Transcutaneous tibial nerve stimulation in patients with multiple sclerosis and overactive bladder: a real-life clinical and urodynamic assessment.

AIMS: The aims of the present study were to assess the effectiveness of transcutaneous tibial nerve stimulation (TTNS) on overactive bladder (OAB) symptoms and on urodynamic parameters in patients with multiple sclerosis (PwMS) and to seek predictive factors of satisfaction. METHODS: All PwMS who performed 12-24 weeks of TTNS and who underwent urodynamic assessment before and after treatment between June 2020 and October 2022 were included retrospectively. Data collected were bladder diaries, symptoms assessed with Urinary Symptoms Profile (USP), and urodynamic parameters (bladder sensations, detrusor overactivity, and voiding phase). Patients with improvement rated as very good or good on Patient Global Impression of Improvement (PGI-I) score were considered as responders. RESULTS: Eighty-two patients were included (mean age: 47.1 ± 11.5 years, 67 (82%) were women). The mean USP OAB sub-score decreased from 7.7 ± 3.5 to 6.0 ± 3.4 (p < 0.0001). On bladder diaries, voided volumes, void frequency, and the proportion of micturition done at urgent need to void significantly improved with TTNS (p < 0.05). No significant change was found in urodynamic parameters. According to the PGI-I, 34 (42.5%) patients were good responders. The only parameter associated with higher satisfaction was the percentage of micturition done at urgent need to void before the initiation of the treatment (39.8% ± 30.5 in the responder group vs 25.1% ± 25.6 in the low/no responder group; p = 0.04). CONCLUSION: TTNS improves OAB symptoms in PwMS, without significant changes on urodynamics. A high rate of strong or urgent need to void in daily life was associated with higher satisfaction.

Validation of the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) in individuals with multiple sclerosis from Mexico.

BACKGROUND: Cognitive impairment is observed in 43-70 % of Multiple sclerosis (MS) patients. One of the most widely used batteries for cognitive assessment in this population is the Brief International Cognitive Assessment for MS (BICAMS). The objective of this study was to validate and assess the reliability of the BICAMS in a Mexican population with MS and to obtain and provide regression-based norms. METHODS: One hundred healthy controls (HCs) and 100 patients with multiple sclerosis participated in the present study, and groups were matched for age, years of education and sex. Subjects completed all three tests of the BICAMS. Test-retest measures were obtained from 30 patients to test reliability. RESULTS: The sample´s average age was 43.39 ± 6.03 years old, and the average years of education was 12.55 ± 2.52 years. Approximately 63 % of the participants were female. The groups did not differ in age, years of education, or sex. The MS group performed significantly worse than the HCs group on all three neuropsychological tests. A significant difference was observed for the SDMT (t = 10.166; p=<0.001), CVLT-II (t = 10.949; p=<0.001), and BVMT-R (t = 2.636; p = 0.009). For all comparisons, the effect size (d) for each test was calculated as follows: SDMT= 0.58 and CVLT-II= 0.61. The test-retest coefficients for each test were as follows: SDMT: r = 0.95; CVLT-II: r = 0.84; and BVMT-R = 0.81. CONCLUSION: The BICAMS can provide information on cognitive impairment in MS patients, and this information can be used by neuropsychologists for cognitive rehabilitation in different domains.

Premorbid cognitive functioning influences differences between self-reported cognitive difficulties and cognitive assessment in multiple sclerosis.

Cognitive difficulties are reported in up to 60% of people with MS (pwMS). There is often a discrepancy between self-reported cognitive difficulties and performance on cognitive assessments. Some of this discrepancy can be explained by depression and fatigue. Pre-MS cognitive abilities may be another important variable in explaining differences between self-reported and assessed cognitive abilities. PwMS with high estimated premorbid cognitive functioning (ePCF) may notice cognitive difficulties in daily life whilst performing within the average range on cognitive assessments. We hypothesised that, taking into account depression and fatigue, ePCF would predict (1) differences between self-reported and assessed cognitive abilities and (2) performance on cognitive assessments. We explored whether ePCF predicted (3) self-reported cognitive difficulties. Eighty-seven pwMS completed the Test of Premorbid Functioning (TOPF), the Brief International Cognitive Assessment for MS (BICAMS), self-report measures of cognitive difficulty (MS Neuropsychological Questionnaire; MSNQ), fatigue (MS Fatigue Impact Scale; MFIS) and depression (Hospital Anxiety and Depression Scale; HADS). Results revealed that, taking into account covariates, ePCF predicted (1) differences between self-reported and assessed cognitive abilities, p < .001 (model explained 29.35% of variance), and (2) performance on cognitive assessments, p < .001 (model explained 46.00% of variance), but not (3) self-reported cognitive difficulties, p = .545 (model explained 35.10% of variance). These results provide new and unique insights into predictors of the frequently observed discrepancy between self-reported and assessed cognitive abilities for pwMS. These findings have important implications for clinical practice, including the importance of exploring premorbid factors in self-reported experience of cognitive difficulties.

Agreement between video-based clinician-rated tools and patient-reported outcomes on gait assessment in individuals with multiple sclerosis.

PURPOSE: To our knowledge, no studies compared the video-clinician-based tools and patient-reported questionnaires in assessing gait and balance in people with MS (pwMS). The present study investigated the correlation and agreement between video-clinician-based objective measurement tools and patient-reported outcome measures (PROMs) in gait and balance evaluation. METHODS: A prospective cross-sectional study was conducted with 55 pwMS. Video analysis-based gait was evaluated by the Tinetti Gait Assessment (TGA), Gait Assessment and Intervention Tool (GAIT), and Functional Ambulation Classification Scale (FACS) by the clinician. Participants' self-reported gait and balance were assessed with the Multiple Sclerosis Walking Scale-12 (MSWS-12) and Activity-Specific Balance Confidence Scale (ABC). RESULTS: There was a moderate positive correlation between ABC with TGA and FACS (r1: 0.552, r2: 0.510, p < 0.001). ABC was strongly correlated with GAIT (r: - 0.652, p < 0.001). A moderate positive correlation was observed between MSWS-12 with TGA and FACS (r1: - 0.575, r2: - 0.524, p < 0.001). In addition, there was a strong positive correlation between MSWS-12 and GAIT (r: - 0.652, p < 0.001). Clinician-rated tools and PROMs were within the agreement limits regarding the unstandardized beta values p < 0.001). CONCLUSIONS: Clinician-based gait and balance tools demonstrate consistent results with PROMs in pwMS. Considering the low cost and practical use of PROMs, in cases where video-based clinician-based measurements cannot be provided (time, space, and technical inadequacies), questionnaires can provide concordant results at moderate and severe levels compared with objective tools.

Reliability and validity of the Arabic version of brief international cognitive assessment for multiple sclerosis in Egyptian pediatric multiple sclerosis patients.

BACKGROUND & OBJECTIVES: About one-third of pediatric-onset MS (POMS) patients report cognitive impairment. This case-control study aimed to assess the reliability and validity of the Arabic version of the Brief International Cognitive Assessment for MS (BICAMS) in Egyptian POMS patients. METHODS: A case-control study was conducted on 30 POMS patients aged 9 to 17 years old and 30 healthy controls. Both groups underwent the following tests: neuropsychological testing using the BICAMS-validated Arabic version battery involving the Symbol Digit Modality Test (SDMT), California Verbal Learning Test 2nd edition (CVLT-II) and revised Brief Visuospatial Retention Test (BVRT-R). Test-retest data were obtained from MS patients and controls 2 weeks following the primary evaluation. Mean variances between both groups were evaluated, controlling for age, gender, and educational level. RESULTS: MS patients scored significantly lower on the SDMT, CVLT-II, and BVMT-R tests than healthy controls (P-value <0.001). Test-retest reliability was satisfactory for SDMT, CVLT-II total, and BVRT-R in MS patients and controls with r values of 0.73, 0.83, and 0.80, respectively. CONCLUSION: BICAMS is a feasible approach to cognitive screening in POMS and adults. The Arabic version of BICAMS is a reliable and valid tool for the cognitive assessment of pediatric MS patients in different clinical and research settings.

Smartphone-based gait assessment for multiple sclerosis.

INTRODUCTION: Multiple Sclerosis causes gait alteration, even in the early stages of the disease. Traditional methods to quantify gait impairment, such as performance-based measures, lab-based motion analyses, and self-report, have limited ecological relevance. The Mon4t® app is a digital tool that uses sensors embedded in standard smartphones to measure various gait parameters. OBJECTIVES: To evaluate the use of Mon4t® technology in monitoring MS patients. METHODS: 100 MS patients and age-matched healthy controls were evaluated using both a human rater and the Mon4t Clinic™ app. Three motor tasks were performed: 3m Timed up and go test (TUG), 10m TUG, and tandem walk. The digital markers were used to compare MS vs. HC, MS with EDSS=0 vs. HC, and MS with EDSS=0 vs. MS with EDSS>0. Within the MS EDSS>0 group, correlations between digital gait markers and the EDSS score were calculated. RESULTS: Significant differences were found between MS patients and HC in multiple gait parameters. When comparing MS patients with minimal disability (EDSS=0) and HC: On the 3m TUG task, MS patients took longer to complete the task (mean difference 0.167seconds, p =0.034), took more steps (mean difference 1.32 steps, p =0.003), and had a weaker ML step-to-step correlation (mean difference 0.1, p = 0.001). The combination of features from the three motor tasks allowed distinguishing a nondisabled MS patient from a HC with high confidence (AUC of 85.65 on the ROC). When comparing MS patients with minimal disability (EDSS=0) to those with higher disability (EDSS>0): On the tandem walk task, patients with EDSS>0 took significantly longer to complete 10 steps than those with EDSS=0 (mean difference 4.63 seconds, p < 0.001), showed greater ML sway (mean difference 0.2, p < 0.001), and had larger angular velocity in the SI axis on average (mean difference 2.31 degrees/sec, p = 0.01). A classification model achieved 81.79 ROC AUC. In the subgroup of patients with EDSS>0, gait features significantly correlated with EDSS score in all three tasks. CONCLUSION: The findings demonstrate the potential of digital gait assessment to augment traditional disease monitoring and support clinical decision making. The Mon4t® app provides a convenient and ecologically relevant tool for monitoring MS patients and detecting early changes in gait impairment.

A multiscale assessment of bowel impairment in an Italian multiple sclerosis cohort.

Bowel dysfunctions (BD) in multiple sclerosis (MS) are under reported despite their clinical relevance. Scales usually applied do not thoroughly assess constipation and fecal incontinence. Instead, a proper qualitative and quantitative description of these symptoms might have relevant clinical and scientific consequences. The aim of this project is to study the prevalence of BD in a cohort of persons with MS (pwMS). Four-hundred and forty-seven pwMS (330 relapsing-remitting MS-RRMS and 117 progressive MS-PMS) were recruited. Three different questionnaires were administered: the neurogenic bowel dysfunction score (NBDS), the Wexner constipation scale (WexCon) and the Wexner incontinence scale (WexInc). All the scales were divided in subscores according to symptom severity. The prevalence of BD, considered as NBDS > 0, was 53.7%. Mean scores in pwMS group were as follows: NBDS 2.6 (SD 3.5), WexInc 1.1 (SD 2.4), WexCon 4.4 (SD 5.9). NBDS, WexCon and WexInc were significantly higher in PMS vs RRMS (p < 0.001), and significantly associated with disease duration, EDSS, multiple sclerosis severity score (p < 0.001), as well as with each other (p < 0.001). Our study confirms the presence of bowel dysfunctions in a large group of pwMS with a wide range of disability and their association with progressive disease phenotype and clinical disability.

Occupational risk factors for multiple sclerosis: a systematic review with meta-analysis.

Objective: We decided to conduct the first systematic review with meta-analysis to provide the highest level of up-to-date evidence on the occupational risk factors for Multiple Sclerosis. Methods: A systematic, comprehensive literature search was performed in four electronic academic databases. We included any case-control study that enrolled working-age subjects and compared the proportion of MS cases with controls who were not exposed to an occupational risk factor. The primary outcome was the occurrence of MS. The quality assessment was performed with the Critical Appraisal Checklist for Case Control Studies, developed, and validated by the Joanna Briggs Institute. All the selection process was also carried out by two independent and previously trained researchers. Results: Overall, the total sample included 19,004 people with MS and 4,164,162 controls. Agricultural workers (OR = 1.44, 95% CI 1.13-1.83), offshore workers (OR = 3.56, 95% CI 2.74-4.61), and hairdressers (OR = 8.25, 95% CI 1.02-66.52) were associated with a higher probability of being diagnosed with MS. In parallel, workers exposed to toxic fumes from oil wells (OR = 16.80, 95% CI 8.33-33.90), low-frequency magnetic fields (OR = 1.71, 95% CI 1.03-2.72), and pesticides (OR = 3.17, 95% CI = 2.53-3.99) also had an increased likelihood of having MS. Conclusion: Our study has the potential to influence more assertive public policies. Nevertheless, future studies on how the occupational setting may contribute to the incidence of MS are highly recommended. Systematic review registration: The protocol was registered in the international prospective register of systematic reviews (PROSPERO- CRD42023443257).

Concurrence of inflammatory bowel disease with multiple sclerosis or Hodgkin lymphoma.

BACKGROUND AND AIMS: Epidemiologic evidence suggests that Hodgkin lymphoma (HL) and multiple sclerosis (MS) share a common set of risk factors with Crohn's disease (CD) and ulcerative colitis (UC). It was hypothesized that such shared risk factors would lead to clustering of the 4 diagnoses in the same patients. METHODS: All patients with HL, MS, CD, or UC were identified in the veterans population from 2016-2020 and the Medicare population from 1986 to 1989. In a case-control study, the observed concurrences amongst these 4 diagnoses were compared with their expected frequencies in the overall veterans or Medicare population during the same time period by calculating odds ratios (OR) with their 95% confidence intervals (CI). RESULTS: The study included 6 million veterans and 35 million Medicare patients. In the veterans population, inflammatory bowel disease (IBD) was significantly associated with a concurrent diagnosis of HL (OR: 1.40, 95% CI: 1.15-1.71) and MS (1.34, 1.19-1.50). In the Medicare population, IBD was also significantly associated with HL (1.84, 1.07-3.17) and MS (2.31, 1.59-3.35). Similar trends were observed in CD or UC when analyzed separately in both datasets. In the veterans population, adjustment for the potentially confounding influence of ethnicity, sex, and age left all OR values largely unaffected and statistically significant. CONCLUSION: The concurrence of IBD with HL or MS could reflect on a common pathway in the etiology or pathogenesis of these 4 diseases.

Internet-delivered cognitive behavioural therapy programme to reduce depressive symptoms in patients with multiple sclerosis: a multicentre, randomised, controlled, phase 3 trial.

BACKGROUND: Depression is three to four times more prevalent in patients with neurological and inflammatory disorders than in the general population. For example, in patients with multiple sclerosis, the 12-month prevalence of major depressive disorder is around 25% and it is associated with a lower quality of life, faster disease progression, and higher morbidity and mortality. Despite its clinical relevance, there are few treatment options for depression associated with multiple sclerosis and confirmatory trials are scarce. We aimed to evaluate the safety and efficacy of a multiple sclerosis-specific, internet-based cognitive behavioural therapy (iCBT) programme for the treatment of depressive symptoms associated with the disease. METHODS: This parallel-group, randomised, controlled, phase 3 trial of an iCBT programme to reduce depressive symptoms in patients with multiple sclerosis was carried out at five academic centres with large outpatient care units in Germany and the USA. Patients with a neurologist-confirmed diagnosis of multiple sclerosis and depressive symptoms were randomly assigned (1:1:1; automated assignment, concealed allocation, no stratification, no blocking) to receive treatment as usual plus one of two versions of the iCBT programme Amiria (stand-alone or therapist-guided) or to a control condition, in which participants received treatment as usual and were offered access to the iCBT programme after 6 months. Masking of participants to group assignment between active treatment and control was not possible, although raters were masked to group assignment. The predefined primary endpoint, which was analysed in the intention-to-treat population, was severity of depressive symptoms as measured by the Beck Depression Inventory-II (BDI-II) at week 12 after randomisation. This trial is registered at ClinicalTrials.gov, NCT02740361, and is complete. FINDINGS: Between May 3, 2017, and Nov 4, 2020, we screened 485 patients for eligibility. 279 participants were enrolled, of whom 101 were allocated to receive stand-alone iCBT, 85 to receive guided iCBT, and 93 to the control condition. The dropout rate at week 12 was 18% (50 participants). Both versions of the iCBT programme significantly reduced depressive symptoms compared with the control group (BDI-II between-group mean differences: control vs stand-alone iCBT 6·32 points [95% CI 3·37-9·27], p<0·0001, effect size d=0·97 [95% CI 0·64-1·30]; control vs guided iCBT 5·80 points [2·71-8·88], p<0·0001, effect size d=0·96 [0·62-1·30]). Clinically relevant worsening of depressive symptoms was observed in three participants in the control group, one in the stand-alone iCBT group, and none in the guided iCBT group. No occurrences of suicidality were observed during the trial and there were no deaths. INTERPRETATION: This trial provides evidence for the safety and efficacy of a multiple sclerosis-specific iCBT tool to reduce depressive symptoms in patients with the disease. This remote-access, scalable intervention increases the therapeutic options in this patient group and could help to overcome treatment barriers. FUNDING: National Multiple Sclerosis Society (USA).

Comparing face-to-face and videoconference assessment of the Brief Repeatable Battery of Neuropsychological Tests in people with multiple sclerosis.

BACKGROUND: The COVID-19 pandemic has underlined the need to evaluate cognitive profile via videoconferencing (teleneuropsychology, TeleNP) as a suitable alternative to face-to-face assessment (F-F). OBJECTIVE: To evaluate the feasibility and the reliability of Rao's Brief Repeatable Battery of Neuropsychological Tests (R-BRB) remote administration in people with multiple sclerosis (PwMS). METHODS: Sixty PwMS underwent R-BRB in two conditions: F-F and TeleNP, 1 month apart. RESULTS: Cognitive test performance was similar, regardless of the administration type, but visuospatial test performance was better in F-F. CONCLUSION: These data suggest that TeleNP is feasible and highly reliable in MS clinical practice.

Assessment of differential item functioning of the PHQ-9, HADS-D and PROMIS-depression scales in persons with and without multiple sclerosis.

OBJECTIVE: We tested for the presence of differential item functioning (DIF) in commonly used measures of depressive symptoms, in people with multiple sclerosis (MS) versus people with a psychiatric disorder without MS. METHODS: Participants included individuals with MS, or with a lifetime history of a depressive or anxiety disorder (Dep/Anx) but no immune-mediated inflammatory disease. Participants completed the Patient Health Questionnaire (PHQ-9), Hospital Anxiety and Depression Scale (HADS), and the Patient Reported Outcome Measurement Information System (PROMIS)-Depression. We assessed unidimensionality of the measures using factor analysis. We evaluated DIF using logistic regression, with and without adjustment for age, gender and body mass index (BMI). RESULTS: We included 555 participants (MS: 252, Dep/Anx: 303). Factor analysis showed that each depression symptom measure had acceptable evidence of unidimensionality. In unadjusted analyses comparing the MS versus Dep/Anx groups we identified multiple items with evidence of DIF, but few items showed DIF effects that were large enough to be clinically meaningful. We observed non-uniform DIF for one PHQ-9 item, and three HADS-D items. We also observed DIF with respect to gender (one HADS-D item), and BMI (one PHQ-9 item). For the MS versus Dep/Anx groups, we no longer observed DIF post-adjustment for age, gender and BMI. On unadjusted and adjusted analyses, we did not observe DIF for any PROMIS-D item. CONCLUSION: Our findings suggest that DIF exists for the PHQ-9 and HADS-D with respect to gender and BMI in clinical samples that include people with MS whereas DIF was not observed for the PROMIS-Depression scale.

Rivastigmine for Cognitive Impairment in Multiple Sclerosis: A Prospective Randomized Open Label study with Blinded End-Point Assessment.

Background and Objective: Nearly 40-65% patients with MS develop cognitive impairment during the disease. There is no treatment clearly effective in improving the cognitive deficits. To evaluate the efficacy and safety of Rivastigmine in cognitively impaired MS patients. Materials and Methods: This was a parallel group randomized open label study with blinded end-point assessment. The patient allocation to treatment and control arm was done by telephonic contact with an independent statistician who used a computer to generate a random sequence of allocation using permuted block randomization (varying block size of 4 and 6) in 1:1 ratio. The outcome assessor was blinded to this allocation. A total of 60 patients were in included in the study (30 in each arm). Primary outcome was improvement in memory functions (using logical memory subset of Wechsler Memory Scale III, India) assessed after 12 weeks. Secondary outcomes included fatigue, depression, and safety. Results: In modified intention to treat analysis (N = 22), treatment arm showed statistically significant improvement in memory function with mean difference of 7.56 [95% CI (0.67,14.46), p 0.032] as compared to control arm. There was no statistically significant difference in outcomes such as fatigue and depression. Vomiting was the most common side effect. No major adverse events were observed in either group. Conclusion: Rivastigmine is safe and effective in improving memory functions in cognitively impaired MS patients. However, our study has a small sample size and tested only a single domain. Larger studies with a validated single comprehensive neuropsychological test are needed.

Longitudinal assessment of neurocognitive function in people with relapsing multiple sclerosis initiating alemtuzumab in routine clinical practice: LEM-COG study results.

BACKGROUND: Alemtuzumab is effective in reducing relapse rate and disability, but limited data exist on its effect on cognitive function in relapsing multiple sclerosis (RMS). The present study assessed neurocognitive function and safety associated with alemtuzumab treatment in RMS. METHODS: This longitudinal, single-arm, prospective study included people with RMS (aged 25-55 years) who were treated with alemtuzumab in clinical practice in the United States of America and Canada. The first participant was enrolled in December 2016. The primary endpoint was the change from baseline to post-baseline (month [M] 12/24) in MS-COGnitive (MS-COG) composite score. Secondary endpoints included Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities Test (SDMT), Brief Visuospatial Memory Test-Revised (BVMT-R), Selective Reminding Test (SRT), Controlled Oral Word Association Test (COWAT), and Automated Neuropsychological Assessment Metrics (ANAM) scores. Depression and fatigue were assessed using Hamilton Rating Scale-Depression (HAM-D) and Fatigue Severity Scale (FSS)/Modified Fatigue Impact Scale (MFIS), respectively. Magnetic resonance imaging (MRI) parameters were assessed when available. Safety was assessed throughout the study. Descriptive statistics were used for the pre-specified statistical analyses. Since the study was terminated early (November 2019) because of operational and resource difficulties, post hoc analyses for statistical inference were performed among participants who had a baseline value and at least one complete post-baseline assessment for cognitive parameters, fatigue, or depression. RESULTS: Of the 112 participants enrolled, 39 were considered as the primary analysis population at M12. At M12, a mean change of 0.25 (95% confidence interval [CI]: 0.04, 0.45; p = 0.0049; effect size [ES]: 0.39) was observed in the MS-COG composite score. Improvements were observed in processing speed (based on PASAT and SDMT; p < 0.0001; ES: 0.62), as well as in individual PASAT, SDMT and COWAT scores. An improvement was also noted in HAM-D (p = 0.0054; ES: -0.44), but not in fatigue scores. Among MRI parameters, decreases in burden of disease volume (BDV; ES: -0.12), new gadolinium-enhancing lesions (ES: -0.41) and newly active lesions (ES: -0.07) were observed at M12. About 92% of participants showed stable or improved cognitive status at M12. There were no new safety signals reported in the study. The most common adverse events (≥10% of participants) were headache, fatigue, nausea, insomnia, urinary tract infection, pain in extremity, chest discomfort, anxiety, dizziness, arthralgia, flushing, and rash. Hypothyroidism (3.7%) was the most frequent adverse event of special interest. CONCLUSION: The findings from this study suggest that alemtuzumab has a positive impact on cognitive function with significant improvements in processing speed and depression in people with RMS over a period of 12 months. The safety profile of alemtuzumab was consistent with previous studies.

Validation of an iPad version of the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS).

BACKGROUND: The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) is the most widely used screening tool for cognitive impairment in Multiple Sclerosis (MS). However, the administration and scoring procedures of the paper version are time consuming and prone to errors. Aim of our study was to develop a tablet version of BICAMS (iBICAMS), and to assess its reliability compared to the paper version. METHODS: We administered both BICAMS and iBICAMS to 139 MS patients in two different sessions. We compared scores on both versions using a paired t-test. We used a repeated measures ANOVA to test the impact of rater, order of administration and test-retest time on test-retest performances. We used the Intraclass Correlation Coefficient (ICC) to assess the reliability between BICAMS and iBICAMS. RESULTS: All three sub-tests of the BICAMS (SDMT, CVLT-II and BVMT-R) were different between the paper and the tablet versions. Order of administration influenced test-retest performances at the SDMT (p<0.001), CVLT- II (p<0.001) and BVMT-R (p<0.001). Intraclass coefficient correlation (ICC) revealed a high level of agreement between the paper BICAMS and the iPad version for all three tests: SDMT (0.92), CVLT-II (0.83) and BVMT-R (0.82). CONCLUSIONS: We found a high reliability between BICAMS and iBICAMS. Considering the inherent advantages of automated scoring, digital storage of data, standardized timing, the iBICAMS could become a standard in clinical practice.

Assessment of cognitive performance in multiple sclerosis using smartphone-based training games: a feasibility study.

BACKGROUND: Cognitive impairment occurs in up to 70% of people with MS (pwMS) and has a large impact on quality of life and working capacity. As part of the development of a smartphone-app (dreaMS) for monitoring MS disease activity and progression, we assessed the feasibility and acceptance of using cognitive games as assessment tools for cognitive domains. METHODS: We integrated ten cognitive games in the dreaMS app. Participants were asked to play these games twice a week for 5 weeks. All subjects underwent a battery of established neuropsychological tests. User feedback on acceptance was obtained via a five-point Likert-scale questionnaire. We correlated game performance measures with predetermined reference tests (Spearman's rho) and analyzed differences between pwMS and Healthy Controls (rank biserial correlation). RESULTS: We included 31 pwMS (mean age 43.4 ± 12.0 years; 68% females; median Expanded Disability Status Scale score 3.0, range 1.0-6.0) and 31 age- and sex-matched HC. All but one game showed moderate-strong correlations with their reference tests, (|rs|= 0.34-0.77). Performance improved in both groups over the 5 weeks. Average ratings for overall impression and meaningfulness were 4.6 (range 4.2-4.9) and 4.7 (range 4.5-4.8), respectively. CONCLUSION: Moderate-strong correlations with reference tests suggest that adaptive cognitive games may be used as measures of cognitive domains. The practice effects observed suggest that game-derived measures may capture change over time. All games were perceived as enjoyable and meaningful, features crucial for long-term adherence. Our results encourage further validation of adaptive cognitive games as monitoring tools for cognition in larger studies of longer duration. STUDY REGISTER: ClinicalTrials.gov: NCT04413032.

Neural bases of motor fatigue in multiple sclerosis: A multimodal approach using neuromuscular assessment and TMS-EEG.

Motor fatigue is one of the most common symptoms in multiple sclerosis (MS) patients. Previous studies suggested that increased motor fatigue in MS may arise at the central nervous system level. However, the mechanisms underlying central motor fatigue in MS are still unclear. This paper investigated whether central motor fatigue in MS reflects impaired corticospinal transmission or suboptimal primary motor cortex (M1) output (supraspinal fatigue). Furthermore, we sought to identify whether central motor fatigue is associated with abnormal M1 excitability and connectivity within the sensorimotor network. Twenty-two patients affected by relapsing-remitting MS and 15 healthy controls (HCs) performed repeated blocks of contraction at different percentages of maximal voluntary contraction with the right first dorsal interosseus muscle until exhaustion. Peripheral, central, and supraspinal components of motor fatigue were quantified by a neuromuscular assessment based on the superimposed twitch evoked by peripheral nerve and transcranial magnetic stimulation (TMS). Corticospinal transmission, excitability and inhibition during the task were tested by measurement of motor evoked potential (MEP) latency, amplitude, and cortical silent period (CSP). M1 excitability and connectivity was measured by TMS-evoked electroencephalography (EEG) potentials (TEPs) elicited by M1 stimulation before and after the task. Patients completed fewer blocks of contraction and showed higher values of central and supraspinal fatigue than HCs. We found no MEP or CSP differences between MS patients and HCs. Patients showed a post-fatigue increase in TEPs propagation from M1 to the rest of the cortex and in source-reconstructed activity within the sensorimotor network, in contrast to the reduction observed in HCs. Post-fatigue increase in source-reconstructed TEPs correlated with supraspinal fatigue values. To conclude, MS-related motor fatigue is caused by central mechanisms related explicitly to suboptimal M1 output rather than impaired corticospinal transmission. Furthermore, by adopting a TMS-EEG approach, we proved that suboptimal M1 output in MS patients is associated with abnormal task-related modulation of M1 connectivity within the sensorimotor network. Our findings shed new light on the central mechanisms of motor fatigue in MS by highlighting a possible role of abnormal sensorimotor network dynamics. These novel results may point to new therapeutical targets for fatigue in MS.

Assessment of muscle fatigue in multiple sclerosis patients in electromyographic examinations.

BACKGROUND: Although surface electromyography (sEMG) is the method used to assess muscle fatigue in patients with multiple sclerosis (PwMS), no pattern of signal change has been established. The differences shown in the parameters of other neurophysiological tests between PwMS and control groups (CG) suggest the differentiation of the sEMG signal. AIM: The purpose of the study was to verify potential differences in the fatigue sEMG signal in PwMS compared to CG. DESIGN: Cross-sectional study. SETTING: Chair and Department of Functional Diagnostics and Physical Medicine. POPULATION: A randomised group of patients diagnosed with MS (30, 20-41 years). A random sample of young, healthy adults (median 28, 20-39 years). METHODS: Measurement of sEMG was performed from extensor carpi radialis (ECR) and FCR (flexor carpi radialis) during 60-80% of maximum voluntary contraction (MVC) of extension and then flexion for 60sec, accordance with the fatigue protocol in Research XP Master Edition software (v. 1.08.27). RESULTS: Root mean square amplitude (ARMS) were lower for muscle in the PwMS compared to the CG (ECR P=0.0001, FCU P<0.0001). In the CG, the ARMS value increases during fatigue contraction (ECR P=0.0003, FCU P<0.0001), while in the PwMS) the ARMS value decreases (ECR: P<0.0001, FCU P<0.0001. CONCLUSIONS: The PwMS show an opposite pattern of preservation of the absolute value of ARMS during prolonged contraction to fatigue, compared with healthy subjects. CLINICAL REHABILITATION IMPACT: The results are important for clinical trials using sEMG to assess fatigue in PwMS. Knowledge of the differences in the time domain changes in sEMG signal between healthy subjects and PwMS is crucial for correctly interpreting the results.

NUTRISEP: Assessment of the nutritional status of patients with multiple sclerosis and link to fatigue.

BACKGROUND: Fatigue is a common complaint in patients with multiple sclerosis (PwMS) and reduces quality of life. Several hypotheses for the pathogenesis of fatigue in MS are proposed ranging from neurological lesions to malnutrition, but none has been conclusively validated through clinical research. OBJECTIVES: The goal of this study was to examine the correlation between fatigue and nutritional status and dietary habits in PwMS. METHODS: This was a cross-sectional, multicenter study conducted at 10 French MS centers and enrolling PwMS with an Expanded Disability Status Scale (EDSS) score between 0 and 7. Plasma level of albumin, magnesium, calcium, iron, vitamin D and B12 evaluated nutritional status. A semi-structured eating behavior questionnaire has been developed to evaluate dietary habits. Evaluation of fatigue used specific questionnaire (EMIF-SEP). Quality of sleep was evaluated by visual analogue scale (VAS), depression with Beck Depression Inventory (BDI-II); dysphagia by DYsphagia in MUltiple Sclerosis questionnaire (DYMUS) and taste disorders by gustometry. Association between nutritional deficiencies and different data such as socio-demographic data, disease characteristics, swallowing and taste disorders, food intake, depression and sleep quality was investigated. RESULTS: A total of 352 patients mean age: 48.1±10.1 years, mean duration of MS: 15.3±9.1 years and median EDSS: 4 were analyzed. Bivariate and multivariate analyses showed a statistically significant correlation between fatigue and depression and use of sleeping pills, while none of the variables related to dietary habits or nutritional status correlated significantly with fatigue. CONCLUSIONS: Dietary habits and nutritional status have little impact on fatigue and general population nutrition recommendations remain the rule for PwMS. In cases of fatigue, specific attention should be paid to depression and use of sleeping pills.

The increased perceived exertion during the six minute walking test is not accompanied by changes in cost of walking, gait characteristics or muscle fatigue in persons with multiple sclerosis.

BACKGROUND: Persons with Multiple Sclerosis (pwMS) frequently experience walking difficulties, often expressed as a slower walking speed during the 6 Minute Walking Test (6MWT). In addition, slower walking speeds are also related to higher levels of perceived exertion. PwMS are also known to have a higher energetic Cost of walking (Cw) and may experience muscle fatigue during prolonged walking. In this study, we aimed to explore changes in Rate of Perceived Exertion (RPE) and the Cw within participants during the 6MWT in pwMS. Additionally, concomitant changes in the mean and variability of gait characteristics and changes in muscle activation describing muscle fatigue were assessed. METHODS: The 6MWT was performed on an instrumented treadmill while three-dimensional motion capture and gas exchange were measured continuously. RPE on the 6-20 borg-scale was questioned directly before and after the 6MWT. Cost of walking was expressed in Joules/kg/m. Muscle fatigue was assessed by increases in Root Median Square (RMdS) and decreases in Median Frequency (MF) of the recorded EMGs. Wilcoxon-Signed Rank test was used to assess a difference in RPE before and after the 6MWT. Linear mixed models, while controlling for walking speed, were used to assess changes in Cw, mean and variability of gait characteristics and RMdS and MF of muscle activation. RESULTS: 28 pwMS (23 females, mean ± standard deviation age 46 ± 10 years, height 1.69 ± 0.08 meter, weight 76 ± 18 kilogram, EDSS 2.7 ± 1.3) were included. Although the RPE increased from 8 to 12, no changes in Cw were found. Walking speed was the only spatiotemporal parameter which increased during the 6MWT and RMdS of the gastrocnemius and tibialis anterior muscles increased. The soleus muscle decreased in MF over time. CONCLUSION: The increases in RPE and walking speed was not accompanied by a change in Cw during the 6MWT which indicates that the perceived exertion was not accompanied by an increased physical exertion. Changes in muscle activation might give an indication for muscle fatigue but were inconclusive. Although the 6MWT reflects daily life walking challenges for pwMS, this test did not show the expected changes in gait parameters in our sample.