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Natalizumab is a highly effective therapy for multiple sclerosis (MS). The aim of this study was to evaluate serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) in patients with relapsing-remitting MS treated with Natalizumab. sNfL and sGFAP were analyzed at baseline, 6 and 12 months post treatment using the single-molecule array (SiMoA) technique. We recruited matched healthy controls for comparison. The study included 54 patients, with a median age of 33 years (Interquartile range (IQR), 29-41), with 32 women (60%) and 76 healthy controls. A decrease in sNfL was observed at 6 (67%, p = 0.005) and 12 (72%, p < 0.0001) months compared to baseline. After two years, six patients experienced evidence of disease activity (EDA-3). The remaining ones had no evidence of disease activity (NEDA-3). NEDA-3 presented a remarkable reduction in sNfL ( p < 0.0001) and sGFAP ( p = 0.01) after 6 months of treatment that continued to be observed after 12 months compared to baseline. EDA-3 only reached a significant decrease in sNfL after 12 months; there were no significant changes in sGFAP values. Natalizumab leads to a decrease in sNfL, which is higher and occurs earlier in NEDA-3 patients. Patients also showed a significant reduction in sGFAP levels, which was not observed in the EDA-3 group.

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.)

Objective: To ascertain the changes of serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) values in relapsing-remitting multiple sclerosis (RRMS) patients treated with ocrelizumab and their association with treatment response., Methods: Multicenter prospective study including 115 RRMS patients initiating ocrelizumab treatment between February 2020 and March 2022 followed during a year. Serum samples were collected at baseline and every 3 months to measure sNfL and sGFAP levels using single-molecule array (SIMOA) technology. Based on age and body mass index, sNfL values were standardized using z-score. NEDA (non-evidence of disease activity)-3 status was defined for patients free of disease activity after a year of follow-up. Inflammation (INFL) was considered when new relapses occurred during follow-up or new MRI lesions were found at 1-year exploration. PIRA (progression independent of relapse activity) was defined as disability progression occurring in the absence of relapses or new MRI activity., Results: After a year on ocrelizumab, 85 patients (73.9%) achieved NEDA-3. Thirty patients did not achieve NEDA: 20 (17.4%) because of INFL and 10 (8.7%) because of PIRA. Of INFL patients, 6 (30.0%) had relapses, and 17 (85.0%) had at least one new MRI lesion at the 12-month examination. At baseline, INFL patients had higher sNfL (p = 0.0003) and sGFAP (p = 0.03) than the NEDA-3 group. PIRA patients mostly exhibited low sNfL and heterogeneous sGFAP levels. After a year, NEDA-3 and INFL patients showed similar decreases in sNfL (p < 0.0001) and sGFAP (p < 0.0001 for NEDA-3 and p = 0.001 for INFL ones). However, the decrease occurred earlier in NEDA-3 patients. Accordingly, sNfL > 1.5 z-score 3 months after ocrelizumab initiation indicated a higher risk of inflammation (OR = 13.6; p < 0.0001). Decrease in sGFAP values occurred later in both groups, with significant reductions observed at 12 months for INFL and 6 and 12 months for NEDA-3. No significant changes in sNfL or sGFAP were observed in PIRA patients., Conclusion: Ocrelizumab induced normalization of sNfL and sGFAP in the majority of NEDA-3 and inflammatory patients but did not cause changes in the PIRA group. Our data suggest that normalization of sNfL and sGFAP is associated with the lack of inflammatory-associated disease progression but it may not affect non-inflammatory PIRA., Competing Interests: FR-J received research grants and travel support for speaking engagements from Janssen, Biogen, Novartis, Roche, Sanofi-Genzyme, Bristol-Myers-Squibb and Merck. JG-G received research support, compensation for participating on advisory boards, lecture fees, and/or travel support from Almirall, Bayer, Biogen, Genzyme‐Sanofi, Novartis, Roche, and Teva. EF received research support, compensation for participating on advisory boards, speaking fees, and/or funding for travel from Almirall, Bayer, Biogen, Genzyme‐Sanofi, Merck, Novartis, and Roche. VM-L received consulting and speaking fees from Almirall, Biogen, Genzyme, Janssen, Merck, Novartis, Roche, Terumo, Sanofi, Teva, and Bristol Myers Squibb. CD-P received funding for training and scientific meetings from Sanofi, Merck, Novartis and Roche. SS received research grants, travel support or honoraria for speaking engagements from Almirall, Biogen, Bristol Myers Squibb, Janssen, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. AQ is funded by a grant from the Fundación Francisco Soria y Melguizo and has received funding from Merck, Novartis, and Horizon Therapeutics to attend conferences. LR-T received compensation for consulting services and speaking fees from Biogen, Novartis, Bayer, Merck, Sanofi, Genzyme, Roche, Bristol-Myers-Squibb, TEVA, and Horizon. SM-Y received honoraria for participating on advisory boards and for collaborations as consultant and scientific communications and also received research support as well as funding for travel and congress expenses from Roche, Biogen Idec, Novartis, TEVA, Merck, Genzyme, Sanofi, Bayer, Almirall, and Bristol Myers Squibb. EM received research grants, travel support, or honoraria for speaking engagements from Almirall, Merck, Roche, Sanofi, Bristol Myers Squibbb, Biogen, Janssen, and Novartis. AL-R received speaker and consultation fees from Biogen, Janssen, Novartis, Roche and Sanofi, and congress travel support from Roche. LBo received research grants and travel support from Merck, Roche, Novartis, Sanofi, Horizon and Bristol Myer Squibb. JC-G received speaker fees, travel support, and/or served on advisory boards by Biogen, Sanofi, Bayer, Janssen, BMS, and Bial. FB received compensation for consulting services and speaking honoraria from Almirall, Biogen, Bristol Myer Squibb, Genzyme, Johnson & Johnson, Merck, Novartis, Roche, Sanofi, Teva. MM-G received compensation for consulting services and speaking fees from Merck, Biogen, Novartis, Sanofi-Genzyme, Almirall, BMS, Janssen, Roche, Horizon, and Viatris. JG-D received honoraria as speaker, advisor and researcher from Almirall, Bristol Myers Squibb, Biogen, Janssen, Merck, Novartis, Roche, Teva, and Sanofi. MM-M received research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries Ltd., Sanofi-Aventis, Merck Serono, Novartis, Bayer Schering Pharma, Bristol Myers Squibb and Roche. JM-L received honoraria as a consultant, lecturer in meetings and has participated in clinical trials and other research projects promoted by Alexion, Almirall, Biogen, Bristol-Meyers-Squibb, Horizon, Johnson & Johnson, Merck, Neuraxpharm, Novartis, Roche, Sandoz, Sanofi and UCB. LC-F received speaker fees, travel support, and/or served on advisory boards by Biogen, Sanofi, Merck, Bayer, Novartis, Roche, Teva, Celgene, Ipsen, Biopas, Almirall. LV received research grants and personal fees from Merck, Roche, Sanofi, Bristol Myers Squibb, Biogen, and Novartis. 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Rodríguez-Jorge, Fernández-Velasco, Villarrubia, Gracia-Gil, Fernández, Meca-Lallana, Díaz-Pérez, Sainz de la Maza, Pacheco, Quiroga, Ramió-Torrentà, Martínez-Yélamos, Bau, Monreal, López-Real, Rodero-Romero, Borrega, Díaz, Eguía, Espiño, Chico-García, Barrero, Martínez-Ginés, García-Domínguez, De la Fuente, Moreno, Sainz-Amo, Mañé-Martínez, Caminero, Castellanos, Gómez López, Labiano-Fontcuberta, Ayuso, Abreu, Hernández, Meca-Lallana, Martín-Aguilar, Muriel García, Masjuan, Costa-Frossard and Villar.)

Objective: To evaluate the safety of COVID-19 vaccines in patients with multiple sclerosis (MS) by assessing their impact on serum neurofilament light chain (sNfL) levels as a marker of neuroaxonal damage., Methods: Single-center observational longitudinal study including patients with MS who consecutively received their initial vaccination against SARS-CoV-2 at Hospital Universitario Ramón y Cajal, following the first national immunization program in Spain. Serum samples were collected at baseline and after receiving the second dose of the vaccine. sNfL levels were quantified using the single molecule array (SIMOA) technique. Adverse events, including clinical or radiological reactivation of the disease, were recorded., Results: Fifty-two patients were included (median age, 39.7 years [range, 22.5-63.3]; 71.2% female). After SARS-CoV-2 vaccination, no increased inflammatory activity, either determined by the presence of relapses and/or new MRI lesions and/or high sNfL levels, was detected. Accordingly, there was no difference between median sNfL levels before and after vaccination (5.39 vs. 5.76 pg/ml, p=0.6). Despite this, when looking at baseline patient characteristics before vaccination, younger age associated with disease activity after vaccination (OR 0.87, 95% CI: 0.77-0.98, p=0.022). Larger studies are needed to validate these results., Conclusion: COVID-19 vaccines did not cause reactivation of disease at a clinical, radiological or molecular level, thus suggesting that they are safe in MS patients., Competing Interests: SS received research grants, travel support or honoraria for speaking engagements from Almirall, Biogen, Bristol Myers Squibb, Janssen, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. EM received research grants, travel support or honoraria for speaking engagements from Almirall, Biogen, Janssen, Merck, Novartis, Roche, and Sanofi-Genzyme. JC-G has received honorary for speaking engagements or consulting services from Biogen, Bayer, Bial, Bristol-Myers, Johnson&Johnson and Sanofi-Genzyme. FR-J has received honorary for speaking engagements or consulting services from Bial, Biogen, Johnson&Johnson and Sanofi-Genzyme. RS-A has received honorary for speaking engagements from Johnson&Johnson. LC-F received speaker fees, travel support, and/or served on advisory boards by Almirall, Bayer, Biogen, Biopas, Bristol Myers Squibb, Celgene, Ipsen, Janssen, Merck, Novartis, Roche, Sanofi and Teva. LV received research grants, travel support or honoraria for speaking engagements from Biogen, Bristol Myers Squibb, Merck, Novartis, Roche 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Sainz de la Maza, Rodero-Romero, Monreal, Chico-García, Villarrubia, Rodríguez-Jorge, Fernández-Velasco, Sainz-Amo, Costa-Frossard, Masjuan and Villar.)

Introduction: Alemtuzumab is a highly effective pulsed immune reconstitution therapy for multiple sclerosis (MS)., Aim: To evaluate serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) in patients with relapsing-remitting MS who have been treated with Alemtuzumab over the course of 2 years., Methods: This prospective study involved MS patients treated with Alemtuzumab at a referral MS center. Both sNfL and sGFAP were analyzed at baseline and then again at 6, 12, and 24 months post-treatment using the single molecule array (SiMoA) technique. We also recruited matched healthy controls (HCs) for comparison., Results: The study included 46 patients (with a median age of 34.2 [Interquartile range (IQR), 28.7-42.3] years, 27 of which were women [58%]) and 76 HCs. No differences in demographic characteristics were observed between patients and HC. The median disease duration was 6.22 (IQR, 1.56-10.13) years. The median annualized relapse rate before treatment was 2 (IQR, 1-3). At baseline, sNfL and sGFAP levels were higher in MS patients (median of 18.8 [IQR, 10.7-52.7] pg/ml and 158.9 [IQR, 126.9-255.5] pg/ml, respectively) when compared to HC (6.11 [IQR, 2.03-8.54] pg/ml and 91.0 [72.6-109] pg/ml, respectively) (p<0.001 for both comparisons). The data indicates that 80% of patients had high (≥10 pg/ml) sNfL values at baseline. We observed a significant decrease in sNfL levels at 6 (65%, p = 0.02), 12 (70.8%, p<0.001), and 24 (78.1%, p<0.001) months. sNfL reached similar levels to HC only after 24 months of Alemtuzumab treatment. During the follow-up period, no changes were identified in the sGFAP values., Conclusion: Alemtuzumab leads to the normalization of sNfL values in MS patients after 2 years of treatment, with no apparent effect on sGFAP values., Competing Interests: RS-A reported receiving research travel support from Roche and Janssen outside the submitted work. EM reported receiving research grants, travel support, or honoraria for speaking engagements from Biogen, Sanofi, Merck, Novartis, Almirall, Roche, Bristol Myers Squibb, and Janssen outside the submitted work. JF reported receiving research travel support from Roche and Janssen outside the submitted work. SM reported receiving personal fees from Almirall, Bristol Myers Squibb, and Teva outside the submitted work and receiving compensation for lectures or travel expenses from Merck Serono, Biogen, Sanofi Genzyme, Roche, Janssen, and Novartis. JC reported receiving personal fees from Sanofi outside the submitted work and receiving speaker honoraria from Biogen Idec and Sanofi. FR reported receiving personal fees from Sanofi outside the submitted work and receiving speaker honoraria from Biogen Idec and Sanofi. LF reported receiving speaker fees and travel support and/or serving on advisory boards for Biogen, Sanofi, Merck, Bayer, Novartis, Roche, Teva, Celgene, Ipsen, Biopas, Bristol Myers Squibb, Janssen, and Almirall. LV reported receiving grants and personal fees from Merck, Roche, Sanofi Genzyme, Bristol Myers Squibb, Celgene, Biogen, and Novartis outside the submitted work. 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Sainz-Amo, Rodero Romero, Monreal, Chico García, Fernández Velasco, Villarrubia, Veiga González, Sainz de la Maza, Rodríguez Jorge, Masjuan, Costa-Frossard and Villar.)

Multiple studies have shown the importance of blood-based biomarkers indicating axonal damage (serum neurofilament light chains [sNfL]) or astroglia activation (serum glial fibrillary acidic protein [sGFAP]) for monitoring different neurological diseases. However, normal values of these variables remain to be clearly defined, partly due to the influence of different demographic factors. We investigated demographic differences in a cohort of healthy volunteers. A cross-sectional study was conducted including 116 healthy controls with ages between 18 and 69 years (67.5% females; n = 79). sNfL and sGFAP concentrations were measured using single-molecule arrays. Age and body mass index affected sNfL values, and age was found to be the most important factor. The normal values changed with age, and we established normal values for individuals younger than 45 years as <10 pg/mL and for controls older than 45 years as <15 pg/mL. We established normal values at <10 pg/mL for individuals younger than 45 years and <15 pg/mL for older individuals. Alternatively, a Z-score of 1.5 was relevant for all controls. sGFAP was only affected by age. Differences in normal values were evident by 55 years. The highest normality limit for sGFAP was 140 pg/mL for controls under 55 years and 280 for older controls. We defined normal levels for sNfL and sGFAP and their corresponding age-associated changes. These data may contribute to the application of such variables in clinical practice.

Background: Alemtuzumab is a high-efficacy treatment approved for relapsing-remitting multiple sclerosis (RRMS). Although clinical trials and observational studies are consistent in showing its efficacy and manageable safety profile, further studies under clinical practice conditions are needed to further support its clinical use., Objective: The aim of this observational retrospective study was to evaluate the effectiveness and safety of alemtuzumab to add to the current real-world evidence on the drug., Methods: A cohort of 115 adult patients with RRMS treated with alemtuzumab between 2014 and 2020 was retrospectively followed up in five centers in Spain. Analysis included annualized relapse rate (ARR), 6-month confirmed disability worsening (CDW), 6-month confirmed disability improvement (CDI), radiological activity, no evidence of disease activity (NEDA-3), and safety signals. Given the different follow-up periods among participants, ARR was calculated using the person-years method. CDI was defined as a ≥ 1.0-point decrease in Expanded Disability Status Scale (EDSS) score assessed in patients with a baseline EDSS score ≥ 2.0 confirmed 6 months apart. CDW was defined as a ≥ 1.0-point increase in EDSS score assessed in patients with a baseline EDSS score ≥ 1.0 (≥ 1.5 if baseline EDSS = 0), confirmed 6 months apart., Results: ARR decreased from 1.9 (95% confidence interval 1.60-2.33) in the year prior to alemtuzumab initiation to 0.28 (0.17-0.37) after 1 year of treatment (87% reduction), and to 0.22 (0.13-0.35) after the second year. Over the entire follow-up period, ARR was 0.24 (0.18-0.30). At year 1, 75% of patients showed no signs of magnetic resonance imaging (MRI) activity and 70% at year 5. One percent of patients experienced 6-month CDW at year 1, 2.6% at year 2, 7.4% at year 3, and no patients over years 4 and 5. A total of 7.7% of patients achieved 6-month CDI in year 1, 3.6% in year 2, and maintained it at years 3 and 4. Most patients achieved annual NEDA-3: year 1, 72%; year 2, 79%; year 3, 80%; year 4, 89%; year 5, 75%. Infusion-related reactions were observed in 95% of patients and infections in 74%. Thyroid disorders occurred in 30% of patients, and only three patients developed immune thrombocytopenia. No cases of progressive multifocal leukoencephalopathy were reported., Conclusions: This study shows that alemtuzumab reduced the relapse rate and disability worsening in real-world clinical practice, with many patients achieving and sustaining NEDA-3 over time. The safety profile of alemtuzumab was consistent with previous findings, and no new or unexpected safety signals were observed. As this was an observational and retrospective study, the main limitation of not having all variables comprehensively available for all patients should be considered when interpreting results., (© 2024. The Author(s).)

Introduction: The immunoglobulin kappa free light chain (KFLC) index has been proposed as a potentially suitable alternative to oligoclonal IgG bands (OCGB) for diagnosing multiple sclerosis (MS), offering automation and reduced processing time. However, there is no consensus on the preferred approach or how to combine both techniques., Methods: This prospective cohort study aimed to determine the best utilization of OCGB and KFLC index in patients with a clinically isolated syndrome (CIS) followed for at least two years. OCGB and KFLC were assessed using isoelectric focusing and immunoblotting and turbidimetry, respectively. Sensitivity, specificity, and accuracy for diagnosing MS were calculated for each method., Results: The study included 371 patients, with 260 (70.1 %) being women, and a median age of 34.9 (27.8 - 43.9) years. Using a cut-off value of 6.1, the KFLC index demonstrated a sensitivity and specificity of 86.3% and 93.9%, respectively. The sensitivity of OCGB (95.3%) was higher (p < 0.001 vs. KFLC index) and the specificity (100%) was comparable to that of the KFLC index (p = 0.5). The concordance between the methods was not uniform across all patients, with 97.8% agreement in patients with KFLC index ≥ 6.1 and 56.0 % in patients with KFLC index < 6.1. In patients with a KFLC index < 6.1, OCGB still identified 75.0 % of MS patients due to its higher sensitivity. An algorithm using the KFLC index as a screening tool and OCGB as an alternative for patients with a negative KFLC index result achieved an accuracy of 96.3 %., Discussion: Combining the KFLC index and OCGB can provide an easily reproducible and accurate method for diagnosing MS, with OCGB primarily reserved for patients with a KFLC index < 6.1., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Monreal, Fernández-Velasco, García-Soidán, Sainz de la Maza, Espiño, Villarrubia, Rodríguez-Jorge, Chico-García, Sainz-Amo, Masjuan, Costa-Frossard and Villar.)

Purpose: To determine the effectiveness and safety outcomes of cenobamate in a cohort of patients with highly refractory focal epilepsy in routine clinical practice., Methods: Observational, retrospective, phase 4 study on subjects receiving cenobamate in three Spanish centers. The primary endpoint was the retention rate at the last follow-up. The main secondary endpoints were the 50%-responder  and seizure-free rates at three months and the last follow-up. Other secondary endpoints were Global Clinical Impressions-Improvement (CGI-I) scores and treatment-emergent adverse events (TEAEs)., Results: Fifty-one patients with highly refractory focal epilepsy with 24.7 years of disease evolution, ten previously tried ASM, and a 23.5% of previous epilepsy surgery were included. The retention rate at the last follow-up was 80.4%. The 50% responder rate in focal seizures at three months was 56.5% (median reduction per month 51%, 0-74.6; p < 0.0001) and in focal to bilateral tonic-clonic seizures was 63.6% (median reduction per month 89%, 0-100; p = 0.022). A total of 54.3% of subjects reported a reduction in the intensity of focal seizures, and 66% manifested clinically significant satisfaction. Cenobamate allowed a significant decrease in concomitant ASM, especially sodium channel blockers. TEAEs were reported in 43.1% of individuals, 85% of whom resolved or improved, with no new safety findings., Conclusion: In this analysis of patients with highly refractory focal epilepsy treated with cenobamate according to standard clinical practice, there was evidence of a high reduction in both seizure frequency and intensity, with a manageable safety profile., Competing Interests: Declaration of Competing Interest Álvaro Beltrán-Corbellini, Irene García-Morales, Rafael Toledano, Ángel Aledo-Serrano and Antonio Gil-Nagel Rein have received funding from Angelini Pharma for research and teaching activities., (Copyright © 2023 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

This single-center study included 68 multiple sclerosis (MS) patients who received the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination from one of several approved vaccine preparations in Spain. Blood samples were collected one to three months after the second dose of the vaccine had been administered. Cellular immune responses to the vaccine were assessed using QuantiFERON analysis, and peripheral blood mononuclear cell subsets were assayed using flow cytometry. Response associated with higher percentages of total lymphocytes, naïve CD4+ T-cells ( p = 0.028), CD8+ T-cells ( p = 0.013), and, mostly, naïve CD8+ T-cells ( p = 0.0003). These results were confirmed by analyzing absolute numbers ( p = 0.019; p = 0.002, and p = 0.0003, respectively). Naïve CD8 T-cell numbers higher than 17 cells/μL were closely associated with an optimal cellular response to SARS-CoV-2 vaccination (odds ratio: 24.0, confidence interval: 4.8-460.3; p = 0.0001). This finding clearly shows that independent of the treatment received, higher numbers of naïve CD8+ T-cells yield a strong cellular response to SARS-CoV-2 vaccines in MS patients. If this finding is validated with other viruses/vaccines, it could provide a good tool for identifying MS patients undergoing treatment who will develop strong cellular responses to anti-virus vaccines.

Background: The application of machine learning (ML) to predict cognitive evolution is exceptionally scarce. Computer-based self-administered cognitive tests provide the opportunity to set up large longitudinal datasets to aid in developing ML prediction models of risk for Multiple Sclerosis-related cognitive decline., Objective: to analyze to what extent clinically feasible models can be built with standard clinical practice features and subsequently used for reliable prediction of cognitive evolution., Methods: This prospective longitudinal study includes 1184 people with MS who received a Processing Speed (PS) evaluation at 12 months of follow-up measured by the iPad®-based Processing Speed Test (PST). Six of the most potent classification models built with routine clinical practice features were trained and tested to predict the 12-month patient class label (PST worsening (PSTw) versus PST stable). A rigorous scheme of all the preprocessing steps run to obtain reliable generalization performance is detailed., Results: Based on a 12-month reduction of 10% of the PST raw score, 187/1184 (15.8%) people with MS were classified as PSTw. The trees-based models (random forest and the eXtreme Gradient Boosting) achieved the best performance, with an area under the receiver operating characteristic curve (AUC) of 0.90 and 0.89, respectively. The timing of high-efficacy disease-modifying therapies (heDMTs) was identified as one of the top importance predictors in all the models evaluated., Conclusion: Using trees-based machine learning models to predict individual future information processing speed deterioration in MS could become a reality in clinical practice., Competing Interests: Declaration of Competing Interest The authors report no disclosures relevant to the manuscript.No targeted funding is reported, (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: This study aimed to evaluate short- and long-term humoral and T-cell-specific immune responses to SARS-CoV-2 vaccines in patients with multiple sclerosis (MS) treated with different disease-modifying therapies (DMTs)., Methods: Single-center observational longitudinal study including 102 patients with MS who consecutively received vaccination against SARS-CoV-2. Serum samples were collected at baseline and after receiving the second dose of the vaccine. Specific Th1 responses following in vitro stimulation with spike and nucleocapsid peptides were analyzed by quantifying levels of IFN-γ. Serum IgG-type antibodies against the spike region of SARS-CoV-2 were studied by chemiluminescent microparticle immunoassay., Results: Patients undergoing fingolimod and anti-CD20 therapies had a markedly lower humoral response than those treated with other DMTs and untreated patients. Robust antigen-specific T-cell responses were detected in all patients except those treated with fingolimod, who had lower IFN-γ levels than those treated with other DMTs (25.8 pg/mL vs. 868.7 pg/mL, p = 0.011). At mid-term follow-up, a decrease in vaccine-induced anti-SARS-CoV-2 IgG antibodies was observed in all subgroups of patients receiving DMTs, although most patients receiving induction DMTs or natalizumab and non-treated patients remained protected. Cellular immunity was maintained above protective levels in all DMT subgroups except the fingolimod subgroup., Conclusions: SARS-CoV-2 vaccines induce robust and long-lasting humoral and cell-mediated specific immune responses in most patients with MS.

Importance: The value of serum neurofilament light chain (sNfL) levels for predicting long-term disability in patients with multiple sclerosis (MS) remains controversial., Objective: To assess whether high sNfL values are associated with disability worsening in patients who underwent their first demyelinating MS event., Design, Setting, and Participants: This multicenter cohort study included patients who underwent their first demyelinating event suggestive of MS at Hospital Universitario Ramón y Cajal (development cohort; June 1, 1994, to September 31, 2021, with follow-up until August 31, 2022) and 8 Spanish hospitals (validation cohort; October 1, 1995, to August 4, 2020, with follow-up until August 16, 2022)., Exposures: Clinical evaluations at least every 6 months., Main Outcomes and Measures: The main outcomes were 6-month confirmed disability worsening (CDW) and an Expanded Disability Status Scale (EDSS) score of 3. Levels of sNfL were measured in blood samples obtained within 12 months after disease onset using a single molecule array kit. The cutoffs used were sNfL level of 10 pg/mL and a standardized score (z score) of 1.5. Multivariable Cox proportional hazards regression models were used to evaluate outcomes., Results: Of the 578 patients included in the study, 327 were in the development cohort (median age at sNfL analysis, 34.1 years [IQR, 27.2-42.7 years]; 226 female [69.1%]) and 251 patients were in the validation cohort (median age at sNfL analysis, 33.3 years [IQR, 27.4-41.5 years]; 184 female [73.3%]). The median follow-up was 7.10 years (IQR, 4.18-10.0 years). Levels of sNfL greater than 10 pg/mL were independently associated with higher risk of 6-month CDW and an EDSS of 3 in the development cohort (6-month CDW: hazard ratio [HR], 2.39; 95% CI, 1.39-4.12; P = .002; EDSS of 3: HR, 4.12; 95% CI, 2.18-7.77; P < .001) and the validation cohort (6-month CDW: HR, 1.61; 95% CI, 1.07-2.42; P = .02; EDSS of 3: HR, 2.03; 95% CI, 1.23-3.33; P = .005). Highly effective disease-modifying treatments were associated with lower risks of 6-month CDW and an EDSS of 3 in patients with high baseline sNfL values., Conclusions and Relevance: This cohort study found that high sNfL values obtained within the first year of disease were associated with long-term disability worsening in MS, suggesting that sNfL level measurement may help identify optimal candidates for highly effective disease-modifying treatments.

Background: Rituximab is extensively used for multiple sclerosis (MS) treatment. However, the best dosage remains to be established. It has been proposed that retreatment could be guided by B lymphocyte (BL) percentages., Objective: To establish the best BL value for retreatment with rituximab in MS and to confirm the safety and efficacy of this approach., Methods: A prospective study was done with an exploratory cohort and a confirmatory cohort of MS patients treated with rituximab between 2017 and 2021. The first one comprised 10 MS patients with BL assessed every 3 months after rituximab infusion and retreatment done when BL values were ≥0.5%. The confirmatory cohort included 41 MS patients (41.5% women, 87.8% with secondary progressive MS, median age = 46.3 (interquartile range: 41.3-52.1) years, disease duration = 14.1 (9-19.6) years, EDSS score = 5.5 (4.0-6.5)). The confirmatory cohort was treated with rituximab following the pattern established in the exploratory cohort., Results: In the exploratory cohort, ≥0.2% BL was established as the best value for retreatment because in most cases, a substantial increase of BL counts was preceded by initial values of 0.2-0.3%. In the confirmatory cohort, rituximab reduced the annualized relapse rate (ARR 0.56 vs. 0.125, p < 0.001), proportion of patients with appearance of new/enlarged T2 lesions (63.4% vs. 12.2%, p < 0.001), gadolinium-enhancing lesions (39% vs. 0%, p < 0.001), and confirmed disability progression (55% vs. 27.5%, p = 0.037). There were 22 patients (53.7%) who achieved NEDA-3. No patients had severe infections, and 10.7% cases had reduced IgG levels., Conclusion: Rituximab treatment guided by BL showed high effectiveness and a good safety profile for MS patients after one year of treatment., Competing Interests: Declaration of Competing Interest JLCG has received honorary for speaking engagements or consulting services from Bayer, Bial and Sanofi-Genzyme. FRJ has received honorary for speaking engagements or consulting services from Bial and Sanofi-Genzyme. EM received research grants, travel support or honoraria for speaking engagements from Biogen, Merck, Novartis, Roche, and Sanofi-Genzyme. LC-F received speaker fees, travel support, and/or served on advisory boards by Biogen, Sanofi, Merck, Bayer, Novartis, Roche, Teva, Celgene, Ipsen, Biopas, Almirall. SSM has received honorary for speaking engagements or consulting services from Almirall, Biogen, BMS, Janssen, Merck, Novartis, Roche and Sanofi-Genzyme. LMV received research grants, travel support or honoraria for speaking engagements from Biogen, Merck, Novartis, Roche, Sanofi-Genzyme and Bristol-Myers. 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 © 2022. Published by Elsevier B.V.)

Background: The potential influence of the timing of high-efficacy disease-modifying therapies (heDMTs) on processing speed (PS) performance is critically lacking in current literature., Objective: To assess the extent to which early commencement of heDMTs would be associated with a better PS evolution as compared to moderate efficacy disease-modifying therapies (meDMTs) and delayed commencement of heDMTs., Methods: In this ongoing prospective longitudinal study, the 695 MS patients that have received a PS evaluation at 12-month of follow-up measured by the iPad®-based Processing Speed Test (PST) were retained for the analysis. All patients who had ever been prescribed a high efficacy disease-modifying therapy (heDMT) were classified in tertiles according to the proportion of their disease duration that had been on heDMTs. Based on these tertiles and the time to the first heDMT from the disease onset, patients were divided into the early heDMT group and the delayed heDMT group. Between-group differences in mean PST standardized (Z-score) change from baseline were analyzed using a linear mixed model., Results: In the multivariable model, each year of delay in starting a heDMT was associated with increased odds of cognitive worsening at 12-month (OR = 1.0324, 95% CI = 1.014-1.062, p<0.05). MeDMT-treated patients were at a significantly higher risk for cognitive worsening than early heDMT patients (OR= 2.57, 95%CI = 1.02-6.17). Linear mixed model-based adjusted mean change in PST Z-score from baseline was significantly better in those patients with the longest proportion of their disease duration treated with heDMT (highest tertile) compared to the lowest tertile (difference 0.37 [95%CI 0.02-0.92;p=0.036) and medium tertile (difference 0.39 [95%CI 0.06-0.31;p=0.037)., Conclusion: Early he-DMT-treated patients are at significantly lower risk for cognitive worsening. Early administration of heDMTs is associated with greater cognitive functioning improvements than delayed commencement or meDMTs., (Copyright © 2022. Published by Elsevier B.V.)

The role of immunosuppression among coronavirus disease 2019 (COVID-19) patients has not been elucidated and management may be challenging. This observational study included confirmed COVID-19 patients. The primary endpoint was the development of moderate-severe acute respiratory distress syndrome (ARDS). Time to moderate-severe ARDS, the need for mechanical or noninvasive ventilation (MV/NIV), death, and a composite of death or MV/NIV were secondary endpoints. Of 138 patients included, 27 (19.6%) were immunosuppressed (IS) and 95 (68.8%) were male, with a median (IQR) age of 68 (54-78) years. A significantly lower proportion of IS patients (25.9%) compared to non-IS patients (52.3%) developed moderate-severe ARDS, in both unadjusted (0.32; 95% CI, 0.13-0.83; p = .017) and adjusted (aOR, 0.25; 95% CI, 0.08-0.80; p = .019) analyses. After stratifying by pathologies, only IS patients with autoimmune diseases remained significant (aOR 0.25; 95% CI, 0.07-0.98; p = .046). Nonsignificant trends toward a longer time to moderate or severe ARDS, a lower need for MV/NIV, and a lower risk of death or MV/NIV were detected among IS. In our cohort of COVID-19 patients, nonsevere immunosuppression was associated with a lower risk of moderate-severe ARDS, especially among AD. This suggests a potential protective effect from a hypothesized hyper-inflammatory response., (© 2020 Wiley Periodicals LLC.)

Introduction: In previous studies the risk of stroke recurrence has been associated with the left atrial appendage (LAA) morphology (non-chicken wing (NCW)), knowing those with a greater risk as malignant LAA. Recently, a simpler morphological classification has been suggested with two categories: Low-risk (LAA-L) and High-risk (LAA-H); which could be easier to apply and may correlate better with the risk of embolic stroke., Methods: Retrospective analysis from a registry of patients with recurrent cardioembolic strokes despite appropriate anticoagulant therapy, in which LAA morphology was studied with cardiac CT scan. LAA morphology was classified according to the four current categories and H-L morphology by the same cardiologist. Other variables associated with a high risk of stroke were also assessed, such as CHA 2 DS 2 -VASc score and left atrial (LA) size., Results: Twenty-six cases were included in the analysis. We identified 22 (84.6%) chicken wing (CW), 1 (3.8%) windsock and 3 (11.5%) cactus by the current classification system, while 15 (57.7%) were classified as LAA-H and 11 (42.3%) as LAA-L by the new system. Half of the 22 cases with CW morphology were considered LAA-H, whereas all NCW were also classified as LAA-H. LA diameter and area were significantly higher in cases with LAA-H morphology (p=0.03 and 0.014), and also in those CW and LAA-H, compared to those CW with LAA-L (p=0.035)., Conclusions: With this new classification system more than half of the cases of our malignant LAAs were classified as high-risk morphology. This morphology was also associated with an increased LA size., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Impulse control disorders (ICDs) have an increased frequency in patients with Parkinson's disease (PD), mainly because of treatment with dopamine agonists (DA). Factors related with the country of origin (culture, economy, healthcare politics) may impact phenomenology., Objectives: To explore phenomenology of ICDs depending on the country., Methods: A systematic review following PRISMA guidelines was performed using Pubmed database. Articles published up to 2018 in which the prevalence of ICDs was analyzed were selected., Results: Thirty-two studies from 22 countries worldwide were included. The highest prevalence of ICDs in each continent was found in UK (59%), USA (39.1%) and India (31.6%). Frequency of ICDs was higher in those studies with lower mean age, higher proportion of males, whenever a screening instrument was used and whenever prescription of DAs was more common. Prevalence of ICDs was higher in Western countries compared to Asian countries (20.8% vs. 12.8%, P  < 0.001) as it was the proportion of patients treated with DAs (66% vs. 48.2%, P  < 0.001). Hypersexuality was the most common ICD overall (up to 23.8%). The highest frequencies of compulsive buying and eating were found in Western countries. Gambling was less commonly diagnosed, but prevalence was relevant Japan (14%)., Conclusion: We observed a tendency towards a different ICD profile in different geographical areas, which may be attributable to socio-economical, cultural or political influences in the phenomenology of these disorders. Acknowledging these differences could help their early detection, which is critical for prognosis., (© 2020 International Parkinson and Movement Disorder Society.)

Background and Purpose: Specific respiratory tract infections, including COVID-19, may cause smell and/or taste disorders (STDs) with increased frequency. The aim was to determine whether new-onset STDs are more frequent amongst COVID-19 patients than influenza patients., Method: This was a case-control study including hospitalized patients of two tertiary care centres. Consecutive patients positive for COVID-19 polymerase chain reaction (cases) and patients positive for influenza polymerase chain reaction (historical control sample) were assessed during specific periods, employing a self-reported STD questionnaire., Results: Seventy-nine cases and 40 controls were included. No significant differences were found in basal features between the two groups. New-onset STDs were significantly more frequent amongst cases (31, 39.2%) than in the control group (5, 12.5 %) [adjusted odds ratio 21.4 (2.77-165.4, P = 0.003)]. COVID-19 patients with new-onset STDs were significantly younger than COVID-19 patients without STDs (52.6 ± 17.2 vs. 67.4 ± 15.1, P < 0.001). Amongst COVID-19 patients who presented STDs, 22 (70.9%) recalled an acute onset and it was an initial manifestation in 11 (35.5%). Twenty-five (80.6%) presented smell disorders (mostly anosmia, 14, 45.2%) and 28 (90.3%) taste disorders (mostly ageusia, 14, 45.2%). Only four (12.9 %) reported concomitant nasal obstruction. The mean duration of STD was 7.5 ± 3.2 days and 12 patients (40%) manifested complete recovery after 7.4 ± 2.3 days of onset., Conclusion: New-onset STDs were significantly more frequent amongst COVID-19 patients than influenza patients; they usually had an acute onset and were commonly an initial manifestation. The use of STD assessment in anamnesis as a hint for COVID-19 and to support individuals' self-isolation in the current epidemic context is suggested., (© 2020 European Academy of Neurology.)

Background: The use of the cardiovascular polypill, a fixed-dose combination treatment, is conceived to improve adherence. However, randomized controlled trials (RCTs) may overestimate it. Studies focusing on cerebrovascular disease and real-life efficacy compared with conventional treatment are lacking., Methods: This is a retrospective, hospital-based cohort study of acute ischaemic stroke patients who were prescribed a polypill (aspirin 100 mg, atorvastatin 20/40 mg, ramipril 2.5/5/10 mg) versus conventional treatment (aspirin 100 mg and other blood pressure/lipid-lowering agents) in secondary prevention (2017-2018). Clinical records were reviewed 90 days after discharge for stroke recurrence, vascular risk factor control, and safety. Adherence was assessed using the adapted Morisky-Green scale., Results: A total of 104 patients were included (61% male; mean age 69.7 ± 13.9 years); 54 were treated with the polypill and 50 with conventional treatment. No baseline differences in clinical or demographic variables were detected. No recurrences were registered in the polypill group, compared to 1 recurrence in the conventional treatment group. A significant reduction of systolic blood pressure (SBP) was achieved in the polypill group (12.1 mm Hg) compared to the conventional treatment group (6.8 mm Hg) (p = 0.002). No significant differences were detected regarding the goal of LDL cholesterol ≤70 mg/dL (41 vs. 44%). The adverse events were mild and their frequency was similar in the two groups (9 vs. 2%, ns). Adherence was similarly good in the two groups (93 vs. 88%, ns). Polypill group adherence was similar to that reported in a previous meta-analysis of RCTs (93 vs. 84%, ns)., Conclusion: In our experience, the cardiovascular polypill achieved a higher reduction in SBP levels and was well tolerated. Adherence was similar to that found in the previous literature, which is remarkable given the real-life setting of our study., (© 2020 The Author(s) Published by S. Karger AG, Basel.)