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Purpose: The ultrasonographic and hemodynamic features of patients with carotid near-occlusion (CNO) are still not well known. Our aim was to describe the ultrasonographic and hemodynamic characteristics of a cohort of patients with CNO. Methods: A prospective, observational, nationwide, and multicenter study was conducted from January/2010 to May/2016. Patients with digital subtraction angiography (DSA)–confirmed CNO were included. We collected information on clinical and demographic characteristics, carotid and transcranial ultrasonography and DSA findings, presence of full-collapse, collateral circulation, and cerebrovascular reactivity (CVR). Results: One hundred thirty-five patients were analyzed. Ultrasonographic and DSA diagnosis of CNO were concordant in only 44%. This disagreement was related to the presence/absence of full-collapse: 45% of patients with CNO with full-collapse were classified as a complete carotid occlusion, and 40% with a CNO without full-collapse were interpreted as severe stenosis (p < 0.001). Mean velocities (mV) and pulsatility indexes (PIs) were significantly lower in the ipsilateral middle cerebral artery compared with the contralateral (43 cm/s vs 58 cm/s, p < 0.001; 0.80 vs 1.00, p < 0.001). Collateral circulation was identified in 92% of patients, with the anterior communicating artery (73%) being the most frequent. CVR was decreased or exhausted in 66% of cases and was more frequent in patients with a poor or absent collateral network compared with patients with ≥ 2 collateral arteries (82% vs 56%, p = 0.051). Conclusion: The accuracy of carotid ultrasonography in the diagnosis of CNO seems to be limited, with significant discrepancies with DSA. Decreased ipsilateral mV, PI, and CVR suggest a hemodynamic compromise in patients with CNO. [ABSTRACT FROM AUTHOR]

The potential for combining serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) levels to predict worsening disability in multiple sclerosis remains underexplored. We aimed to investigate whether sNfL and sGFAP values identify distinct subgroups of patients according to the risk of disability worsening and their response to disease-modifying treatments (DMTs). This multicentre study, conducted across 13 European hospitals, spanned from 15 July 1994 to 18 August 2022, with follow-up until 26 September 2023. We enrolled patients with multiple sclerosis who had serum samples collected within 12 months from disease onset and before initiating DMTs. Multivariable regression models were used to estimate the risk of relapse-associated worsening (RAW), progression independent of relapse activity (PIRA) and Expanded Disability Status Scale (EDSS) score of 3. Of the 725 patients included, the median age was 34.2 (interquartile range, 27.6-42.4) years, and 509 patients (70.2%) were female. The median follow-up duration was 6.43 (interquartile range, 4.65-9.81) years. Higher sNfL values were associated with an elevated risk of RAW [hazard ratio (HR) of 1.45; 95% confidence interval (CI) 1.19-1.76; P < 0.001], PIRA (HR of 1.43; 95% CI 1.13-1.81; P = 0.003) and reaching an EDSS of 3 (HR of 1.55; 95% CI 1.29-1.85; P < 0.001). Moreover, higher sGFAP levels were linked to a higher risk of achieving an EDSS score of 3 (HR of 1.36; 95% CI 1.06-1.74; P = 0.02) and, in patients with low sNfL values, to PIRA (HR of 1.86; 95% CI 1.01-3.45; P = 0.04). We also examined the combined effect of sNfL and sGFAP levels. Patients with low sNfL and sGFAP values exhibited a low risk of all outcomes and served as a reference. Untreated patients with high sNfL levels showed a higher risk of RAW, PIRA and reaching an EDSS of 3. Injectable or oral DMTs reduced the risk of RAW in these patients but failed to mitigate the risk of PIRA and reaching an EDSS of 3. Conversely, high-efficacy DMTs counteracted the heightened risk of these outcomes, except for the risk of PIRA in patients with high sNfL and sGFAP levels. Patients with low sNfL and high sGFAP values showed an increased risk of PIRA and achieving an EDSS of 3, which remained unchanged with either high-efficacy or other DMTs. In conclusion, evaluating sNfL and sGFAP levels at disease onset in multiple sclerosis might identify distinct phenotypes associated with diverse immunological pathways of disability acquisition and therapeutic response., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

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., Competing Interests: ÓF has received honoraria in the past as consultant in advisory boards, and as chairmen or lecturer in meetings, and has also participated or participates at present in clinical trials and other research projects promoted by Biogen, Bayer, Merck-Serono, Teva, Novartis, Actelion, Almirall, Roche, Allergan, Horizon, and Ala Diagnostics. LC-F has served at scientific advisory boards, participated in meetings sponsored by and received speaking honoraria or travel funding or research grants from Biogen, Bristol-Myers Squibb, Janssen, Horizon, Merck-Serono, Novartis, Roche and Sanofi. MM has received honoraria as speaker, consultant in advisory boards, travel support or research grants from Merck, Biogen, Novartis, Sanofi-Genzyme, Almirall, Viatris, Horizon, Bristol-Myers Squibb, Roche, Sandoz and Janssen. PM has received compensation for consulting services and speaking fees from Allergan, Almirall, Biogen, Merz and Sanofi. JP has served as consultant, speaker and/or moderator for Bayer Pharmaceuticals, Biogen, Bristol-Myers Squibb, Daiichi Sankyo, Genzyme Corporation, Janssen, Merck Serono, Novartis, Sanofi, Sandoz, Teva, Roche Pharma, Almirall and Celgene. LR-T has received compensation for consulting services and speaking fees from Biogen, Novartis, Bayer, Merck, Sanofi, Genzyme, Roche, Bristol-Myers Squibb, Teva and Janssen. AM has received honoraria for scientific and commercial activities from Biogen, Teva, Merck, Sanofi, Novartis, Roche, Almirall, and Mylan. YA has received research grants, travel support and lecturing and consulting fees from Bayer, Biogen, Roche, Merck, Novartis, Almirall, Sanofi-Genzyme, Janssen and Bristol-Myers Squibb. AA has received honoraria as a speaker or advisor from Almirall, Biogen, Bristol-Myers Squibb, Janssen, Merck, Novartis, Roche and Sanofi. EÁ has received collaborations and fees for participation in advisories, scientific and educational activities from Almirall, Biogen, Janssen Cilag, Sanofi-Genzyme, Merck, Novartis, Roche and Teva. AL-F reports no disclosures relevant to the manuscript. LL has received collaborations and fees for participation in advisories, scientific and educational activities, from Almirall, Bayer, Biogen, Bristol-Myers Squibb, Sanofi-Genzyme, Merck, Novartis, UCB Pharma, Roche and Teva. EM has received honoraria as consultant in advisory boards, and or as chairperson or lecturer in meetings, attendance to congresses and has also participated in clinical trials and other research projects promoted by Almirall, Bayer, Biogen, Bristol Myers Squibb, Janssen, Merck, Teva, Novartis, Roche, Sandoz and Sanofi-Genzyme. PO-N has received collaborations and fees for participation in advisories, scientific and educational activities from Almirall, Biogen, Bristol-Myers Squibb, Sanofi-Genzyme, Merck, Novartis, UCB Pharma, Roche and Teva., (Copyright © 2024 Fernández Fernández, Costa-Frossard, Martínez Ginés, Montero Escribano, Prieto González, Ramió-Torrentà, Aladro, Alonso Torres, Álvarez Rodríguez, Labiano-Fontcuberta, Landete Pascual, Miralles Martínez, Moral Torres and Oliva-Nacarino.)

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 ( p FDR < 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., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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., Competing Interests: IG-S: reports compensation for consulting services and speaker honoraria from Biogen, Janssen, Merck-Serono, Novartis, Sanofi, and Roche. LV: has served at scientific advisory boards, participated in meetings sponsored by and received speaking honoraria or travel funding or research grants from Roche, Sanofi, Merck, Biogen, Bristol Myers, and Novartis. LC-F: reports compensation for consulting services and speaker honoraria from Biogen, Bristol Myers Squibb, Janssen, Merck-Serono, Novartis, Sanofi, Roche, and Teva. BP: has received speaker honoraria by Novartis and Almirall, travel honoraria by Merck, and training honoraria by Sanofi and Merck. XM: speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past 3 years with Actelion, Alexion, Biogen, Celgene, EMD Serono, Genzyme, Immunic, MedDay, Merck, Mylan, Novartis, Roche, Sanofi-Genzyme, and Teva Pharmaceutical. MC: compensation for consulting services and speaking honoraria from Bayer Schering Pharma, Merk Serono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-Aventis, Genzyme, Bristol-Myers Squibb, and Novartis. IC-P: having received payments as speaker, and support for attending meetings from Bayern, Biogen, Merck, Novartis, Roche Sanofi, and Teva. MM-G: has received compensation for consulting services and speaking fees from Merck, Biogen, Novartis, Sanofi-Genzyme, Almirall, ROCHE, BMS, and TEVA. JG-D: honoraria as speaker, advisor or researcher from Almirall, Bristol-Myers-Squibb, Biogen, Janssen, Merck, Novartis, Roche, Teva, and Sanofi. RA: has been a speaker or has participated in the advisory board of Novartis, Teva, Roche, Bristol, Janssen, Biogen, Merck, and Sanofi-Genzyme. RA-L: has received support for attending meetings from Biogen, Novartis, and Sanofi-Genzyme. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Domínguez-Mozo, González-Suárez, Villar, Costa-Frossard, Villarrubia, Aladro, Pilo, Montalbán, Comabella, Casanova-Peño, Martínez-Ginés, García-Domínguez, García-Martínez, Arroyo and Álvarez-Lafuente.)

Introduction: On 4 and 5 November 2022, Madrid hosted the 15th edition of the Post-ECTRIMS Meeting, where neurologists specialised in multiple sclerosis outlined the latest developments presented at the 2022 ECTRIMS Congress, held in Amsterdam from 26 to 28 October., Aim: To synthesise the content presented at the 15th edition of the Post-ECTRIMS Meeting, in an article broken down into two parts., Development: This second part describes the new developments in terms of therapeutic strategies for escalation and de-escalation of disease-modifying therapies (DMT), when and in whom to initiate or switch to highly effective DMT, the definition of therapeutic failure, the possibility of treating radiologically isolated syndrome and the future of personalised treatment and precision medicine. It also considers the efficacy and safety of autologous haematopoietic stem cell transplantation, different approaches in clinical trial design and outcome measures to assess DMT in progressive stages, challenges in the diagnosis and treatment of cognitive impairment, and treatment in special situations (pregnancy, comorbidity and the elderly). In addition, results from some of the latest studies with oral cladribine and evobrutinib presented at ECTRIMS 2022 are shown.

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., Competing Interests: Declaration of Competing Interest The author(s) declared the following potential conflicts of interest with respect to the research, authorship and/ or publication of this article: C.C.M: has received support for attending congresses from sanofi, merk, teva and novartis. E.Q: has nothing to disclose. M.B: has nothing to disclose. J.S.P: has nothing to disclose. L.G: has nothing to disclose. A.Q.V: has nothing to disclose. L.C.F: has received compensation for consulting services and speaking fees from Biogen, Novartis, Bayer, Merck, Sanofi, Janssen, Roche, Bristol Myers Squibb, TEVA and Almirall. LM.V: Received com compensation for consulting services and speaking fees from Biogen, Novartis, Merck, Sanofi, Genzyme, Roche, and Bristol Myers Squibb, Almirall. E.F.D: has received compensation for consulting services and/or speaking fees from Almirall, Biogen, Merck, Roche and Sanofi-Genzyme. J.G: has received compensation for consulting services and speaking fees from Biogen, Novartis, Merck, Sanofi, Genzyme, Roche and TEVA. Y.A: has received funding for research projects or in the form of conference fees, mentoring, and assistance for conference attendance from: Bayer, Biogen, Roche, Merck, Novartis, Allmirall and Sanofi-Genzime and Bristol Myers Squibb. A.M.B: has nothing to disclose. M.C: has nothing to disclose. L.R.T: has received compensation for consulting services and speaking fees from Biogen, Novartis, Bayer, Merck, Sanofi, Genzyme, Roche, Bristol Myers Squibb, TEVA and Almirall. J.G.F: has received speaking fees from Novartis, Teva, Sanofi and Merck., (Copyright © 2022. Published by Elsevier B.V.)

Background and Purpose: The treatment of symptomatic carotid near-occlusion is controversial. Our aim was to analyze the results of carotid endarterectomy and carotid artery stent placement in patients with symptomatic carotid near-occlusion and to identify factors related to technical failure, periprocedural complications, and restenosis., Materials and Methods: We conducted a multicenter, prospective nonrandomized study. Patients with angiography-confirmed carotid near-occlusion were included. We assessed the revascularization rate and periprocedural stroke or death. Twenty-four-month clinical and carotid imaging follow-up was performed, and rates of carotid restenosis or occlusion, ipsilateral stroke, and mortality were analyzed. Carotid artery stent placement, carotid endarterectomy, and medical treatment were compared., Results: One hundred forty-one patients were included. Forty-four carotid artery stent placement and 23 carotid endarterectomy procedures were performed within 6 months after the event. Complete revascularization was achieved in 83.6%, 81.8% in the carotid artery stent placement group and 87% with carotid endarterectomy ( P = .360). Periprocedural stroke or death occurred in 6% (carotid artery stent placement = 2.3%; carotid endarterectomy = 13%; P = .077) and was not related to revascularization failure. The carotid restenosis or occlusion rate was 8.3% (5% restenosis, 3.3% occlusion); with carotid artery stent placement it was 10.5%; and with carotid endarterectomy it was 4.5% ( P = .419). The 24-month cumulative rate of ipsilateral stroke was 4.8% in the carotid artery stent placement group, 17.4% for carotid endarterectomy, and 13.1% for medical treatment ( P = .223). Mortality was 12%, 4.5%, and 5.6%, respectively ( P = .422). Revascularization failure and restenosis occurred more frequently in patients with full collapse compared with patients without full collapse (33.3% versus 5.6%, P = .009; 21.4% versus 2.9%, P = .032, respectively)., Conclusions: Carotid artery stent placement and carotid endarterectomy are associated with high rates of failure and periprocedural stroke. Carotid near-occlusion with full collapse appears to be associated with an increased risk of technical failure and restenosis. Carotid near-occlusion revascularization does not seem to reduce the risk of stroke at follow-up compared with medical treatment., (© 2022 by American Journal of Neuroradiology.)

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., (Copyright © 2022. Published by Elsevier B.V.)

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., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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., (© 2021 European Academy of Neurology.)

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., (© 2021. The Author(s).)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Picón, Tejeda-Velarde, Fernández-Velasco, Comabella, Álvarez-Lafuente, Quintana, Sainz de la Maza, Monreal, Villarrubia, Álvarez-Cermeño, Domínguez-Mozo, Ramió-Torrentà, Rodríguez-Martín, Roldán, Aladro, Medina, Espiño, Masjuan, Matute-Blanch, Muñoz-San Martín, Espejo, Guaza, Muriel, Costa-Frossard and Villar.)

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., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

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., Competing Interests: LV received a research grant from Biogen. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Toboso, Tejeda-Velarde, Alvarez-Lafuente, Arroyo, Hegen, Deisenhammer, Sainz de la Maza, Alvarez-Cermeño, Izquierdo, Paramo, Oliva, Casanova, Agüera-Morales, Franciotta, Gastaldi, Fernández, Urbaneja, Garcia-Dominguez, Romero, Laroni, Uccelli, Perez-Sempere, Saiz, Blanco, Galimberti, Scarpini, Espejo, Montalban, Rasche, Paul, González, Álvarez, Ramo, Caminero, Aladro, Calles, Eguía, Belenguer-Benavides, Ramió-Torrentà, Quintana, Martínez-Rodríguez, Oterino, López de Silanes, Casanova, Landete, Frederiksen, Bsteh, Mulero, Comabella, Hernández, Espiño, Prieto, Pérez, Otano, Padilla, García-Merino, Navarro, Muriel, Frossard and Villar.)

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.

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

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.

Introduction: Like every year, after the ECTRIMS Congress, renowned Spanish neurologists who are experts in multiple sclerosis presented the main novelties in research in this field at the Post-ECTRIMS Meeting., Aim: To summarise the content presented at the 12th edition of the Post-ECTRIMS Meeting, which took place in September 2019 in Sevilla and is presented in two parts., Development: In this second part, the most recent evidence on the use of disease-modifying treatments during pregnancy is presented. Details are provided concerning the results of phase 3 clinical trials conducted to evaluate the efficacy and safety of two potential disease-modifying treatments for relapsing-remitting multiple sclerosis: ponesimod and ofatumumab. For the progressive forms, both available disease modifying treatments and others still in the research phase are reviewed. In the field of stem cell therapies, the article includes the results of the only clinical trial carried out to date comparing patients with relapsing-remitting multiple sclerosis treated with autologous haematopoietic stem cell transplantation and those treated with disease-modifying therapies. There are no important developments as regards symptomatic treatments, although the European Academy of Neurology has published a guide on palliative care. The various sources of information that collect pharmacovigilance data in the post-marketing setting are reviewed., Conclusions: Patients diagnosed in recent years tend to have less severe multiple sclerosis, probably due to the fact that it is diagnosed in its milder stages together with the steady increase in the number of treatments available.

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 (r 1  = 0.92, p 1  = 0.008; r 2  = 0.93, p 2  = 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., (Copyright © 2018. Published by Elsevier Ltd.)

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.

The Post-ECTRIMS Meeting is an emblematic event in the field of multiple sclerosis in Spain. Its chief aim is bring together the country's leading specialist neurologists to analyse the main advances made in multiple sclerosis and to review the most important topics addressed at the ECTRIMS Congress. The tenth Post-ECTRIMS Meeting was held in November 2017. Over the years this event has firmly established itself as an important meeting point where experts from all over the country get together to foster communication, establish synergies and promote and enhance research ultimately aimed at improving the prognosis and quality of life of patients with multiple sclerosis. This second part addresses the different strategies for the management of patients in advanced stages of the disease and the safety of therapy in multiple sclerosis. Likewise, attention is also drawn to the areas that require further scientific and clinical evidence. In this edition, particular importance is given to multiple sclerosis in the paediatric population and ageing in the disease. At the same time emphasis is placed on the need to conduct collaborative studies and to foster greater awareness among specialists regarding the detection and management of the comorbidities in multiple sclerosis.

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.

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.