenotype with a special focus on identifying differences/similarities between primary progressive MS (PPMS) and secondary progressive MS (SPMS).MethodsA total of 6890 MS patients aged 21−64 years and living in Sweden in 2010 were identified for this cross-sectional study. Descriptive statistics, logistic, truncated linear, and zero-inflated negative binomial regression models were used to estimate differences in income between SPMS, PPMS and relapsing-remitting MS (RRMS) patients.ResultsRRMS patients earned almost twice as much as PPMS and SPMS patients (on average SEK 204,500, SEK 114,500, and SEK 79,800 in 2010, respectively). The difference in earnings between PPMS and SPMS was not statistically significant when analyzed with multivariable regression. The estimated odds ratio for PPMS patients to have income from earnings was not significantly different from SPMS patients (95% CI 0.98 to 1.59). PPMS and RRMS patients were less likely to receive benefits when compared to SPMS patients (by 6% and 27% lower, respectively).ConclusionOur findings argue for similarities between PPMS and SPMS and highlight the socioeconomic importance of preventing RRMS patients convert to SPMS.

Fampridine is the only drug approved by the US Food and Drug Administration (FDA) for people with multiple sclerosis (MS) to improve their movement and has exhibited a clinically significant improvement in gait function in a subset of MS patients with Expanded Disability Status Scale (ESDSS) from 4 to 7. Nevertheless, this drug has been reported to possess some adverse effects (AEs) like seizure because of its pharmacological features. The aim of this study was to evaluate the incidence rate of post-medication side effects (SEs) of fampridine in MS patients. This prospective cohort study includes MS patients aged between 18 and 65 years, referred to the neurology clinic of Kashani Hospital from April 2022 to October 2022, all with administration of fampridine (10 mg tablet twice daily according to the product specifications). Safety in these patients was monitored through monthly SEs checklist questions during 6 months of screening. SPSS version 18 was used to analyze the data of this study. From 319 participants screened at baseline, 254 patients with MS, including 127 relapsing-remitting multiple sclerosis (RRMS), 101 secondary progressive multiple sclerosis (SPMS), and 26 primary progressive multiple sclerosis (PPMS), were included in the study. The most observed AEs in SPMS and RRMS patients were dry mouth (13.9% vs. 15%) and insomnia (12.9% vs. 11%), respectively. Urinary tract infection (UTI) (11.5%) and stomachache (11.5%) were the most common SEs in PPMS patients. The most severe complication of the patients was back pain, while digestive complications were less severe. Also, insomnia and UTI were the patients' most persistent SEs. The drug seems to be safe and well tolerated, as the SEs were mild and transient and they were consistent with most of the previous studies focusing on this medication.