Do patients' and referral centers' characteristics influence multiple sclerosis phenotypes? Results from the Italian multiple sclerosis and related disorders register.

BACKGROUND: Multiple sclerosis (MS) is characterized by phenotypical heterogeneity, partly resulting from demographic and environmental risk factors. Socio-economic factors and the characteristics of local MS facilities might also play a part. METHODS: This study included patients with a confirmed MS diagnosis enrolled in the Italian MS and Related Disorders Register in 2000-2021. Patients at first visit were classified as having a clinically isolated syndrome (CIS), relapsing-remitting (RR), primary progressive (PP), progressive-relapsing (PR), or secondary progressive MS (SP). Demographic and clinical characteristics were analyzed, with centers' characteristics, geographic macro-areas, and Deprivation Index. We computed the odds ratios (OR) for CIS, PP/PR, and SP phenotypes, compared to the RR, using multivariate, multinomial, mixed effects logistic regression models. RESULTS: In all 35,243 patients from 106 centers were included. The OR of presenting more advanced MS phenotypes than the RR phenotype at first visit significantly diminished in relation to calendar period. Females were at a significantly lower risk of a PP/PR or SP phenotype. Older age was associated with CIS, PP/PR, and SP. The risk of a longer interval between disease onset and first visit was lower for the CIS phenotype, but higher for PP/PR and SP. The probability of SP at first visit was greater in the South of Italy. DISCUSSION: Differences in the phenotype of MS patients first seen in Italian centers can be only partly explained by differences in the centers' characteristics. The demographic and socio-economic characteristics of MS patients seem to be the main determinants of the phenotypes at first referral.

Preserved brain functional plasticity after upper limb task-oriented rehabilitation in progressive multiple sclerosis.

BACKGROUND AND PURPOSE: Limited research has been dedicated to upper limb (UL) rehabilitation in progressive multiple sclerosis (PMS). The objective in this pilot study was to investigate the effect of task-oriented UL rehabilitation in PMS and to perform explorative analyses of the magnetic resonance imaging (MRI) correlates of changes in motor performance. METHODS: Twenty-six PMS patients with mild UL impairment were prospectively enrolled and randomized into two groups: an active treatment group (ATG, n = 13) and a passive treatment group (PTG, n = 13). At baseline and after training, patients underwent MRI scans with structural and functional imaging and were evaluated with the action research arm test, the nine-hole peg test, the ABILHAND scale and the modified fatigue impact scale (MFIS). Measures of motor finger performance were obtained by engineered glove measuring. RESULTS: After rehabilitation, the ATG improved in several finger motor tasks (0.001 ≤ P ≤ 0.03, 0.72 ≤ Cohen's d ≤ 1.22) and showed reduced MFIS scores compared with the PTG (P = 0.03). The ATG showed increased functional connectivity within the cerebellar and thalamic resting state networks compared with the PTG (P < 0.05). Correlations were found between several measures of motor improvement and thalamic and sensorimotor networks (0.87 ≤ r ≤ 0.93, 0.001 ≤ P ≤ 0.03). No changes in cerebral volumes and diffusion tensor imaging derived measures were detected. CONCLUSIONS: Progressive multiple sclerosis patients with mild UL dysfunction benefit from task-oriented UL rehabilitation, which seems to be more efficient than simple passive mobilization. Despite a high burden of disability and brain damage, functional adaptive capacities seem to be preserved, thus providing a rationale for the use of rehabilitative treatments in late PMS.

Box and block test, hand grip strength and nine-hole peg test: correlations between three upper limb objective measures in multiple sclerosis.

BACKGROUND AND PURPOSE: Limited data are available in the literature for upper limb impairment in multiple sclerosis (MS). This study aimed to report the distribution of values of hand grip strength (HGS), of the box and block test (BBT) and of the nine-hole peg test (9HPT) correlated with demographic and clinical data in subjects with MS. METHODS: This study involved five Italian neurological centres. The inclusion criteria were age ≥ 18, MS diagnosis, stable disease phase, right-hand dominance. All subjects underwent HGS, BBT and 9-HPT evaluation. RESULTS: In all, 202 subjects with MS were enrolled: 137 females; mean age 48.4 years; mean Expanded Disability Status Scale (EDSS) 4.17; mean disease duration 14.12 years; disease course 129 relapsing-remitting, 21 primary progressive and 52 secondary progressive MS subjects; mean right HGS 25.3 kg, left 23.2 kg; mean right BBT 45.7 blocks, left 44.9 blocks; mean right 9-HPT 30.7 s, left 33.4 s. All results were statistically significantly different compared to healthy controls. HGS, BBT and 9-HPT were associated with age, EDSS and disease duration, whilst disease course correlated with BBT and 9-HPT. The BBT and 9-HPT scores significantly differed according to level of disability (EDSS ≤3.0, 3.5-5.5, ≥6.0). CONCLUSION: Hand grip strength and BBT value distribution in a large MS population is reported. Correlations between HGS, BBT and 9-HPT were generally low.

Associations between fatigue impact and physical and neurobehavioural factors: An exploration in people with progressive multiple sclerosis.

BACKGROUND: Fatigue is common in people with multiple sclerosis (MS). Understanding the relationship between fatigue, physical and neurobehavioural factors is important to inform future research and practice. Few studies explore this explicitly in people with progressive MS (pwPMS). OBJECTIVE: To explore relationships between self-reported fatigue, physical and neurobehavioural measures in a large, international progressive MS sample of cognitively impaired people recruited to the CogEx trial. METHODS: Baseline assessments of fatigue (Modified Fatigue Impact Scale; MFIS), aerobic capacity (VO2peak), time in moderate-vigorous physical activity (MVPA; accelerometery over seven-days), walking performance (6-minute walk test; 6MWT), self-reported walking difficulty (MS Walking Scale; MSWS-12), anxiety and depression (Hospital Anxiety and Depression Scale; HADS and Beck Depression Inventory-II; BDI-II), and disease impact (MS Impact Scale-29, MSIS-29) were assessed. Participants were categorised as fatigued (MFISTotal >=38) or non-fatigued (MFISTotal ≤38). STATISTICAL ANALYSIS: Differences in individuals categorised as fatigued or non-fatigued were assessed (t-tests, chi square). Pearson's correlation and partial correlations (adjusted for EDSS score, country, sex, and depressive symptoms) determined associations with MFISTotal, MFISPhysical, MFISCognitive and MFISPsychosocial, and the other measures. Multivariable logistic regression evaluated the independent association of fatigue (categorised MFISTotal) with physical and neurobehavioural measures. RESULTS: The sample comprised 308 pwPMS (62 % female, 27 % primary progressive, 73 % secondary progressive), mean age 52.5 ± 7.2 yrs, median EDSS score 6.0 (4.5-6.5), mean MFISTotal 44.1 ± 17.1, with 67.2 % categorised as fatigued. Fatigued participants walked shorter distances (6MWT, p = 0.043), had worse MSWS-12 scores (p < 0.001), and lower average % in MVPA (p = 0.026). The magnitude of associations was mostly weak between MFISTotal and physical measures (r = 0.13 to 0.18), apart from the MSWS-12 where it was strong (r = 0.51). The magnitude of correlations were strong between the MFISTotal and neurobehavioural measures of anxiety (r = 0.56), depression (r = 0.59), and measures of disease impact (MSIS-physical r = 0.67; MSIS-mental r = 0.71). This pattern was broadly similar for the MSIF subscales. The multivariable model indicated a five-point increase in MSWS-12 was associated with a 14 % increase in the odds of being fatigued (OR [95 %CI]: 1.14 [1.07-1.22], p < 0.0001) CONCLUSION: Management of fatigue should consider both physical and neurobehavioural factors, in cognitively impaired persons with progressive MS.

Profiling cognitive-motor interference in a large sample of persons with progressive multiple sclerosis and impaired processing speed: results from the CogEx study.

BACKGROUND: Performing cognitive-motor dual tasks (DTs) may result in reduced walking speed and cognitive performance. The effect in persons with progressive multiple sclerosis (pwPMS) having cognitive dysfunction is unknown. OBJECTIVE: To profile DT-performance during walking in cognitively impaired pwPMS and examine DT-performance by disability level. METHODS: Secondary analyses were conducted on baseline data from the CogEx-study. Participants, enrolled with Symbol Digit Modalities Test 1.282 standard deviations below normative value, performed a cognitive single task ([ST], alternating alphabet), motor ST (walking) and DT (both). Outcomes were number of correct answers on the alternating alphabet task, walking speed, and DT-cost (DTC: decline in performance relative to the ST). Outcomes were compared between EDSS subgroups (≤ 4, 4.5-5.5, ≥ 6). Spearman correlations were conducted between the DTCmotor with clinical measures. Adjusted significance level was 0.01. RESULTS: Overall, participants (n = 307) walked slower and had fewer correct answers on the DT versus ST (both p < 0.001), with a DTCmotor of 15.8% and DTCcognitive of 2.7%. All three subgroups walked slower during the DT versus ST, with DTCmotor different from zero (p's < 0.001). Only the EDSS ≥ 6 group had fewer correct answers on the DT versus ST (p < 0.001), but the DTCcognitive did not differ from zero for any of the groups (p ≥ 0.039). CONCLUSION: Dual tasking substantially affects walking performance in cognitively impaired pwPMS, to a similar degree for EDSS subgroups.

A comparison of upper limb function in subjects with multiple sclerosis and healthy controls using an inertial measurement unit.

Upper limbs (UL) dysfunction is frequent in people with Multiple Sclerosis (PwMS). Several objective measures of UL function are proposed; however, their use is mostly confined to assess subjects with mild-to-moderate disability and requires fine motor skills, often impaired in high disability level subjects. Thus, a tool to score UL function in the advanced disease stage is lacking. The aim of the study is to analyse and compare UL unilateral and bilateral movements of healthy control (HC) and PwMS, at different disability levels, using an instrumented version (Inertial Measurement Unit, IMU) of the 15-seconds finger-to-nose test (FNT). Each movement cycle was segmented in going/adjusting/returning phases. The inter-hand interval (IHI) allowed assessing bilateral coordination (i.e. synchrony) in each phase. The larger IHI, the more severe the bilateral coordination impairment is. After stratifying PwMS for disability level (PwMSLOW, Expanded Disability Status Scale, EDSS≤5.5 and PwMSHIGH, EDSS≥6), the ANOVA on IHI showed significant differences between PwMS and HC (p<0.001) in all phases. However, only the going phase IHI showed significantly higher asynchrony in PwMSHIGH than PwMSLOW and HC (p<0.001) and no differences between PwMSLOW and HC. The going phase IHI seems to be a clinical marker specific for high disability level PwMS. These findings suggest inertial sensors during FNT could be an easy-to-use method for a more detailed quantitative characterization of UL function in PwMS also in subjects with EDSS greater than 6.

The patients' perspective on the perceived difficulties of dual-tasking: development and validation of the Dual-task Impact on Daily-living Activities Questionnaire (DIDA-Q).

BACKGROUND: Everyday-life activities often require performing dual tasks (DT), with consequent possible occurrence of motor-cognitive or motor-motor interference. This could reduce quality of life, in particular in people with neurological diseases. However, there is lack of validated tools to assess the patients' perspective on DT difficulties in this population. Therefore, we developed the Dual-task Impact on Daily-living Activities-Questionnaire (DIDA-Q) and tested its psychometric properties in people with multiple sclerosis (PwMS). METHODS: Items were generated based on existing scales, DT paradigms used in previous studies and the opinion of a multi-stakeholder group, including both experts and PwMS. Twenty DT constituted the preliminary version of the DIDA-Q which was administered to 230 PwMS. The psychometric properties of the scale were evaluated including internal consistency, validity and reliability. RESULTS: Nineteen items survived after exploratory factor analysis, showing a three-factor solution which identifies the components mostly contributing to DT perceived difficulty (i.e., balance and mobility, cognition and upper-limb ability). The DIDA-Q appropriately fits the graded response model, with first evaluations supporting internal consistency (Cronbach's alpha=0.95), validity (70% of the hypotheses for convergent and discriminant constructs confirmed) and reliability (intraclass correlation coefficients=0.95) of this tool. CONCLUSION: The DIDA-Q could be used in research and clinical settings to discriminate individuals with low vs. high cognitive-motor or motor-motor interference, and to develop and evaluate the efficacy of personalized DT rehabilitative treatments in PwMS.

Activity, tolerability and efficacy of levetiracetam on cerebellar symptoms in multiple sclerosis patients: a pilot kinematic study.

BACKGROUND AND PURPOSE: The aim of this study was to evaluate the activity measured by kinematic analysis, tolerability and efficacy of levetiracetam (LEV) in multiple sclerosis (MS) patients affected by cerebellar symptoms, in a randomized single-blind, placebo-controlled cross-over study. METHODS: Eight MS subjects with cerebellar signs (five female and three male; mean EDSS: 4.77; mean disease duration 9.2) performed a reaching task on a digitizing tablet and their trajectories went through a kinematic analysis. The subjects were assessed at baseline, after 21 days of treatment, after wash-out period (day 35) and after 21 days of treatment (day 56). LEV was used at the maximum dosage of 1500 mg daily. The primary outcome was the modification on smoothness (JERK) whilst aiming error (AAI) and centripetal acceleration (CA) were considered as secondary outcomes. RESULTS: Two subjects were excluded from the final analysis. Primary outcome (i.e. JERK) was significantly affected by the administration of LEV overtime (nine arms in active treatment versus three arms in placebo decreased the mean values of their JERK). Regarding secondary outcomes CA was significantly affected by the administration of LEV. No statistical significant results were found comparing clinical scales during the four assessments. DISCUSSION: The results indicate that LEV was able to modify kinematic parameter so the medication was active but no improvement in clinical scales was observed. LEV needs to be tested in a larger group of subjects designed to verify treatment efficacy using higher dosage of the medication.

Analysis of upper limb movement in Multiple Sclerosis subjects during common daily actions.

The goal of this study was to investigate the movement and muscle activity of the upper limb during common activities of daily life in people with Multiple Sclerosis (PwMS) with low and mild-moderate level of upper limb impairments. We found significant changes in muscles activity in PwMS compared to healthy subjects when holding and lifting objects used in everyday life. These differences were particularly remarkable in subjects with moderate level of impairment, in which the disease affected also movement smoothness. Remarkably, the smoothness of the movement during the interaction with common objects of daily activities highly correlated with the subjects' ability measured with the Abilhand scale.

Italian validation of the 12-item multiple sclerosis walking scale.

Objective. Gait impairment is commonly in people with multiple sclerosis (MS). The 12-item MS walking scale (MSWS-12) assesses patients' measurement of walking quality. The aim of this study was to cross-culturally adapt and validate the MSWS-12 for the Italian population with MS. Methods. Six MS out-patient clinics across Italy enrolled subjects between June 2013 and December 2013. Construct validity of MSWS-12 was determined by examining correlations with the Italian version of the EDSS, the timed 25-foot walk (T25FW), and the Fatigue Severity Scale (FSS). Results. 321 MS subjects were enrolled. Mean age was 47.55 years and mean disease duration was 13.8 years. Mean EDSS score was 4.46. 185 subjects had a relapsing-remitting course, 92 were secondary progressive, 43 were primary progressive, and 1 had a clinically isolated syndrome. The mean total score of the MSWS-12 was 49.6 (SD: 31) with values ranging between 0 and 100. Correlations between the MSWS-12 with age, disease duration, and disease course were found but not with gender. Values of the MSWS-12/IT were significantly related to EDSS (0.71), to the T25FW (0.65), and to the FSS (0.51). Conclusion. MSWS-12/IT has been adapted and validated, it is a reliable and reproducible scale for Italian patients with MS.

Subtle upper limb impairment in asymptomatic multiple sclerosis subjects.

We evaluated upper limb function in multiple sclerosis (MS) subjects (11 clinically definite MS patients and seven clinically isolated syndrome (CIS) subjects), with a normal upper limb standard neurological examination. Subjects performed center-out reaching movements under visual control, with and without vision of the hand. Their movements were recorded through a digitizing tablet. Motor performance was also related to lesion load, estimated from magnetic resonance imaging (MRI). We found that in MS and CIS subjects, under the hand vision condition, movements were significantly less smooth, and had a less symmetric speed profile. However, the observed impairment did not correlate with MRI findings. This result may be interpreted as evidence of a compensatory strategy, elicited by subtle alterations in sensorimotor control.

Evaluation of physical therapy in parkinsonian patients with freezing of gait: a pilot study.

OBJECTIVE: Freezing of gait is a frequently disabling symptom in Parkinson's disease, poorly responding to dopaminergic treatment. We investigated the short-term effectiveness of a rehabilitation protocol in parkinsonian patients with freezing of gait. DESIGN: Prospective, uncontrolled pilot study with open label design. SETTING: Outpatient service for rehabilitation of neurological disorders. SUBJECTS: Twelve patients (8 male, 4 female; aged 59-78 years; Hoehn-Yahr stage: 2-3; mean disease duration: 14.2 +/- SD 4.1 years). INTERVENTIONS: Patients attended three (45 min) sessions every week, over a six-week period, of physical therapy focused to improve balance, postural control and walking, and to learn new strategies for overcoming freezing of gait. MAIN OUTCOME MEASURES: Patients were evaluated before (T0), at the end (T1), and one month after (T2) rehabilitation by means of clinical rating scales (Unified Parkinson Disease Rating Scale--Motor Section; Freezing of Gait Questionnaire; Parkinson Disease Quality of Life Score) and gait parameters (number of strides, stride length and velocity) during a standardized walking test. RESULTS: The scores of Freezing of Gait Questionnaire and of Parkinson Disease Quality of Life Questionnaire (but not of the Unified Parkinson Disease Rating Scale--Motor Section) were significantly improved after treatment (T1). Gait parameters were significantly improved at T1 and T2. CONCLUSIONS: We showed the potential short-term efficacy of a rehabilitative approach to freezing of gait in Parkinson's disease. The positive outcome was documented by clinical rating scales and objective gait evaluation. The rapid reversibility of the clinical benefit suggests that further studies are needed to better define the optimal frequency and duration of treatment.

Prevalence of oedema of the lower limbs in multiple sclerosis patients: a vascular and lymphoscintigraphic study.

The aim of the study was to evaluate the frequency of oedema of the lower limbs in multiple sclerosis (MS) patients utilizing a multidisciplinary approach. A total of 205 patients with definite MS were included in the study. Seventy-five were male and 130 female, with a mean age of 50.53, mean Expanded Disability Status Scale (EDSS) score of 5.27 and mean disease duration of 16.6 years. Seventy-one patients had a relapsing-remitting (RR) disease course, 85 were secondary progressive (SP) and 49 were primary progressive (PP). Ninety-three patients (45%) showed oedema at the examination. EDSS, disease duration and disease course, but not gender, were statistically different between oedema and non-oedema patients. Out of 93 patients with oedema, 69 agreed to undergo a vascular examination. Of 69 patients, 45 (65.2%) had a CEAP score (specific rating scale for oedema) of 3 (presence of oedema) and 24 (34.8%) had a score of 4 (presence of a trophic disorder). Out of 69 subjects, 33 agreed to undergo a lymphoscintigraphy, which was normal in only 29 extremities out of 66. Lower limb oedema is common in MS patients, especially in those with reduced mobility. Early screening is advised in patients with an elevated EDSS.

Antiepileptic medications in multiple sclerosis: adverse effects in a three-year follow-up study.

Neuropathic pain and paroxysmal symptoms are common in multiple sclerosis (MS) patients, although no double-blind clinical trial has been conducted to support antiepileptic medications (AED) use in MS. The aim of the study was to evaluate the frequency of AED utilisation and reported adverse events, in a cohort of MS patients. For a period of 3 years the rationale for prescribing AED, adverse effects, treatment duration and reasons for discontinuation were recorded in a database. Carbamazepine (CBZ) was prescribed in 36 patients, with adverse effects reported in 20 cases, of which 12 mimicked a relapse. Gabapentin (GBP) was prescribed in 94 patients, with adverse effects reported in 16 cases and in one case mimicked a relapse. Lamotrigine (LMT) was prescribed in 22 patients, with adverse effects reported in 4 cases, none mimicking a relapse. The present study found a significantly higher incidence of adverse effects in patients treated with CBZ, with a high rate of discontinuation at low dosages and episodes of evident worsening of neurological functioning compared to GBP or LMT.

Symptomatic medication use in multiple sclerosis.

Multiple sclerosis (MS) is one of the most studied neurological diseases, although scarce attention has been placed on symptomatic therapy. The aim of the study was to evaluate the frequency of medication prescription for the major symptoms related to MS in order to better understand the needs of patients. The study was conducted during an epidemiological survey in the province of Genoa, Italy. Out of 856 patients with MS in the study area, 665 agreed to participate in a structured interview. Two hundred and forty-nine (37%) subjects, with a mean age of 53 years and a mean Expanded Disability Status Scale (EDSS) score of 5.2, were taking at least one symptomatic medication. Four hundred and sixteen (63%) subjects, with a mean age of 49 years and a mean EDSS score of 4.5, were not using symptomatic therapy. The most commonly treated symptoms were pain (28%), spasticity (27%) and mood disorder (16%), while bladder dysfunction (8%) and fatigue (3%) were less frequently treated with medication. Seventy-seven patients (12%) were taking medications for reasons not directly related to MS. This cross-sectional study underlines the frequency of medication prescription for symptoms such as spasticity and pain, while other common symptoms, such as bladder dysfunction and fatigue, may perhaps be undertreated. The present findings also underline the need for clinical trials on symptomatic therapies.

The prevalence of pain in multiple sclerosis: a multicenter cross-sectional study.

In a multicenter cross-sectional study, the authors assessed pain in patients with multiple sclerosis (MS) using a symptom-oriented approach. Out of 2,077 questionnaires, we used 1,672 for data analysis. Pain and frequencies included trigeminal neuralgia 2%, Lhermitte's sign 9%, dysesthetic pain 18.1%, back pain 16.4%, and painful tonic spasms 11%. Comparison between different groups showed significant differences for age, Expanded Disability Status Scale, disease duration, and disease course, but not for sex. This study underlines the relevance of pain in the clinical history of MS.