The still under-investigated role of cognitive deficits in PML diagnosis

Background: Despite cognitive deficits frequently represent the first clinical manifestations of Progressive Multifocal Leukoencephalopathy (PML) in Natalizumab-treated MS patients, the importance of cognitive deficits in PML diagnosis is still under-investigated. The aim of the current study is to investigate the cognitive deficits at PML diagnosis in a group of Italian patients with PML. Methods: Thirty-four PML patients were included in the study. The demographic and clinical data, the lesion load and localization, and the longitudinal clinical course was compared between patients with (n = 13) and without (n = 15) cognitive deficit upon PML suspicion (the remaining six patients were asymptomatic). Clinical presentation of cognitive symptoms was described in detail. Result: After symptoms detection, the time to diagnosis resulted to be shorter for patients presenting with cognitive than for patients with non cognitive onset (p = 0.03). Within patients with cognitive onset, six patients were presenting with language and/or reading difficulties (46.15%); five patients with memory difficulties (38.4%); three patients with apraxia (23.1%); two patients with disorientation (15.3%); two patients with neglect (15.3%); one patients with object agnosia (7.7%), one patient with perseveration (7.7%) and one patient with dementia (7.7%). Frontal lesions were less frequent (p = 0.03), whereas temporal lesions were slightly more frequent (p = 0.06) in patients with cognitive deficits. The longitudinal PML course seemed to be more severe in cognitive than in non cognitive patients (F = 2.73, p = 0.03), but differences disappeared (F = 1.24, p = 0.29) when balancing for the incidence of immune reconstitution syndrome and for other treatments for PML (steroids, plasma exchange (PLEX) and other therapies (Mefloquine, Mirtazapine, Maraviroc). Conclusion: Cognitive deficits at PML onset manifest with symptoms which are absolutely rare in MS. Their appearance in MS patients should strongly suggest PML. Clinicians should be sensitive to the importance of formal neuropsychological evaluation, with particular focus on executive function, which are not easily detected without a formal assessment

6-Month Effects of Fingolimod on Indexes of Cardiovascular Autonomic Control in Multiple Sclerosis

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ADC Histograms from Routine DWI for Longitudinal Studies in Cerebral Small Vessel Disease: A Field Study in CADASIL.

Diffusion tensor imaging (DTI) histogram metrics are correlated with clinical parameters in cerebral small vessel diseases (cSVD). Whether ADC histogram parameters derived from simple diffusion weighted imaging (DWI) can provide relevant markers for long term studies of cSVD remains unknown. CADASIL patients were evaluated by DWI and DTI in a large cohort study overa6-year period. ADC histogram parameters were compared to those derived from mean diffusivity (MD) histograms in 280 patients using intra-class correlation and Bland-Altman plots. Impact of image corrections applied to ADC maps was assessed and a mixed effect model was used for analyzing the effects of scanner upgrades. The results showed that ADC histogram parameters are strongly correlated to MD histogram parameters and that image corrections have only limited influence on these results. Unexpectedly, scanner upgrades were found to have major effects on diffusion measures with DWI or DTI that can be even larger than those related to patients' characteristics. These data support that ADC histograms from daily used DWI can provide relevant parameters for assessing cSVD, but the variability related to scanner upgrades as regularly performed in clinical centers should be determined precisely for longitudinal and multicentric studies using diffusion MRI in cSVD

Predictors of hospital-based multidisciplinary rehabilitation effects in persons with multiple sclerosis: a large-scale, single-centre study

open7Background: Persons with multiple sclerosis may benefit from hospital-based multidisciplinary rehabilitation. Objectives: To investigate the effects of hospital-based multidisciplinary rehabilitation and to identify their potential predictors in a large sample of persons with multiple sclerosis. Methods: From the charts of 655 persons with multiple sclerosis consecutively admitted to our unit, disease profiles, modified Barthel index, Expanded Disability Status Scale (EDSS), pain numerical rating score and type of interventions were retrospectively collected. We defined an improvement at discharge as follows: modified Barthel index increase of at least 5 points, EDSS decrease of 1.0 if baseline score was 5.5 or less and of 0.5 if baseline score was greater than 5.5; any numerical rating score decrease. Results: After a median admission period of 36 days, at discharge 65%, 22% and 89% of persons with multiple sclerosis improved for modified Barthel index, EDSS and numerical rating score, respectively. The modified Barthel index improvement was associated with shorter disease duration, lower EDSS at baseline and with access to psychological counselling. EDSS improvement was associated with shorter disease duration, relapsing-remitting course, female gender and longer duration of the admission period. Conclusions: Inpatient multidisciplinary rehabilitation was associated with improved autonomy in activities of daily living in a relevant proportion of persons with multiple sclerosis. The effect seems to be more evident in individuals with shorter multiple sclerosis duration and relapsing-remitting disease course.openGroppo, Elisabetta; Signori, Alessio; Sormani, Maria Pia; Grosso, Cristina; Mantia, Loredana La; Cattaneo, Davide; Rovaris, MarcoGroppo, Elisabetta; Signori, Alessio; Sormani, Maria Pia; Grosso, Cristina; Mantia, Loredana La; Cattaneo, Davide; Rovaris, Marc

Vitamin D Receptor Gene Polymorphism Predicts the Outcome of Multidisciplinary Rehabilitation in Multiple Sclerosis Patients

Better knowledge about the possible role of genetic factors in modulating the response to multiple sclerosis (MS) treatment, including rehabilitation, known to promote neural plasticity, could improve the standard of care for this disease. Vitamin D receptor (VDR) gene polymorphisms are associated with MS risk, probably because of the role played by vitamin D in regulating inflammatory and reparative processes. The aim of this study was to evaluate the association of the most important functional VDR SNPs (TaqI (T/C), ApaI (A/C), and FokI (C/T)) with functional outcome in MS patients undergoing multidisciplinary inpatient rehabilitation (MDR) treatment, in order to determine whether genetic profiling might be useful to identify subjects with a higher chance of recovery. To this end, 249 MS inpatients with a diagnosis of either progressive (pMS; n = 155) or relapsing remitting (RRMS; n = 94) disease who underwent MDR treatment (average duration = 5.1 weeks) were genotyped for VDR SNPs by real-time allelic discrimination. The rehabilitation outcome was assessed using the modified Barthel Index (mBI), Expanded Disability Status Scale (EDSS), and pain numerical rating scores (NRS) at the beginning and the end of MDR treatment. A positive correlation was observed in RRMS patients between the VDR TaqI major allele (TT) and mBI increase (i.e., better functional recovery), as assessed by the linear and logistic regression analysis adjusted for gender, age, disease duration, time of hospitalization, HLA-DRB1*15.01 positivity, and number of rehabilitative interventions (Beta = 6.35; p = 0.0002). The VDR-1 TaqI, ApaI, FokI: TCC haplotype was also associated with mBI increase in RRMS patients (Beta = 3.24; p = 0.007), whereas the VDR-2: CAC haplotype was correlated with a lower mBI increase (Beta = −2.18 p = 0.04) compared with the other haplotypes. VDR TaqI major allele (TT), as well as the VDR-1 TaqI, ApaI, FokI: TCC haplotype could be associated with a better rehabilitation outcome in RRMS patients

Serum miR-34a-5p, miR-103a-3p, and miR-376a-3p as possible biomarkers of conversion from relapsing-remitting to secondary progressive multiple sclerosis

Relapsing-remitting (RR) Multiple Sclerosis (MS) is the most common form of the disease; RRMS patients can maintain their clinical phenotype throughout life or can develop a secondary progressive (SP) course over time. We investigated whether circulating miRNAs can predict RR-to-SPMS conversion. A serum miRNAs profile was initially analyzed in a cross-sectional study by qPCR in 16 patients (8 RRMS and 8 SPMS) (Discovery cohort). Three miRNAs, i.e. miR-34a-5p, miR-103a-3p and miR-376a-3p, were significantly up-regulated in SPMS compared to RRMS patients (p < 0.0 5). Serum concentration of the same miRNAs was subsequently analyzed in a retrospective study by ddPCR at baseline in 69 RRMS patients who did (N = 36 cSPMS) or did not (N = 33) convert into SPMS over a 10-year observation period (Study cohort). The results showed that these miRNAs were significantly increased at baseline only in those RRMS patients who converted to SPMS over time. miR-34a-5p and miR-376a-3p alone were significantly increased in cSPMS sera at the end of the 10-years period too. Serum concentration of miR-34a-5p, miR-103a-3p and miR-376a-3p is increased in RRMS patients several years before their conversion to SPMS. These miRNAs might be useful biomarkers to predict the conversion from RRMS to SPMS

Telerehabilitation for Lee Silverman Voice Treatment (Tele-LSVT)-Loud on voice intensity and voice use in daily living in people with multiple sclerosis: A protocol for a feasibility and pilot randomized controlled study

Objective: Alterations in voice intensity and quality may constitute a social life limitation in people with multiple sclerosis (MS), but only 2% of cases receive speech therapy. Especially the Lee Silverman Voice Treatment (LSVT)-Loud is a highly effective intensive method for voice intensity, requiring subjects’ repeated attendance at the clinic. Telerehabilitation may represent a feasible solution to bypass potential barriers related to speech therapy attendance, scaling up the beneficial effects of the treatment to a broader population. The proposed protocol aims to test the feasibility and the pilot efficacy of the LSVT-Loud delivered in telerehabilitation (Tele-LSVT-Loud), compared to the same treatment delivered in the clinic (LSVT-Loud). Methods: A single-blinded, parallel, two-arm, pilot randomized (1:1 ratio) controlled trial will be performed involving 20 people with MS. Patients will be allocated to 4 weeks of Tele-LSVT-Loud by accessing a telerehabilitation platform at home or LSVT-Loud conventionally delivered in the clinic. Feasibility and pilot effectiveness will be evaluated three times: before (T0), after the treatment (T1), and 3-month follow-up (T2). Feasibility measures will include adherence, adverse events, user experience, motivation, engagement, and acceptability. Vocal intensity during a 1-minute monologue will be the primary outcome measure. Secondary outcome measures will be the vocal quality during a 1-minute monologue, sustained /a/ voice intensity, quality and stability, voice use in daily life, voice subjective perception in daily life, and quality of life. Results: Expected results will be (1) high feasibility of Tele-LSVT-Loud and (2) a non-inferiority effect of Tele-LSVT-Loud compared with face-to-face treatment delivery on voice intensity and quality outcomes. Conclusions: Tele-LSVT-Loud may be a feasible intervention for MS alteration in voice intensity and quality with a non-inferior effect compared to LSVT-Loud

MicroRNA-572 expression in multiple sclerosis patients with different patterns of clinical progression

BACKGROUND: Demyelination and failure of remyelination are core mechanisms in the pathogenesis of multiple sclerosis (MS); the factor(s) modulating these processes are still mostly unknown. MicroRNA 572 (miR-572) is deregulated in MS and is suggested to targets neural cell adhesion molecule (NCAM), a glycoprotein involved in CNS reparative mechanisms. The aim of this study is to analyze miR-572 in patients with different clinical phenotypes of MS. METHODS: qPCR quantification of miR-572 isolated from serum was performed in 16 primary progressive (PP), 15 secondary progressive (SP), 31 relapsing remitting (RR) MS patients and 15 sex-and age-matched healthy controls. RESULTS: miR-572 expression was reduced overall in MS patients (p < 0.05) compared to HC; this miRNA was significantly upregulated in SPMS and in RRMS during disease relapse, whereas it was downregulated in PPMS and in quiescent phases of RRMS. miR-572 expression correlated with EDSS scores (R(Sp) = 0.491; p < 0.05) independently of the clinical phenotype. The results suggest that this miRNA might be a tool that helps distinguishing between PPMS and SPMS and between relapsing and remitting phases in RRMS. CONCLUSIONS: Evaluation of miR-572 may serve as a non-invasive biomarker for remyelination. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12967-015-0504-2) contains supplementary material, which is available to authorized users

Intensive Multimodal Training to Improve Gait Resistance, Mobility, Balance and Cognitive Function in Persons With Multiple Sclerosis: A Pilot Randomized Controlled Trial

Introduction: Persons with multiple sclerosis (MS) have deficits in many aspects of physical and cognitive functioning that can impact on mobility and participation in daily life. The effect of a 4 week intensive multimodal treadmill training on functional mobility, balance, executive functions and participation in persons with MS with moderate to severe disability was investigated.Methods: Thirty eight persons with MS admitted to a rehabilitation center participated in a two arm randomized 2:1 controlled trial. Participants in the experimental group received supervised intensive treadmill training including cognitive and motor dual tasks (DT-group, N = 26), 5 sessions per week and a control group received the same amount of supervised strength training (S-group, N = 12). The participants were assessed before and after the rehabilitation period with the 2 Minutes Walking Test (2MWT), speed and, static and dynamic balance measures, the Frontal Assessment Battery and the Short Form-12 questionnaire. The main hypothesis was related to the superiority of the treadmill intervention based on a greater proportion of people making a clinically relevant gain (15% increase on 2MWT) in gait resistance following treatment. ANCOVA (Analysis of covariance) models adjusting for baseline measurement of the respective outcome variable, as well as sex and age, were used to evaluate differences in efficacy for all variables. P was set at 0.05.Results: Nineteen out of 26 persons in the DT-group made a clinically relevant gain and two out of 12 in the S-Group (P = 0.001). The DT-group improved more in gait resistance, speed and mobility (P &lt; 0.01). Balance and executive functions instead improved moderately in both groups following training while perception of health remained similar in both groups.Conclusion: A four week multimodal training on treadmill was highly effective in augmenting gait resistance and mobility in moderately to severely affected persons with MS

Acute Thermoregulatory and Cardiovascular Response to Submaximal Exercise in People With Multiple Sclerosis

Background: Heat sensitivity occurs in a high percentage of people with multiple sclerosis (PwMS), in response to environmental or exercise-induced increase in body temperature. However, the kinetic and magnitude of adaptation of the internal load and of the core body temperature (CBT) to a submaximal continuous exercise has been poorly addressed in PwMS; this may be relevant for the brief exercise bouts usually occurring in normal daily life. The aim of this work was to evaluate whether multiple sclerosis influences the acute adaptation of the internal load, the CBT and the perceptual load in response to a constant submaximal work step. Methods: CBT has been continuously monitored (0.5 Hz) by a validated wearable heat-flux sensor and electrocardiography was recorded (250 Hz) by a wearable device during a standard 6-minute walk test (6MWT) in 14 PwMS (EDSS, 4.7 ± 1.2; disease duration: 13.0 ± 10.2 years; m ± SD) and 14 age, sex and BMI-matched healthy subjects (HS). The rate of perceived exertion (RPE) of the lower limbs was assessed during the 6MWT by the Borg scale (6-20). Results: As expected, PwMS walked a significantly shorter distance (361 ± 98 m) than the HS group (613 ± 62 m, p&lt;0.001 vs PwMS). However, the kinetics of adaptation of CBT and the magnitude of CBT change from baseline did not differ between groups. Similarly, heart rate (HR) kinetics and HR change from baseline were comparable between groups during the 6MWT. Finally, lower limbs RPE gradually increased during the exercise test, but without significant differences between groups. Conclusion: The internal load, the metabolic heat production, and the perceptive load due to a standard submaximal walking exercise seems to be preserved in PwMS, suggesting a comparable acute heat production and dissipation during exercise. Therefore, it is unlikely that the different distance achieved during the 6MWT may be caused by altered thermoregulatory responses to exercise. Rather, this appears to be a consequence of the known increased energy cost of locomotion in PwMS