Practical tool to identify Spasticity-Plus Syndrome amongst patients with multiple sclerosis. Algorithm development based on a conjoint analysis.

Introduction: The Spasticity-Plus Syndrome (SPS) in multiple sclerosis (MS) refers to a combination of spasticity and other signs/symptoms such as spasms, cramps, bladder dysfunction, tremor, sleep disorder, pain, and fatigue. The main purpose is to develop a user-friendly tool that could help neurologists to detect SPS in MS patients as soon as possible. Methods: A survey research based on a conjoint analysis approach was used. An orthogonal factorial design was employed to form 12 patient profiles combining, at random, the eight principal SPS signs/symptoms. Expert neurologists evaluated in a survey and a logistic regression model determined the weight of each SPS sign/symptom, classifying profiles as SPS or not. Results: 72 neurologists participated in the survey answering the conjoint exercise. Logistic regression results of the survey showed the relative contribution of each sign/symptom to the classification as SPS. Spasticity was the most influential sign, followed by spasms, tremor, cramps, and bladder dysfunction. The goodness of fit of the model was appropriate (AUC = 0.816). Concordance between the experts' evaluation vs. model estimation showed strong Pearson's (r = 0.936) and Spearman's (r = 0.893) correlation coefficients. The application of the algorithm provides with a probability of showing SPS and the following ranges are proposed to interpret the results: high (> 60%), moderate (30-60%), or low (< 30%) probability of SPS. Discussion: This study offers an algorithmic tool to help healthcare professionals to identify SPS in MS patients. The use of this tool could simplify the management of SPS, reducing side effects related with polypharmacotherapy.

Teriflunomide and Epstein-Barr virus in a Spanish multiple sclerosis cohort: in vivo antiviral activity and clinical response.

Background: Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6) have been associated with multiple sclerosis (MS). Teriflunomide is an oral disease-modifying therapy approved for treatment of relapsing forms of MS. In the preclinical Theiler's murine encephalitis virus model of MS, the drug demonstrated an increased rate of viral clearance versus the vehicle placebo. Furthermore, teriflunomide inhibits lytic EBV infection in vitro. Objective: 1. To evaluate the humoral response against EBV and HHV-6 prior to teriflunomide treatment and 6 months later. 2. To correlate the variation in the humoral response against EBV and HHV-6 with the clinical and radiological response after 24 months of treatment with teriflunomide. 3. To analyze the utility of different demographic, clinical, radiological, and environmental data to identify early biomarkers of response to teriflunomide. Methods: A total of 101 MS patients (62 women; mean age: 43.4 years) with one serum prior to teriflunomide onset and another serum sample 6 months later were recruited. A total of 80 had been treated for at least 24 months, 13 had stopped teriflunomide before 24 months, and 8 were currently under teriflunomide therapy but with less than 24 months of follow-up. We analyzed the levels of the viral antibodies titers abovementioned in serum samples with ELISA commercial kits, and the levels of serum neurofilament light chain (Nf-L). Results: Antiviral antibody titers decreased for EBNA-1 IgG (74.3%), VCA IgG (69%), HHV-6 IgG (60.4%), and HHV-6 IgM (73.3%) after 6 months of teriflunomide. VCA IgG titers at baseline correlated with Nf-L levels measured at the same time (r = 0.221; p = 0.028) and 6 months later (r = 0.240; p = 0.017). We found that higher EBNA-1 titers (p = 0.001) and a higher age (p = 0.04) at baseline were associated with NEDA-3 conditions. Thus, 77.8% of patients with EBNA-1 >23.0 AU and >42.8 years (P50 values) were NEDA-3. Conclusion: Treatment with teriflunomide was associated with a reduction of the levels of IgG antibody titers against EBV and HHV-6. Furthermore, higher EBNA-1 IgG titers prior to teriflunomide initiation were associated with a better clinical response.

Abnormal functional connectivity in radiologically isolated syndrome: A resting-state fMRI study.

BACKGROUND: Radiologically isolated syndrome (RIS) patients might have psychiatric and cognitive deficits, which suggests an involvement of major resting-state functional networks. Notwithstanding, very little is known about the neural networks involved in RIS. OBJECTIVE: To examine functional connectivity differences between RIS and healthy controls using resting-state functional magnetic resonance imaging (fMRI). METHODS: Resting-state fMRI data in 25 RIS patients and 28 healthy controls were analyzed using an independent component analysis; in addition, seed-based correlation analysis was used to obtain more information about specific differences in the functional connectivity of resting-state networks. Participants also underwent neuropsychological testing. RESULTS: RIS patients did not differ from the healthy controls regarding age, sex, and years of education. However, in memory (verbal and visuospatial) and executive functions, RIS patients' cognitive performance was significantly worse than the healthy controls. In addition, fluid intelligence was also affected. Twelve out of 25 (48%) RIS patients failed at least one cognitive test, and six (24.0%) had cognitive impairment. Compared to healthy controls, RIS patients showed higher functional connectivity between the default mode network and the right middle and superior frontal gyri and between the central executive network and the right thalamus (pFDR < 0.05; corrected). In addition, the seed-based correlation analysis revealed that RIS patients presented higher functional connectivity between the posterior cingulate cortex, an important hub in neural networks, and the right precuneus. CONCLUSION: RIS patients had abnormal brain connectivity in major resting-state neural networks and worse performance in neurocognitive tests. This entity should be considered not an "incidental finding" but an exclusively non-motor (neurocognitive) variant of multiple sclerosis.

Oligoclonal IgM bands are a promising biomarker for long-term cognitive outcomes in multiple sclerosis.

BACKGROUND: The presence of lipid-specific oligoclonal IgM bands (LS-OCMB) in cerebrospinal fluid is associated with a more severe clinical multiple sclerosis (MS) course. OBJECTIVE: To investigate LS-OCMB as a prognostic biomarker of cognitive long-term outcomes in MS. METHODS: Ninety-nine patients underwent neuropsychological assessment. Cognitive performance between LS-OCMB- and LS-OCMB+ patients was compared adjusting by age, education, anxiety-depression, disease duration, and disability. RESULTS: LS-OCMB+ patients of ∼13 years of disease duration performed worse on Symbol Digit Modalities Test (SDMT) (p = 0.005). CONCLUSION: LS-OCMB+ perform worse on information processing speed and working memory (SDMT), suggesting that LS-OCMB could be a useful biomarker for long-term cognitive outcomes.

Baseline Inflammatory Status Reveals Dichotomic Immune Mechanisms Involved In Primary-Progressive Multiple Sclerosis Pathology.

Objective: To ascertain the role of inflammation in the response to ocrelizumab in primary-progressive multiple sclerosis (PPMS). Methods: Multicenter prospective study including 69 patients with PPMS who initiated ocrelizumab treatment, classified according to baseline presence [Gd+, n=16] or absence [Gd-, n=53] of gadolinium-enhancing lesions in brain MRI. Ten Gd+ (62.5%) and 41 Gd- patients (77.4%) showed non-evidence of disease activity (NEDA) defined as no disability progression or new MRI lesions after 1 year of treatment. Blood immune cell subsets were characterized by flow cytometry, serum immunoglobulins by nephelometry, and serum neurofilament light-chains (sNfL) by SIMOA. Statistical analyses were corrected with the Bonferroni formula. Results: More than 60% of patients reached NEDA after a year of treatment, regardless of their baseline characteristics. In Gd+ patients, it associated with a low repopulation rate of inflammatory B cells accompanied by a reduction of sNfL values 6 months after their first ocrelizumab dose. Patients in Gd- group also had low B cell numbers and sNfL values 6 months after initiating treatment, independent of their treatment response. In these patients, NEDA status was associated with a tolerogenic remodeling of the T and innate immune cell compartments, and with a clear increase of serum IgA levels. Conclusion: Baseline inflammation influences which immunological pathways predominate in patients with PPMS. Inflammatory B cells played a pivotal role in the Gd+ group and inflammatory T and innate immune cells in Gd- patients. B cell depletion can modulate both mechanisms.

Early predictive risk factors for dimethyl fumarate-associated lymphopenia in patients with multiple sclerosis.

BACKGROUND: Lymphopenia is a major concern in MS patients treated with dimethyl-fumarate (DMF) as it increases the risk of progressive multifocal leukoencephalopathy. A pronounced reduction in absolute lymphocyte counts (ALCs) early after treatment initiation has been suggested to be associated with the occurrence of lymphopenia thereafter. OBJECTIVES: To identify risk factors for DMF-induced lymphopenia and evaluate whether the degree of decrease in the ALCs three months after initiation of DMF treatment is a predictor of the subsequent development of lymphopenia. METHODS: In this real-world Spanish prospective multicenter study conducted in MS patients who started DMF between 2014 and 2019, we analyzed the association between DMF-related lymphopenia and the percentage of early ALCs decline using regression models, considering both, significant lymphopenia (grades 2 + 3) and severe lymphopenia (grade 3). The cutoff values of early ALCs declines were obtained using the ROC curve. RESULTS: Among 532 MS patients treated with DMF, 193 (36.3%) developed any grade of lymphopenia. Older age and lower ALCs at treatment onset predicted the risk for lymphopenia but the best predictive risk factor was the reduction of ALCs within the three first months of treatment. Specifically, a reduction in ALCs≥21.2% was associated with a 6.5-fold higher risk of developing significant lymphopenia, and a decrease in ALCs≥40.2% with a 12.7-fold higher risk of developing severe lymphopenia. CONCLUSIONS: A pronounced reduction in ALCs early after initiation of DMF in MS patients is the best predictive risk factor for the subsequent development of significant lymphopenia.

Patients' self-assessment of essential tremor severity by a validated scale: A useful tool in telemedicine?

INTRODUCTION: There are some validated rating scales to assess severity of Essential tremor (ET), the most common cause of action tremor. Clinical evaluation through telematic consultations has been expanding in the last decade. Patients' self-assessment of tremor severity at home could constitute a useful tool in telemedicine. This paper aims to assess intrarater and interrater reliability of ET severity using Fahn-Tolosa Marin Tremor Rating Scale (FTMTRS) for patients' and neurologists' ratings. MATERIAL AND METHODS: Patients were instructed on how to perform and rate the FTMTRS tasks. Supervised by neurologists, each patient performed one FTMTRS self-assessment at the hospital, which was rated in a blinded way by two neurologists, and six more self-assessments at home afterwards. Postural, intention and specific-tasks tremor were rated. A cumulative linked mixed model was used to assess intrarater and interrater reliability. RESULTS: A total of 161 self-assessments from 19 patients were analyzed. Intrarater reliability of patients' self-ratings at home showed ICCs between 0.843 and 0.962. Interrater ICCs of neurologists' ratings were also excellent for all tremor types (0.903-0.987). Concordance between neurologists' and patients' assessments showed ICCs ranging from 0.407 to 0.824, with the higher agreement for writing/drawing-related tremor (0.824; CI 95% 0.634-0.989). CONCLUSIONS: The rating of ET severity from FTMTRS self-assessments performed by well-trained patients at home could be a suitable clinical measure to assess tremor in non-face-to-face medical consultations. The assessment of tremor during specific tasks could be the most efficient measure for the patient self-assessment at home. These results could be useful in telemedicine.

Genetic variation in NDFIP1 modifies the metabolic patterns in immune cells of multiple sclerosis patients.

One of the 233 polymorphisms associated with multiple sclerosis (MS) susceptibility lies within the NDFIP1 gene, and it was previously identified as eQTL in healthy controls. NDFIP1 shows interesting immune functions and is involved in the development of the central nervous system. We aimed at studying the NDFIP1 variant on activation and metabolism of immune cells. NDFIP1 mRNA and protein expression were assessed in PBMCs by qPCR and western blot in 87 MS patients and 84 healthy controls genotyped for rs4912622. Immune activation after PHA stimulation was evaluated by CD69 upregulation, and metabolic function of both basal and PHA-activated lymphocytes was studied by Seahorse Xfp-Analyzer. In minor-allele homozygous controls but not in patients, we found higher NDFIP1 expression, significantly reduced protein levels, and CD69 upregulation in B- and T-cells. PBMCs from minor-allele homozygous controls showed significantly higher basal mitochondrial respiration and ATP production compared to major-allele carriers, while minor-allele homozygous patients showed significantly lower metabolic activity than carriers of the major allele. In conclusion, we describe associations in minor-allele homozygous controls with lower levels of NDFIP1 protein, CD69 upregulation, and raised mitochondrial activity, which are not replicated in MS patients, suggesting a NDFIP1 differential effect in health and disease.

Identification of the Immunological Changes Appearing in the CSF During the Early Immunosenescence Process Occurring in Multiple Sclerosis.

Patients with multiple sclerosis (MS) suffer with age an early immunosenescence process, which influence the treatment response and increase the risk of infections. We explored whether lipid-specific oligoclonal IgM bands (LS-OCMB) associated with highly inflammatory MS modify the immunological profile induced by age in MS. This cross-sectional study included 263 MS patients who were classified according to the presence (M+, n=72) and absence (M-, n=191) of LS-OCMB. CSF cellular subsets and molecules implicated in immunosenescence were explored. In M- patients, aging induced remarkable decreases in absolute CSF counts of CD4+ and CD8+ T lymphocytes, including Th1 and Th17 cells, and of B cells, including those secreting TNF-alpha. It also increased serum anti-CMV IgG antibody titers (indicative of immunosenescence) and CSF CHI3L1 levels (related to astrocyte activation). In contrast, M+ patients showed an age-associated increase of TIM-3 (a biomarker of T cell exhaustion) and increased values of CHI3L1, independently of age. Finally, in both groups, age induced an increase in CSF levels of PD-L1 (an inductor of T cell tolerance) and activin A (part of the senescence-associated secretome and related to inflammaging). These changes were independent of the disease duration. Finally, this resulted in augmented disability. In summary, all MS patients experience with age a modest induction of T-cell tolerance and an activation of the innate immunity, resulting in increased disability. Additionally, M- patients show clear decreases in CSF lymphocyte numbers, which could increase the risk of infections. Thus, age and immunological status are important for tailoring effective therapies in MS.

Risk and outcomes of COVID-19 in patients with multiple sclerosis.

BACKGROUND AND PURPOSE: Limited information is available on incidence and outcomes of COVID-19 in patients with multiple sclerosis (MS). This study investigated the risks of SARS-CoV-2 infection and COVID-19-related outcomes in patients with MS, and compared these with the general population. METHODS: A regional registry was created to collect data on incidence, hospitalization rates, intensive care unit admission, and death in patients with MS and COVID-19. National government outcomes and seroprevalence data were used for comparison. The study was conducted at 14 specialist MS treatment centers in Madrid, Spain, between February and May 2020. RESULTS: Two-hundred nineteen patients were included in the registry, 51 of whom were hospitalized with COVID-19. The mean age ± standard deviation was 45.3 ± 12.4 years, and the mean duration of MS was 11.9 ± 8.9 years. The infection incidence rate was lower in patients with MS than the general population (adjusted incidence rate ratio = 0.78, 95% confidence interval [CI] = 0.70-0.80), but hospitalization rates were higher (relative risk = 5.03, 95% CI = 3.76-6.62). Disease severity was generally low, with only one admission to an intensive care unit and five deaths. Males with MS had higher incidence rates and risk of hospitalization than females. No association was found between the use of any disease-modifying treatment and hospitalization risk. CONCLUSIONS: Patients with MS do not appear to have greater risks of SARS-CoV-2 infection or severe COVID-19 outcomes compared with the general population. The decision to start or continue disease-modifying treatment should be based on a careful risk-benefit assessment.

Effect of Ocrelizumab in Blood Leukocytes of Patients With Primary Progressive MS.

OBJECTIVE: To analyze the changes induced by ocrelizumab in blood immune cells of patients with primary progressive MS (PPMS). METHODS: In this multicenter prospective study including 53 patients with PPMS who initiated ocrelizumab treatment, we determined effector, memory, and regulatory cells by flow cytometry at baseline and after 6 months of therapy. Wilcoxon matched paired tests were used to assess differences between baseline and 6 months' results. p Values were corrected using the Bonferroni test. RESULTS: Ocrelizumab reduced the numbers of naive and memory B cells (p < 0.0001) and those of B cells producing interleukin (IL)-6, IL-10, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNFα) (p < 0.0001 in all cases). By contrast, the proportions of plasmablasts and B cells producing GM-CSF and TNFα increased significantly, suggesting the need for treatment continuation. We also observed a decrease in CD20+ T-cell numbers (p < 0.0001) and percentages (p < 0.0001), and a clear remodeling of the T-cell compartment characterized by relative increases of the naive/effector ratios in CD4+ (p = 0.002) and CD8+ (p = 0.002) T cells and relative decreases of CD4+ (p = 0.03) and CD8+ (p = 0.004) T cells producing interferon-gamma. Total monocyte numbers increased (p = 0.002), but no changes were observed in those producing inflammatory cytokines. The immunologic variations were associated with a reduction of serum neurofilament light chain (sNfL) levels (p = 0.008). The reduction was observed in patients with Gd-enhanced lesions at baseline and in Gd- patients with baseline sNfL >10 pg/mL. CONCLUSIONS: In PPMS, effector B-cell depletion changed T-cell response toward a low inflammatory profile, resulting in decreased sNfL levels.

Three-Year Effectiveness of Dimethyl Fumarate in Multiple Sclerosis: A Prospective Multicenter Real-World Study.

BACKGROUND: Dimethyl fumarate (DMF) has demonstrated efficacy in phase III studies. However, real-world data are still limited. OBJECTIVE: The objective of this study was to describe the profile of patients who receive DMF and to assess the effectiveness of DMF regarding relapses, disability progression, magnetic resonance imaging activity, and NEDA (No Evidence Disease Activity)-3 status in a Spanish population in a real-world setting. METHODS: We conducted a multicenter prospective study of patients who started DMF between 2014 and 2019 in Spain. Three subgroups were considered: naïve, switch to DMF because of inefficacy, and switch to DMF because of adverse effects. The effects of DMF on clinical and radiological measures were evaluated. RESULTS: Among 886 patients, 25.3% were naïve, 28.8% switched because of adverse effects, and 45.9% because of inefficacy. Median follow-up was 38.9 (interquartile range 22.6-41.8) months. Annualized relapse rates were 0.15, 0.10, and 0.10 at 12, 24, and 36 months respectively, and 77.7% of patients were relapse free at month 42. At 12, 24, and 42 months, 96.1%, 87.4%, and 79.7% of patients were progression free, respectively. The number of T1 gadolinium-enhancement (T1Gd+) lesions was 0.19, 0.14, and 0.18 at 12, 24, and 36 months. NEDA-3 status at month 42 was maintained by 49.8% of patients. Relapsing was associated with higher annualized relapse rates the year before (hazard ratio 1.34, p < 0.001) and to the inefficacy switch vs naïve group (hazard ratio 1.76, p = 0.003). A higher baseline Expanded Disability Status Scale score was associated with disability progression (hazard ratio 1.15, p = 0.003) and more T1Gd+ lesions (hazard ratio 1.07, p < 0.001) with radiological progression. A higher baseline Expanded Disability Status Scale score, a larger number of T1Gd+ lesions, and a switch because of inefficacy (vs adverse events) were all risk factors for losing NEDA-3 status. DMF was discontinued in 29.9% of patients, in 13.5% because of inefficacy. CONCLUSIONS: Our findings confirm the sustained effectiveness of DMF on the clinical and radiological activity of multiple sclerosis in a real-world setting, both in naïve patients and in those switching from other multiple sclerosis therapies.

Tolerability and safety of dimethyl fumarate in relapsing multiple sclerosis: a prospective observational multicenter study in a real-life Spanish population.

BACKGROUND: Dimethyl fumarate (DMF) tolerability and safety in multiple sclerosis (MS) has been analyzed in randomized clinical trials. Real-life studies are needed to assess possible harms of this therapy in a wider MS population. OBJECTIVE: To evaluate DMF tolerability, safety and persistence in MS in a real-world setting. METHODS: We conducted a multicenter prospective study of patients who started DMF, attended in 16 public hospitals of Spain. A specific database was elaborated to collect data on most frequent adverse events (AE). Regression models were used to analyze the effect of demographic and clinical characteristics on risk of AEs and DMF discontinuation. RESULTS: We collected data of 886 patients (2681 patients/years-exposition) with median 39.5 (IQR 23, 51.5) months on DMF exposure; 25.3% were treatment naïve and 74.7% switched to DMF from other disease-modifying therapies. DMF was discontinued in 29.9% of patients, in 13.2% due to AEs and in 13.5% to inefficacy. AEs were experienced by 71.2%, being flushing the most frequent (44.1%), 5.4% developed grade III lymphopenia, without cases of grade IV. Females showed a higher risk of flushing and gastroenteric symptoms (OR 1.49, p = 0.011; OR 1.69, p = 0.001, respectively); lymphopenia was associated with older age (OR 1.04, p < 0.001), and a higher EDSS with lymphopenia (OR 1.10, p = 0.035) and DMF withdrawal (HR 1.43, p = 0.012). No safety problems were reported. CONCLUSIONS: Our findings confirm good tolerability and safety of DMF in real-world setting and suggest that women have an increased risk of AEs and higher baseline disability involves greater risk of drug discontinuation.

Progression of carotid near-occlusion to complete occlusion: related factors and clinical implications.

BACKGROUND: The clinical consequences and factors related to the progression from a carotid near-occlusion (CNO) to a complete occlusion are not well established. Our aim is to describe the rate, predictive factors and clinical implications of the progression to complete carotid occlusion (PCCO) in a population of patients with symptomatic CNO. METHODS: We conducted a multicenter, nationwide, prospective study from January 2010 to May 2016. Patients with angiography-confirmed CNO were included. We collected information on demographic data, clinical manifestations, radiological and hemodynamic findings, and treatment modalities. A 24 month carotid-imaging follow-up of the CNO was performed. RESULTS: 141 patients were included in the study, and carotid-imaging follow-up was performed in 122 patients. PCCO occurred in 40 patients (32.8%), and was more frequent in medically-treated patients (34 out of 61; 55.7%) compared with patients treated with revascularization (6 out of 61; 9.8%) (p<0.001). 7 of the 40 patients with PCCO (17.5%) suffered ipsilateral symptoms. Factors independently related with PCCO in the multivariate analysis were: age ≥75 years (OR 2.93, 95% CI 1.05 to 8.13), revascularization (OR 0.07, 95% CI 0.02 to 0.20), and collateral circulation through the ipsilateral ophthalmic artery (OR 3.25, 95% CI 1.01 to 10.48). CONCLUSIONS: PCCO occurred within 24 months in more than half of the patients under medical treatment. Most episodes of PCCO were not associated with ipsilateral symptoms. Revascularization reduces the risk of PCCO.

New Algorithms Improving PML Risk Stratification in MS Patients Treated With Natalizumab.

Overview: We assessed the role of age and disease activity as new factors contributing to establish the risk of progressive multifocal leucoencephalopathy in multiple sclerosis patients treated with natalizumab in 36 University Hospitals in Europe. We performed the study in 1,307 multiple sclerosis patients (70.8% anti-John Cunninghan virus positive antibodies) treated with natalizumab for a median time of 3.28 years. Epidemiological, clinical, and laboratory variables were collected. Lipid-specific IgM oligoclonal band status was available in 277 patients. Factors associated with progressive multifocal leucoencephalopathy onset were explored by uni- and multivariate logistic regression. Results: Thirty-five patients developed progressive multifocal leucoencephalopathy. The multivariate analysis identified anti-John Cunninghan virus antibody indices and relapse rate as the best predictors for the onset of this serious opportunistic infection in the whole cohort. They allowed to stratify progressive multifocal leucoencephalopathy risk before natalizumab initiation in individual patients [area under the curve (AUC) = 0.85]. The risk ranged from <1/3,300 in patients with anti-John Cunninghan virus antibody indices <0.9 and relapse rate >0.5, to 1/50 in the opposite case. In patients with lipid-specific IgM oligoclonal bands assessment, age at natalizumab onset, anti-John Cunninghan virus antibody indices, and lipid-specific IgM oligoclonal band status predicted progressive multifocal leucoencephalopathy risk (AUC = 0.92). The absence of lipid-specific IgM oligoclonal bands was the best individual predictor (OR = 40.94). The individual risk ranged from <1/10,000 in patients younger than 45 years at natalizumab initiation, who showed anti John Cunningham virus antibody indices <0.9 and lipid-specific IgM oligoclonal bands to 1/33 in the opposite case. Conclusions: In a perspective of personalized medicine, disease activity, anti-lipid specific IgM oligoclonal bands, anti Jonh Cunninghan virus antibody levels, and age can help tailor natalizumab therapy in multiple sclerosis patients, as predictors of progressive multifocal leucoencephalopathy.

Activity-aware essential tremor evaluation using deep learning method based on acceleration data.

BACKGROUND: Essential tremor (ET), one of the most common neurological disorders is typically evaluated with validated rating scales which only provide a subjective assessment during a clinical visit, underestimating the fluctuations tremor during different daily activities. Motion sensors have shown favorable performances in both quantifying tremor and voluntary human activity recognition (HAR). OBJECTIVE: To create an automated system of a reference scale using motion sensors supported by deep learning algorithms to accurately rate ET severity during voluntary activities, and to propose an IOTA based blockchain application to share anonymously tremor data. METHOD: A smartwatch-based tremor monitoring system was used to collect motion data from 20 subjects while they were doing standard tasks. Two neurologists rated ET by Fahn-Tolosa Marin Tremor Rating Scale (FTMTRS). Supported by deep learning techniques, activity classification models (ACMs) and tremor evaluation models (TEMs) were created and algorithms were implemented, to distinguish voluntary human activities and evaluate tremor severity respectively. RESULT: A practical application example showed that the proposed ACMs can classify six typical activities with high accuracy (89.73%-98.84%) and the results produced by the TEMs are significantly correlated with the FTMTRS ratings of two neurologists (r1 = 0.92, p1 = 0.008; r2 = 0.93, p2 = 0.007). CONCLUSION: This study demonstrated that motion sensor data, supported by deep learning algorithms, can be used to classify human activities and evaluate essential tremor severity during different activities.

Relationship between episodic memory and volume of the brain regions of two functional cortical memory systems in multiple sclerosis.

BACKGROUND/OBJECTIVE: Two functional networks are proposed as neuronal support for the complex processes of memory: the anterior temporal and the medial posterior systems. We examined the atrophy of hippocampus (HC) and of those areas constituting the two functional memory systems in multiple sclerosis (MS) patients with low disability. METHODS: Episodic memory (EM) was assessed in 88 relapsing MS patients and in 40 healthy controls using Wechsler Memory Scale III (Spanish adaptation). FreeSurfer software was used to calculate normalized volume of total cortex, grey matter, white matter, subcortical grey matter (thalamus and striatum), HC and both the anterior temporal (entorhinal, ventral temporopolar, lateral orbitofrontal, amygdala) and posterior medial systems (thalamus, parahippocampal, posterior cingulate, precuneus, lateral parietal and medial prefrontal). Linear regression analysis was used to identify predictors of memory performance. RESULTS: Total grey matter and cortex volumes correlated with all subtypes of EM, and the precuneus volume correlated with overall, immediate and delayed memories. Univariant regression analysis identified an association between the volumes of the posterior medial memory network regions and EM scores. The volume of the left precuneus area was the unique and independent predictor for all EM subtypes except for visual memory, for which left HC volume was also an independent predictor. CONCLUSION: Left precuneus volume was the best predictor of memory in relapsing MS patients with low disability and mild deficits in EM.

Early risk of recurrent stroke in patients with symptomatic carotid near-occlusion: Results from CAOS, a multicenter registry study.

Background The risk of recurrent stroke among patients with symptomatic carotid near-occlusion is not well established, and management of the condition remains controversial. Symptomatic carotid near-occlusion with full collapse has been identified as a strong predictor of early recurrence. We aimed to analyze the 90-day risk of recurrent ipsilateral ischemic stroke in medically treated patients with symptomatic carotid near-occlusion. Methods We performed a multicenter, nationwide, prospective study from January 2010 to May 2016. Patients with angiography-confirmed symptomatic carotid near-occlusion were included. The primary endpoint was ipsilateral ischemic stroke or transient ischemic attack (TIA) within 90 days after the presenting event. For this analysis, patients who underwent revascularization within 90 days after stroke were excluded. Results The study population comprised 141 patients from 17 Spanish centers; 83 patients were treated medically. Primary endpoint occurred in eight patients, resulting in a cumulative rate of 10.6% (95% CI, 3.7-17.5). Previous history of stroke or transient ischemic attack was identified as an independent predictor for recurrence in the multivariate Cox regression analysis (HR, 4.37 [95% CI, 1.05-18.18]; p = 0.043), while the presence of full collapse was not associated with an increased risk (HR, 0.81 [95% CI, 0.17-3.92]; p = 0.793). The risk of recurrence was also not affected by the presence of significant stenosis or occlusion of the contralateral carotid artery, or by the collateral circulation. Conclusions Patients with symptomatic carotid near-occlusion seem to have an increased risk of early ipsilateral recurrent stroke. Our results contrast with the low risk of symptomatic carotid near-occlusion reported to date. Full collapse did not increase the risk of recurrent stroke in our study.

Continuous Monitoring of Essential Tremor Using a Portable System Based on Smartwatch.

INTRODUCTION: Essential tremor (ET) shows amplitude fluctuations throughout the day, presenting challenges in both clinical and treatment monitoring. Tremor severity is currently evaluated by validated rating scales, which only provide a timely and subjective assessment during a clinical visit. Motor sensors have shown favorable performances in quantifying tremor objectively. METHODS: A new highly portable system was used to monitor tremor continuously during daily lives. It consists of a smartwatch with a triaxial accelerometer, a smartphone, and a remote server. An experiment was conducted involving eight ET patients. The average effective data collection time per patient was 26 (±6.05) hours. Fahn-Tolosa-Marin Tremor Rating Scale (FTMTRS) was adopted as the gold standard to classify tremor and to validate the performance of the system. Quantitative analysis of tremor severity on different time scales is validated. RESULTS: Significant correlations were observed between neurologist's FTMTRS and patient's FTMTRS auto-assessment scores (r = 0.84; p = 0.009), between the device quantitative measures and the scores from the standardized assessments of neurologists (r = 0.80; p = 0.005) and patient's auto-evaluation (r = 0.97; p = 0.032), and between patient's FTMTRS auto-assessment scores day-to-day (r = 0.87; p < 0.001). A graphical representation of four patients with different degrees of tremor was presented, and a representative system is proposed to summarize the tremor scoring at different time scales. CONCLUSION: This study demonstrates the feasibility of prolonged and continuous monitoring of tremor severity during daily activities by a highly portable non-restrictive system, a useful tool to analyze efficacy and effectiveness of treatment.