Life space assessment and falls in older adults with multiple sclerosis.

BACKGROUND/OBJECTIVE: Falls research in older adults with MS (OAMS) is scarce, and no studies have reported on the association between life-space mobility and falls in this group. Herein, we hypothesized that higher baseline life-space scores would be associated with reduced odds of reporting falls during follow-up, and explored whether the association differed by MS subtype (progressive vs. relapsing-remitting). METHODS: OAMS (n = 91, mean age = 64.7 ± 4.3ys, %female = 66.9,%progressive MS = 30.7) completed the University of Alabama at Birmingham Life-Space-Assessment (UAB-LSA) scale and reported falls during a structured monthly telephone interview during follow-up (mean = 16.39 ± 11.44 months). General Estimated Equations (GEE) models were utilized to determine whether UAB-LSA scores predicted falls during follow-up. RESULTS: GEE models revealed that higher UAB-LSA scores were associated with a significant reduction in the odds of falling during follow-up (OR = 0.69, p = 0.012, 95 %CI = 0.51 to 0.92). Stratified analyses revealed that this association was significant in progressive (OR = 0.57, p = 0.004, 95 %CI = 0.39 to 0.84), but not relapsing-remitting (OR = 0.93, p = 0.779, 95 %CI = 0.57 to 1.53) MS. CONCLUSION: Higher life-space mobility was associated with lower odds of falling among OAMS with progressive subtype. The UAB-LSA may complement existing mobility measures for predicting fall risk.

ACTIVE-FIT program: Assessment of sleep quality and its relationship with physical activity in patients with relapsing-remitting multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) causes sleep disturbances in up to 70 % of individuals. These problems are linked to fatigue, mood and cognitive performance, thereby affecting the quality of life in people with MS (PwMS). The frequent and debilitating side effects of sleep medications prompt the exploration of alternative therapies. Physical activity has shown benefits in improving sleep, reducing fatigue, and enhancing quality of life. Combined with a controlled exercise program tailored for PwMS, the study aims to analyze the impact of moderate physical exercise on sleep quality, cognitive function, quality of life, mood, and fatigue. METHODS: A single-center prospective cohort study was designed to assess the impact of a 12-week physical exercise program on patients with relapsing-remitting multiple sclerosis. Changes in sleep and activity parameters are evaluated using an actigraph and cognitive, quality of life, fatigue and mood changes are assessed through specific questionnaires before, during, and after the exercise program application. RESULTS: 23 patients completed the study (women = 84.6 %) Mean age was 37.2 years (SD 7.5). The mean EDSS score was 1.9, and 80.8 % were diagnosed within the last six years. Significant improvements were noted in sleep efficiency between baseline and final measurements (χ2 = 27.5; p.adj = 0.004), sleep latency (χ2 = 275; p.adj = 0.000), sleep duration (χ2 = 251; p.adj = 0.001) and in the number of awakenings (χ2 = 269.5; p.adj = 0.000), with a decreased in total time in bed from 8.5 h to 7.35 h post-intervention. Regarding activity variables, an increase in caloric expenditure and an increase in the time participants engaged in light activity were observed. We found significant improvements in fatigue, quality of life and mood. Concerning neuropsychological exploration results, improvements were observed in all studied parameters, with statistically significant improvement in Verbal SRT (χ2 = 43; p = 0.022). CONCLUSION: Our study showed a positive impact of a 12-week physical exercise program on sleep performance, cognition and mood in PwMS. The observed improvements underscore the potential of tailored exercise interventions in promoting a more comprehensive and holistic care paradigm for PwMS.

The multidimensional assessment of body representation and interoception in multiple sclerosis.

BACKGROUND: The mental representation of the body (or body representation, BR) derives from the processing of multiple sensory and motor inputs and plays a crucial role in guiding our actions and in how we perceive our body. Fundamental inputs for BR construction come also from the interoceptive systems which refer to the whole bidirectional processes between the brain and the body. People with Multiple sclerosis (MS) show an abnormal multisensory integration which may compromise BR and interoception integrity. However, no study has evaluated possible deficits on distinct and dissociable dimensions of body representation (i.e., action-oriented, aBR; and a nonaction-oriented body representation, NaBR) and interoception (i.e., interoceptive accuracy, interoceptive sensibility, and interoceptive awareness) in MS. OBJECTIVE: In the present study, we aimed to determine whether participants with MS present changes in BR and interoceptive dimensions. METHODS: We performed comparison analyses on tasks and questionnaires tapping all BR and interoceptive dimensions between 36 people with relapsing-remitting MS (RRMS) and 42 healthy controls, and between 23 people with progressive MS (PMS) and 33 healthy controls. RESULTS: Overall, patients with MS exhibited lower interoceptive accuracy than matched controls. The RRMS group also showed higher visceral interoceptive sensibility levels. No differences were found in BR accuracy measures, but the PMS reported longer response times when performing the aBR task. CONCLUSION: These findings open a new issue on the role of inner-signal monitoring in the body symptomatology of MS and highlight the need for an accurate BR and interoceptive assessment in a clinical setting.

Passive assessment of tapping speed through smartphone is useful for monitoring multiple sclerosis.

INTRODUCTION: Continuously acquired smartphone keyboard interactions may be useful to monitor progression in multiple sclerosis (MS). We aimed to study the correlation between tapping speed (TS), measured as keys/s, and baseline disability scales in patients with MS. METHODS: Single-center prospective study in patients with MS. We passively assessed TS during first week, measured by an "in house" smartphone application. Reliability was assessed by intraclass correlation coefficient (ICC). Correlations between median and maximum keys/s of first week of assessment and baseline disability measures were explored. RESULTS: One-hundred three patients were included: 62.1 % women, with a median (IQR) age of 47 (40.4-54.8) years-old and an EDSS score of 3.0 (2.0-4.0). Distribution by MS subtypes was: 77.7 % relapsing-remitting MS (RRMS), 17.5 % secondary-progressive MS (SPMS) and 4.9 % primary-progressive MS (PPMS). ICC during first week was 0.714 (p < 0.00001). Both median and maximum keys/s showed a negative correlation with Expanded Disability Status Score, 9-hole peg test and timed 25-foot walk and a positive correlation with Processing Speed Test CogEval® raw and Z-score. Median and maximum keys/s were lower in patients diagnosed with SPMS than in RRMS. Both measures of tapping speed were associated with MS phenotype independently of age. CONCLUSION: TS measured through our application is reliable and correlates with baseline disability scales.

The Impact of Motor Disability and the Level of Fatigue on Adherence to Therapeutic Recommendations in Patients with Multiple Sclerosis Treated with Immunomodulation.

Aim: The aim of the study was to clarify whether the motor disability and the fatigue-related syndrome affect the level of compliance with therapeutic recommendations. Methods: Prospective studies were conducted among 165 patients treated under the drug program - Treatment of Multiple Sclerosis (MS) at the Department of Neurology and Clinical Neuroimmunology of the Regional Specialist Hospital in Grudziadz (Poland). The research was carried out by the method of diagnostic survey, questionnaire technique with the use of standardized research tools. The Adherence in Chronic Diseases Scale (ACDS) was used to assess the level of compliance with therapeutic recommendations. The Expanded Disability Status Scale (EDSS) was used to assess the degree of disability, and the Modified Fatigue Impact Scale (MFIS) was used to assess the degree of disability. The Chi-square test, Shapiro-Wilk test and Kruskal-Wallis were used. Results: The statistical analysis showed that there is a relationship (p=0.0055) between the patient's motor disability assessed in the EDSS scale and the level of compliance with therapeutic recommendations assessed in the ACDS scale. The higher the patient's disability level (EDSS 4.5-6.5), the lower the treatment adherence rate. The conducted research shows that the average score in the MFIS scale for individual levels of compliance with therapeutic recommendations expressed in the ACDS scale is, respectively: for the low level - 38.3 MFIS points, for the medium level - 34.4 MFIS points and for the high level- 33.2 MFIS points. The obtained results were not statistically significant (p=0.6098). Conclusion: It was found that the level of adherence to therapeutic recommendations in patients with relapsing-remitting multiple sclerosis treated with immunomodulation in the study group remained high. There is a relationship between the patient's disability and the level of adherence to therapeutic recommendations.

Differentiating societal costs of disability worsening in multiple sclerosis.

BACKGROUND: In multiple sclerosis (MS), confirmed disability progression (CDP) can be either the result of progression independent of relapse activity (PIRA) or relapse-associated worsening (RAW). However, the economic effect of PIRA and RAW on societal economic costs in patients with MS is not well understood. OBJECTIVE: To determine societal economic costs of patients achieving disease activity free status (DAF) and compare them with those having PIRA and RAW events. METHODS: We used a roving EDSS score analysis to detect PIRA and RAW events with confirmation after at least 6 months. We estimated the age-, gender-, EDSS-adjusted effects of PIRA and RAW on total, direct medical, direct non-medical and indirect societal economic costs. Patients achieving DAF were assigned to as reference. RESULTS: Overall, 1959 patients were analyzed. Total mean quarterly societal economic costs including disease-modifying therapies (DMTs) were 6929€ (SD: 2886€) per patient averaged over a period of 2 years. Excluding DMTs, patients achieving DAF had total mean quarterly costs of 1703€ (SD: 2489€). PIRA caused 29% (IRR: 1.29; CI 1.06-1.50, p < 0.05) higher total costs compared to DAF. On the contrary, RAW increased total costs by factor 1.56 (CI 1.30-1.87, p < 0.001). The effect of PIRA and RAW was striking for direct medical costs which increased by factor 1.48 (95% CI 1.13-1.95, p < 0.01) and 2.25 (95% CI 1.72-2.94, p < 0.001), respectively. CONCLUSION: Disease progression increases societal economic costs significantly. Thus, delaying or even preventing disease progression in MS may reduce the societal economic burden of MS.

Cost-effectiveness of Cladribine Tablets and fingolimod in the treatment of relapsing multiple sclerosis with high disease activity in Spain.

OBJECTIVE: To estimate the cost-effectiveness of Cladribine Tablets in the treatment of relapsing multiple sclerosis (RMS) with high disease activity compared with fingolimod, from the perspective of the National Health System (NHS) in Spain. METHODS: A Markov model was developed. The annual transition probabilities, were adjusted to patients with RMS with high disease activity. The effect of the treatments compared on the Expanded Disability Status Scale (EDSS) was modeled by hazard ratios for the confirmed progression of disability. The annual relapse rate and the probability of suffering adverse reactions were obtained from a meta-analysis and the literature. The derived costs were calculated from Spanish unit costs. The utilities were obtained from the CLARITY clinical trial and the literature. Deterministic and probabilistic sensitivity analyzes were performed. RESULTS: Cladribine tablets was the dominant treatment: lower costs (-86,536 €) and more effective (+1.11 quality-adjusted life years - QALYs) compared to fingolimod. The probability that Cladribine Tablets was cost-effective compared to fingolimod ranged between 94.6% and 96.1% for willingness to pay from € 20,000 to € 30,000 per QALY gained. CONCLUSIONS: Cladribine Tablets is a cost-effective treatment, compared to fingolimod, for the treatment of RMS with high disease activity. EXPERT OPINION: According to the present study, compared to fingolimod, treatment with Cladribine Tablets of relapsing multiple sclerosis with high disease activity is an option that could generate savings for the Spanish National Health System, with a considerable gain in QALYs. Cladribine Tablets is considered cost-effective and dominant (less costs and more effectiveness) than fingolimod treatment option in this population.

Fatigue scores correlate with other self-assessment data, but not with clinical and biomarker parameters, in CIS and RRMS.

BACKGROUND: Fatigue is common in multiple sclerosis and is associated with reduced quality of life. This study aimed to assess the correlation between fatigue scores and data from other self-assessment questionnaires, neuropsychological tests and neuroimaging, as well as data on neuroimmunological markers in cerebrospinal fluid (CSF) and serum/plasma, in clinically isolated syndrome (CIS) and relapsing remitting MS (RRMS). METHODS: Modified fatigue impact scale (MFIS) scores were determined in 38 patients with newly diagnosed CIS or RRMS at baseline and after one year in a prospective longitudinal cohort study. Non-parametric correlation analyses were used to assess associations between MFIS scores and other self-assessment questionnaire data (Hospital Anxiety and Depression scale (HAD), Multiple Sclerosis Impact Scale 29 (MSIS-29) and Short Form 36 (SF-36)), as well as with neuropsychological test performances (e.g. Auditory Consonant Trigram Test (ACTT)), clinical parameters (e.g. disease duration and expanded disability status scale (EDSS)), magnetic resonance imaging (MRI) data (number of T2 lesions in brain MRI and total brain volume) and several neurodegenerative/neuroinflammatory markers in CSF and serum/plasma (IL-1ß, IL-6, CXCL1, CXCL10, CXCL13, CCL-22 in plasma; neurofilament light chain (NFL) in serum; IL-6, CXCL1, CXCL10, CXCL13, CCL22, NFL and chitinase-3-like-1 (CHI3L1) in CSF. CSF and serum/plasma from 21 age- and sex-matched healthy controls were available for comparison. RESULTS: At both baseline and one-year follow-up, fatigue scores correlated significantly with HAD, MSIS-29 and SF-36 scores and ACTT performance (Spearman´s rho 0.45-0.78, all p ≤ 0.01) but not with the other neuropsychological test results, disease duration, EDSS ratings, number of T2 lesions, total brain volume or neurodegenerative/neuroinflammatory markers, including neurofilament light chain levels in CSF and serum. In group comparisons, MFIS scores were similar in patients fulfilling no evidence of disease activity-3 (NEDA-3) (n = 18) and patients not fulfilling NEDA-3 (n = 20) during one year of follow-up (p > 0.01). CONCLUSIONS: In this cohort of patients with newly diagnosed CIS and RRMS, fatigue scores were associated with mood, disease impact on daily life and quality of life as well as with alterations of attentive functions. Study results indicate that subjective fatigue scores are not well reflected by some commonly used and objectively measurable disease parameters like EDSS, T2 lesions and NFL levels.

Quality of life assessment in migraine and relapsing remitting multiple sclerosis: self-perceived health is similar.

OBJECTIVE: The aim of this study was to compare self-perceived health between migraine and early stages of relapsing-remitting multiple sclerosis (RRMS) and to explore whether and how accurate those health domains predict overall quality of life. METHODS: Ninety patients aged 18-55 years were enrolled in this cross-sectional study. Thirty follow-up outpatients were recruited with migraine (with or without aura), 30 patients with RRMS, and 30 healthy subjects. They were asked to complete the Health status questionnaire (SF-36) and Personal Wellbeing Index (PWI). RESULTS: Patients with RRMS and migraine had significantly worse self-reported health regarding role limitation due to physical problems and general health than the healthy control group. Additionally, migraine patients had more bodily pain, while RRMS patients expressed more difficulties regarding physical functioning. Differences between migraine and RRMS patients were not significant. Hierarchical regression analysis revealed that role limitation due to physical problems, mental health, and general health represents significant predictors of overall quality of life. CONCLUSIONS: Migraine may affect quality of life similarly to early stages of RRMS. Bio-psycho-socio-medical understanding of the two diseases and their impact on patients QoL should be reconsidered.

Joint assessment of brain and spinal cord motor tract damage in patients with early RRMS: predominant impact of spinal cord lesions on motor function.

BACKGROUND: In patients with MS, the effect of structural damage to the corticospinal tract (CST) has been separately evaluated in the brain and spinal cord (SC), even though a cumulative impact is suspected. OBJECTIVE: To evaluate CST damages on both the cortex and cervical SC, and examine their relative associations with motor function, measured both clinically and by electrophysiology. METHODS: We included 43 patients with early relapsing-remitting MS. Lesions were manually segmented on SC (axial T2*) and brain (3D FLAIR) scans. The CST was automatically segmented using an atlas (SC) or tractography (brain). Lesion volume fractions and diffusion parameters were calculated for SC, brain and CST. Central motor conduction time (CMCT) and triple stimulation technique amplitude ratio were measured for 42 upper limbs, from 22 patients. RESULTS: Mean lesion volume fractions were 5.2% in the SC portion of the CST and 0.9% in the brain portion. We did not find a significant correlation between brain and SC lesion volume fraction (r = 0.06, p = 0.68). The pyramidal EDSS score and CMCT were both significantly correlated with the lesion fraction in the SC CST (r = 0.39, p = 0.01 and r = 0.33, p = 0.03), but not in the brain CST. CONCLUSION: Our results highlight the major contribution of SC lesions to CST damage and motor function abnormalities.

Cost-effectiveness analysis of escalating to natalizumab or switching among immunomodulators in relapsing-remitting multiple sclerosis in Italy.

BACKGROUND: Published literature suggests that early treatment with natalizumab ("escalation strategy") is more effective than switch within the same class of immunomodulators (interferons/glatiramer acetate, "switching strategy") in relapsing-remitting multiple sclerosis (RRMS) patients who failed first-line self-injectable disease-modifying treatment (DMT). The present analysis aims to evaluate the cost-effectiveness profile of escalation strategy vs. switching strategy, adopting the Italian societal perspective. METHODS: A lifetime horizon Markov model was developed to compare early escalation to natalizumab vs. switching among immunomodulators, followed by subsequent escalation to natalizumab. The two compared treatment algorithms were: a) early escalation until progression to Expanded Disability Status Scale (EDSS) = 7.0 vs. b) switching until EDSS = 4.0, followed by escalation until EDSS = 7.0. The model analyzed social costs, quality-adjusted survival and effects of therapies in prolonging time without disability progression and burden of relapses. Clinical data were mainly extracted from a published observational study. RESULTS: Lifetime costs of early escalation to natalizumab and switching among immunomodulators amounted to €699,700 and €718,600 per patient, respectively. Early escalation was associated with prolonged quality-adjusted survival (11.19 vs. 9.67 QALYs, + 15.8%). A slight overall survival increase was also observed (20.10 vs. 19.67 life years). Both deterministic and probabilistic sensitivity analyses confirmed the robustness of findings. CONCLUSIONS: Adopting the Italian social perspective, early escalation to natalizumab is dominant vs. switching among immunomodulators, in RRMS patients who do not respond adequately to conventional immunomodulators.

Longitudinal assessment of hand function in individuals with multiple sclerosis.

OBJECTIVE: Little is known about the frequency and severity of hand dysfunction in individuals with multiple sclerosis (MS). Hence, we sought to determine the extent that quantitative tests of hand function detect changes over time, evaluate their relationship to global disability measures, and identify predictors of hand function. METHODS: One-hundred and forty-seven individuals with MS were included (96 women, 84 relapsing-remitting MS [RRMS]) along with 35 age-and-sex matched controls. Quantitative tests of hand function (grip strength, pinch strength, 9 hole peg test [9HPT], finger tapping) and leg strength were acquired and normalized to age and sex. Expanded Disability Status Scale (EDSS) and timed 25 foot walk were also obtained. Spearman correlations, multivariate regression models and mixed effects linear regression were used for analysis. RESULTS: Our cohort had an EDSS of 3.6 ±â€¯2.2 (median ± SD) and age 44.6 ±â€¯11.9 years. Follow up time was up to 5 years. At baseline, 14/63 individuals with progressive MS (PMS) required more than twice as much time to complete the 9HPT using their dominant hand, compared to controls. Similarly, 11 individuals with PMS had less than 50% of grip strength and 6 had less than 50% of pinch strength, compared to controls. Additionally, 7 individuals with PMS were found to be at least 50% slower than controls in finger tapping. Over two years, 27/85 individuals with MS had more than 20% worsening in their 9HPT results from baseline (17 RRMS, 10 PMS) and 37/74 (20 RRMS, 17 PMS) had more than 20% worsening in their grip strength compared to baseline. CONCLUSIONS: Hand function is commonly impaired in individuals with MS. Assessing hand dysfunction with dynamometry and the 9HPT could help improve the precision of detecting changes in hand function over time in MS, and may be more sensitive in detecting changes in PMS. These quantitative tests may be useful as outcome measures in clinical trials using neuroprotective or reparative therapies and rehabilitative interventions.

Development and Validation of the FSIQ-RMS: A New Patient-Reported Questionnaire to Assess Symptoms and Impacts of Fatigue in Relapsing Multiple Sclerosis.

OBJECTIVES: A new patient-reported outcome (PRO) instrument to measure fatigue symptoms and impacts in relapsing multiple sclerosis (RMS) was developed in a qualitative stage, followed by psychometric validation and migration from paper to an electronic format. METHODS: Adult patients with relapsing-remitting multiple sclerosis (RRMS) were interviewed to elicit fatigue-related symptoms and impacts. A draft questionnaire was debriefed in cognitive interviews with further RRMS patients, and revised. Content confirmation interviews were conducted with patients with progressive-relapsing multiple sclerosis (PRMS) and relapsing secondary-progressive multiple sclerosis (RSPMS). Psychometric analyses used data from adult patients with different RMS subtypes and matched non-RMS controls in a multicenter, observational study. After item reduction, the final instrument was migrated to a smartphone (eDiary) and usability was confirmed in interviews with additional adult RMS patients. RESULTS: The qualitative stage included 37 RRMS, 5 PRMS, and 5 RSPMS patients. Saturation of concepts was reached during concept elicitation. Cognitive interviews confirmed that participants understood the instructions, items, and response options of the instrument-named FSIQ-RMS-as intended. Psychometric validation included 164 RMS and 74 control patients. Internal consistency and test-retest reliability were demonstrated. The symptoms domain discriminated along the RMS symptom-severity continuum and between patients and controls. Patients were able to attribute fatigue-related symptoms to RMS. Usability and conceptual equivalence of the eDiary were confirmed (n = 10 participants). CONCLUSIONS: With 7 symptom items and 13 impact items (in 3 impacts subdomains: physical, cognitive and emotional, and coping) after item reduction, the FSIQ-RMS is a comprehensive, valid, and reliable measure of fatigue-related symptoms and impacts in RMS patients.

Outcomes of Stable Multiple Sclerosis Patients Staying on Initial Interferon Beta Therapy Versus Switching to Another Interferon Beta Therapy: A US Claims Database Study.

INTRODUCTION: This study was designed to assess real-world outcomes of patients with multiple sclerosis (MS) who were stable on interferon (IFN) beta therapy in the year prior to switching to another IFN beta therapy versus those who continued on the initial treatment. METHODS: This study used administrative claims from MarketScan Commercial Claims and Encounters Database, from January 1, 2010, to March 31, 2015, to identify MS patients aged 18-64 years who remained relapse free for at least 1 year while continuously treated with an IFN beta therapy. Stable patients remaining on their initial IFN beta therapy (no-switch patients) were matched with stable patients who switched IFN beta therapy (switch patients) using propensity score matching (first claim = index date). Outcome measures included annualized relapse rate (ARR), the percentage of patients who relapsed, medication possession ratio, and the proportion of days covered and were measured during the year following the index date. RESULTS: This study identified 531 patients in the no-switch group and 177 patients in the switch group, with subsets of 270 patients in the no-switch group and 90 patients in the switch group stable on intramuscular (IM) IFN beta-1a therapy. All outcomes during the follow-up year were significantly better in the no-switch group than in the switch group. For all patients, ARR in the switch group was more than twice that in the no-switch group (P = 0.002). For patients stable on IM IFN beta-1a at baseline, ARR was twice as high in the switch group as in the no-switch group (P = 0.012). CONCLUSION: Among all patients stable on IFN beta therapy and the subset stable on IM IFN beta therapy in particular, those who remained on therapy had significantly better outcomes than those who switched to another IFN beta therapy. FUNDING: Biogen (Cambridge, MA, USA).

Multimodal assessment of normal-appearing corpus callosum is a useful marker of disability in relapsing-remitting multiple sclerosis: an MRI cluster analysis study.

BACKGROUND AND PURPOSE: Corpus callosum (CC) is frequently involved in relapsing-remitting multiple sclerosis (RRMS). Magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) allow to study CC macrostructural and microstructural tissue integrity. Here, we applied a data-driven approach to MRI and DTI data of normal-appearing CC in RRMS subjects, and subsequently evaluated if differences in tissue integrity corresponded to different levels of physical disability and cognitive impairment. METHODS: 74 RRMS patients and 20 healthy controls (HC) underwent 3 T MRI and DTI. Thickness and fractional anisotropy (FA) along midsagittal CC were extracted, and values from RRMS patients were fed to a hierarchical clustering algorithm. We then used ANOVA to test for differences in clinical and cognitive variables across the imaging-based clusters and HC. RESULTS: We found three distinct MRI-based subgroups of RRMS patients with increasing severity of CC damage. The first subgroup showed callosal integrity similar to HC (Cluster 1); Cluster 2 had milder callosal damage; a third subgroup showed the most severe callosal damage (Cluster 3). Cluster 3 included patients with longer disease duration and worst scores in Expanded Disability Status Scale. Cognitive domains of verbal memory, executive functions and processing speed were impaired in Cluster 3 and Cluster 2 compared to Cluster 1 and HC. CONCLUSIONS: Within the same homogeneous cohort of patients, we could identify three neuroimaging RRMS clusters characterized by different involvement of normal-appearing CC. Interestingly, these corresponded to three distinct levels of clinical and cognitive disability.

Progressive multiple sclerosis patients have a higher burden of autonomic dysfunction compared to relapsing remitting phenotype.

OBJECTIVE: To determine autonomic dysfunction (AD) differences in patients with relapsing remitting multiple sclerosis (pwRRMS) and progressive MS (pwPMS). METHODS: Composite autonomic scoring scale (CASS) and heart rate variability (HRV) were performed in 40 pwRRMS and 30 pwPMS. RESULTS: pwPMS had a significantly higher sudomotor index and total CASS score compared to pwRRMS (p < 0.001 and p < 0.001, respectively). Disease duration positively correlated with sudomotor index and total CASS (rs = 0.409, p < 0.001 and rs = 0.472, p < 0.001, respectively), while the Expanded Disability Status Scale (EDSS) positively correlated with sudomotor index and total CASS (rs = 0.411, p < 0.001 and rs = 0.402, p = 0.001, respectively) in all patients. Type of multiple sclerosis (pwRRMS or pwPMS) corrected for age, sex and disease duration, was a statistically significant predictor of CASS value (B = 1.215, p = 0.019). Compared to pwRRMS, pwPMS had a significantly lower standard deviation of NN intervals (SDNN), low frequency (LF), and high frequency (HF), during both the supine and tilt-up phases (all p-values <0.006). pwPMS had a significantly lower LF/HF (p = 0.008) during tilt-up. CONCLUSION: There is a significant difference in autonomic function in pwRRMS and pwPMS; with pwPMS having a higher burden of AD, which is particularly evident for sweating dysfunction. SIGNIFICANCE: Further research is needed to establish whether parasympathetic and sudomotor dysfunction may serve as markers of progressive MS.

Multimodal evoked potentials in patients with multiple sclerosis in assessment of the course of the disease.

INTRODUCTION: Multiple sclerosis (MS) is a chronic inflammatory, demyelinating disease of the central nervous system with a multifocal damage. THE AIM: The assessment of the MS course by multimodal evoked potentials (EP). MATERIAL AND METHODS: We evaluated 95 patients (63 female, 32 male) with relapsing-remitting MS in the average age of 36.4±10.4. The average disease duration was 4.6±7.4 year. Among them, 48 patients (50.5%) were treated with immunomodulatory drugs. All patients underwent neurological examination and EP testing: VEP (visual evoked potentials), SEP (somatosensory evoked potentials), endogenous potential P300. The latencies of following waves were evaluated: P100 (VEP), N4 , N9 , N13, N20, P22 (SEP) and P300, with the reference values of the Neurophysiological Research Laboratory of the Department of Neurology in Zabrze. RESULTS: Abnormal VEP(I) was found in 80 patients (84.2%), SEP(I) in 9 patients (9.5%), P300(I) in 15 patients (15.8%). Abnormal result of the control research VEP (II) was found in 23 patients (82.1%), SEP(II) in 1 patient (3.6%), P300(II) in 4 patients (14.3%). The average values of the waves latencies in the control study were higher, however the statistical significance was not found. The correlation was observed between EDSS, and N20 and P22. No relationship was found between EP and age, disease duration, number of relapses and treatment. CONCLUSIONS: In the era of neuroimaging, usage of EP in the diagnosis and assessment of MS is limited. Electrophysiological studies may be used in addition to the clinical examination to confirm the multifocal damage.

Longitudinal quantitative MRI assessment of cortical damage in multiple sclerosis: A pilot study.

PURPOSE: Quantitative MRI (qMRI) allows assessing cortical pathology in multiple sclerosis (MS) on a microstructural level, where cortical damage has been shown to prolong T1 -relaxation time and increase proton density (PD) compared to controls. However, the evolution of these changes in MS over time has not been investigated so far. In this pilot study we used an advanced method for the longitudinal assessment of cortical tissue change in MS patients with qMRI in comparison to cortical atrophy, as derived from conventional MRI. MATERIALS AND METHODS: Twelve patients with relapsing-remitting MS underwent 3T T1 /PD-mapping at two timepoints with a mean interval of 12 months. The respective cortical T1 /PD-values were extracted from the middle of the cortical layer and the cortical thickness was measured for surface-based identification of clusters with increasing/decreasing values. RESULTS: Statistical analysis showed clusters with increasing PD- and T1 -values over time (annualized rate for T1 /PD increase in these clusters: 3.4 ± 2.56% for T1 , P = 0.0007; 2.3 ± 2.59% for PD, P = 0.01). Changes are heterogeneous across the cortex and different patterns of longitudinal PD and T1 increase emerged. Analysis of the cortical thickness yielded only one small cluster indicating a decrease of cortical thickness. CONCLUSION: Changes of cortical tissue composition in MS seem to be reflected by a spatially inhomogeneous, multifocal increase of the PD values, indicating replacement of neural tissue by water, and of the T1 -relaxation time, a surrogate of demyelination, axonal loss, and gliosis. qMRI changes were more prominent than cortical atrophy, showing the potential of qMRI techniques to quantify microstructural alterations that remain undetected by conventional MRI. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2017;46:1485-1490.

Joint assessment of dependent discrete disease state processes.

In multiple sclerosis, the primary clinical measure of disability level is an ordinal score, the expanded disability severity scale score. In relapsing-remitting multiple sclerosis, measures of relapse are additionally of interest. Multiple sclerosis patients are typically assessed with regard to both the expanded disability severity scale and relapse state at each follow-up visit. As both are discrete measures, the two can be viewed as jointly dependent Markov processes. One of the main goals of multiple sclerosis research is to accurately model, over time, both transitions between expanded disability severity scale states and change in relapse state. This objective requires a number of significant modeling decisions, including decisions about whether or not the combination of specific disease states is warranted and assessment of the dependence structure between the two disease processes. Historically, such decisions are often made in an ad hoc manner and are not formally justified. We propose novel use of Bayes factors and Bayesian variable selection in the assessment of jointly dependent Markovian processes in multiple sclerosis. Methods are assessed using both simulated data and data collected from the Partners Multiple Sclerosis Center in Boston, MA.

Dynamic Contrast-Enhanced Magnetic Resonance Imaging Suggests Normal Perfusion in Normal-Appearing White Matter in Multiple Sclerosis.

OBJECTIVES: Multiple sclerosis (MS) is a chronic, inflammatory disease of the central nervous system and has been associated with reduced perfusion in normal-appearing white matter (NAWM). The magnitude of this hypoperfusion is unclear. The present study aims to quantify NAWM perfusion with dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) in patients with relapsing-remitting (RR) MS and in a control group. MATERIALS AND METHODS: The statistical power of a DCE-MRI acquisition to reveal hypoperfusion in MS was estimated using a Monte Carlo simulation: synthetic tissue curves with a contrast-to-noise ratio of 8 were generated for MS patients and control group using perfusion values reported in previous studies. A compartment-uptake model was fitted to these curves, yielding estimates of cerebral blood flow (CBF), cerebral blood volume (CBV), and permeability-surface area product (PS). This was repeated 1000 times. Mean and standard deviation of the resulting distributions were used to calculate the statistical power of a DCE-MRI study to detect perfusion differences between 16 control subjects and 24 MS subjects.In an institutional review board-approved study, patients with RR-MS (n = 24; mean age, 36 years; 17 women, mean Enhanced Disability Status Scale score, 3.25) and patients without history or symptoms of neurological disorder (n = 16; mean age, 49 years; 9 women) underwent a DCE-MRI examination with a previously established MRI protocol (3D SPGR sequence; 2.1 seconds temporal resolution; 44 slices; spatial resolution, 1.7 × 1.7 × 3 mm). Regions were defined manually in the middle cerebral artery; in the frontal, periventricular, and occipital NAWM; in the pons; and in the thalamus, and CBF, CBV, and PS were quantified using a compartment-uptake model.Parameter differences between MS and control groups were evaluated using a mixed linear model with subjects as random effect and controlling for age and sex. A P value of less than 0.05 was considered to indicate statistical significance. RESULTS: For all but one of previously reported effect sizes, the simulation study estimated a statistical power of 80% to 100% to detect reduced CBF in MS. In the patient study, mean (standard deviation) CBF in NAWM was 11.0 (15.1) and 10.4 (8.2) mL/100 mL per minute in the MS and control groups, respectively. Mean CBV in NAWM was 0.50 (0.45) mL/100 mL in the MS group and 0.48 (0.28) mL/100 mL in the control group. Mean values of PS in NAWM were 0.002 mL (0.027)/100 mL per minute in the control group and -0.001 (0.015) mL/100 mL per minute in the MS patients. Differences between patient groups were not statistically significant for CBF, CBV, mean transit time, and PS (P = 0.44, P = 0.20, P = 0.78, P = 0.66, respectively). In both groups, the influence of age on any parameter was nonsignificant. Cerebral blood flow and CBV in the thalamus and pons were significantly higher than in NAWM regions (P < 1e-4); mean transit time was significantly shorter than in NAWM (P < 1e-4). Permeability-surface area product was not significantly different from zero (P > 0.25) in all evaluated regions. CONCLUSIONS: Despite high statistical power, we could not confirm previous reports of NAWM hypoperfusion in MS. This indicates that, at least in our patient cohort, potential hypoperfusion is much less pronounced than reported in previous studies.