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Ischemic strokes are caused by a reduction in cerebral blood flow and both the ischemic period and subsequent reperfusion induce brain injury, with different tissue damage depending on the severity of the ischemic insult, its duration, and the particular areas of the brain affected. In those areas vulnerable to cerebral ischemia, the inhibition of protein translation is an essential process of the cellular response leading to delayed neuronal death. In particular, translation initiation is rate-limiting for protein synthesis and the eukaryotic initiation factor (eIF) 4F complex is indispensable for cap-dependent protein translation. In the eIF4F complex, eIF4G is a scaffolding protein that provides docking sites for the assembly of eIF4A and eIF4E, binding to the cap structure of the mRNA and stabilizing all proteins of the complex. The eIF4F complex constituents, eIF4A, eIF4E, and eIF4G, participate in translation regulation by their phosphorylation at specific sites under cellular stress conditions, modulating the activity of the cap-binding complex and protein translation. This work investigates the phosphorylation of eIF4G1 involved in the eIF4E/eIF4G1 association complex, and their regulation in ischemia-reperfusion (IR) as a stress-inducing condition. IR was induced in an animal model of transient cerebral ischemia and the results were studied in the resistant cortical region and in the vulnerable hippocampal CA1 region. The presented data demonstrate the phosphorylation of eIF4G1 at Ser 1147 , Ser 1185 , and Ser 1231 in both brain regions and in control and ischemic conditions, being the phosphorylation of eIF4G1 at Ser 1147 the only one found in the eIF4E/eIF4G association complex from the cap-containing matrix (m 7 GTP-Sepharose). In addition, our work reveals the specific modulation of the phosphorylation of eIF4G1 at Ser 1147 in the vulnerable region, with increased levels and colocalization with eIF4E in response to IR. These findings contribute to elucidate the molecular mechanism of protein translation regulation that underlies in the balance of cell survival/death during pathophysiological stress, such as cerebral ischemia.

Background: The aim of this study was to analyze the impact of the presence of heart failure (HF) on the clinical profile and outcomes in patients with atrial fibrillation (AF) anticoagulated with rivaroxaban., Methods: Observational and non-interventional study that included AF adults recruited from 79 Spanish centers, anticoagulated with rivaroxaban ≥ 6 months before inclusion. Data were analyzed according to baseline HF status., Results: Out of 1,433 patients, 326 (22.7%) had HF at baseline. Compared to patients without HF, HF patients were older (75.3 ± 9.9 vs. 73.8 ± 9.6 years; p = 0.01), had more diabetes (36.5% vs. 24.3%; p < 0.01), coronary artery disease (28.2% vs. 12.9%; p < 0.01), renal insufficiency (31.7% vs. 22.6%; p = 0.01), higher CHA2DS2-VASc (4.5 ± 1.6 vs. 3.2 ± 1.4; p < 0.01) and HAS-BLED (1.8 ± 1.1 vs. 1.5 ± 1.0; p < 0.01). After a median follow-up of 2.5 years, among HF patients, annual rates of stroke/systemic embolism/transient ischemic attack, major adverse cardiovascular events (MACE) (non-fatal myocardial infarction, revascularization and cardiovascular death), cardiovascular death, and major bleeding were 1.2%, 3.0%, 2.0%, and 1.4%, respectively. Compared to those patients without HF, HF patients had greater annual rates of MACE (3.0% vs. 0.5%; p < 0.01) and cardiovascular death (2.0% vs. 0.2%; p < 0.01), without significant differences regarding other outcomes, including thromboembolic or bleeding events. Previous HF was an independent predictor of MACE (odds ratio 3.4; 95% confidence interval 1.6-7.3; p = 0.002) but not for thromboembolic events or major bleeding., Conclusions: Among AF patients anticoagulated with rivaroxaban, HF patients had a worse clinical profile and a higher MACE risk and cardiovascular mortality. HF was independently associated with the development of MACE, but not with thromboembolic events or major bleeding.

Objective: To explore if baseline blood lymphocyte profile could identify relapsing remitting multiple sclerosis (RRMS) patients at higher risk of developing secondary autoimmune adverse events (AIAEs) after alemtuzumab treatment., Methods: Multicenter prospective study including 57 RRMS patients treated with alemtuzumab followed for 3.25 [3.5-4.21] years, (median [interquartile range]). Blood samples were collected at baseline, and leukocyte subsets determined by flow cytometry. We had additional samples one year after the first cycle of alemtuzumab treatment in 39 cases., Results: Twenty-two patients (38.6%) developed AIAEs during follow-up. They had higher B-cell percentages at baseline (p=0.0014), being differences mainly due to plasmablasts/plasma cells (PB/PC, p=0.0011). Those with no AIAEs had higher percentages of CD4+ T cells (p=0.013), mainly due to terminally differentiated (TD) (p=0.034) and effector memory (EM) (p=0.031) phenotypes. AIAEs- patients also showed higher values of TNF-alpha-producing CD8+ T cells (p=0.029). The percentage of PB/PC was the best variable to differentiate both groups of patients. Baseline values >0.10% closely associated with higher AIAE risk (Odds ratio [OR]: 5.91, 95% CI: 1.83-19.10, p=0.004). When excluding the 12 patients with natalizumab, which decreases blood PB/PC percentages, being the last treatment before alemtuzumab, baseline PB/PC >0.1% even predicted more accurately the risk of AIAEs (OR: 11.67, 95% CI: 2.62-51.89, p=0.0007). The AIAEs+ group continued having high percentages of PB/PC after a year of alemtuzumab treatment (p=0.0058)., Conclusions: A PB/PC percentage <0.1% at baseline identifies MS patients at low risk of secondary autoimmunity during alemtuzumab treatment.​., Competing Interests: EM received research grants, travel support or honoraria for speaking engagements from Biogen, Merck, Novartis, Roche, and Sanofi-Genzyme. SS received payment for lecturing or travel expenses from Almirall, Biogen, Merck-Serono, Novartis Roche, Sanofi-Genzyme, and Teva. MC has received compensation for consulting services and speaking honoraria from Bayer Schering Pharma, Merk Serono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-Aventis, Genzyme, and Novartis. LR-T has received speaking honoraria and travel expenses for scientific meetings and has participated in advisory boards in the past years with Bayer Schering Pharma, Biogen, EMD Merck Serono, Sanofi Genzyme, Novartis, Sanofi-Aventis, Teva Phramaceuticals, Almirall and Roche. XM has received speaking honoraria and travel expenses for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Actelion, Alexion, Bayer, Biogen, Celgene, EMD Serono, Genzyme, Immunic, Medday, Merck KGaA, Darmstadt Germany, Mylan, Nervgen, Novartis, Roche, Sanofi-Genzyme, Teva MSIF and NMSS. LM has received travel funding from Genzyme, Roche, Biogen Idec and Novartis, and personal fee for lectures from Roche. JM-L received grants and consulting or speaking fees from Almirall, Biogen, Celgene, Genzyme, Merck, Novartis, Roche and Teva. RA-L reports grants and personal fees from Merck Serono, personal fees and non-financial support from Biogen IDEC, grants, personal fees and non-financial support from Novartis Pharmaceuticals S.A., grants and personal fees from Genzyme, non-financial support from TEVA Pharma, S.L. 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, 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 © 2021 Walo-Delgado, Monreal, Medina, Quintana, Sainz de la Maza, Fernández-Velasco, Lapuente, Comabella, Ramió-Torrentà, Montalban, Midaglia, Villarrubia, Carrasco-Sayalero, Rodríguez-Martín, Roldán, Meca-Lallana, Alvarez-Lafuente, Masjuan, Costa-Frossard and Villar.)

Cerebral ischemia induces an inhibition of protein synthesis and causes cell death and neuronal deficits. These deleterious effects do not occur in resilient areas of the brain, where protein synthesis is restored. In cellular stress conditions, as brain ischemia, translational repressors named eukaryotic initiation factor (eIF) 4E-binding proteins (4E-BPs) specifically bind to eIF4E and are critical in the translational control. We previously described that 4E-BP2 protein, highly expressed in brain, can be a molecular target for the control of cell death or survival in the reperfusion after ischemia in an animal model of transient cerebral ischemia. Since these previous studies showed that phosphorylation would not be the regulation that controls the binding of 4E-BP2 to eIF4E under ischemic stress, we decided to investigate the differential detection of 4E-BP2-interacting proteins in two brain regions with different vulnerability to ischemia-reperfusion (IR) in this animal model, to discover new potential 4E-BP2 modulators and biomarkers of cerebral ischemia. For this purpose, 4E-BP2 immunoprecipitates from the resistant cortical region and the vulnerable hippocampal cornu ammonis 1 (CA1) region were analyzed by two-dimensional (2-D) fluorescence difference in gel electrophoresis (DIGE), and after a biological variation analysis, 4E-BP2-interacting proteins were identified by matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry. Interestingly, among the 4E-BP2-interacting proteins identified, heat shock 70 kDa protein-8 (HSC70), dihydropyrimidinase-related protein-2 (DRP2), enolase-1, ubiquitin carboxyl-terminal hydrolase isozyme-L1 (UCHL1), adenylate kinase isoenzyme-1 (ADK1), nucleoside diphosphate kinase-A (NDKA), and Rho GDP-dissociation inhibitor-1 (Rho-GDI), were of notable interest, showing significant differences in their association with 4E-BP2 between resistant and vulnerable regions to ischemic stress. Our data contributes to the first characterization of the 4E-BP2 interactome, increasing the knowledge in the molecular basis of the protection and vulnerability of the ischemic regions and opens the way to detect new biomarkers and therapeutic targets for diagnosis and treatment of cerebral ischemia.

Purpose: The benefit of intravenous alteplase is well established for patients with disabling stroke symptoms regardless of age, although data on outcomes in centenarian patients are scarce. We present our experience in patients beyond 100 years., Methods: Descriptive study including centenarians from our single-centre prospective registry who underwent intravenous thrombolysis with alteplase for acute ischemic stroke in our tertiary university hospital. Clinical variables and functional outcome at 3 months were collected., Results: Four patients, all women, functionally independent (mRS ≤ 2) were included. Treatment with alteplase was applied within 4.5 h of stroke onset. One patient complicated with pneumonia and died. Two patients were functionally independent (mRS ≤ 2) at discharge, while the third was partially dependent (mRS of 3 at discharge), improving after 3 months, (mRS 2). No serious hemorrhagic or systemic adverse events were registered., Conclusion: In our experience, intravenous thrombolysis may be beneficial and should be considered in patients over 100 years old with no previous disability., (© 2021. European Geriatric Medicine Society.)

Objective: To determine the best method to measure intrathecal immunoglobulin (Ig) M synthesis (ITMS), a biomarker of worse prognosis in multiple sclerosis (MS). We compared the ability for predicting a poor evolution of 4 methods assessing ITMS (IgM oligoclonal bands [OCMBs], lipid-specific OCMBs [LS-OCMBs], Reibergram, and IgM index) in patients with a clinically isolated syndrome (CIS)., Methods: Prospective study with consecutive patients performed at a referral MS center. We used unadjusted and multivariate Cox regressions for predicting a second relapse, Expanded Disability Status Scale (EDSS) scores of 4 and 6, and development of secondary progressive MS (SPMS)., Results: A total of 193 patients were included, with a median (interquartile range) age of 31 (25-38) years and a median follow-up of 12.9 years. Among all methods, only OCMB, LS-OCMB, and Reibergram significantly identified patients at risk of some of the pre-established outcomes, being LS-OCMB the technique with the strongest associations. Adjusted hazard ratio (aHR) of LS-OCMB for predicting a second relapse was 2.50 (95% CI 1.72-3.64, p < 0.001). The risk of reaching EDSS scores of 4 and 6 and SPMS was significantly higher among patients with LS-OCMB (aHR 2.96, 95% CI 1.54-5.71, p = 0.001; aHR 4.96, 95% CI 2.22-11.07, p < 0.001; and aHR 2.31, 95% CI 1.08-4.93, p = 0.03, respectively)., Conclusions: ITMS predicts an aggressive MS at disease onset, especially when detected as LS-OCMB., Classification of Evidence: This study provides Class II evidence that lipid-specific IgM oligoclonal bands can predict progression from CIS to MS and a worse disease course over a follow-up of at least 2 years., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

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.)

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.

Serum neurofilament light chains (sNfL) are biomarkers of disease activity in multiple sclerosis (MS), but their value to predict response to treatment, and their association with patient immunological profile, need to be further explored. We studied 80 relapsing-remitting MS patients initiating dimethyl fumarate (DMF) treatment. sNfL levels were explored at baseline and at 3, 6 and 12 months by single molecule array. Blood lymphocyte subsets were measured at baseline and at 6 months by flow cytometry. Patients were followed a year and classified as NEDA (no evidence of disease activity) or ODA (ongoing disease activity). NEDA patients had lower sNfL levels at baseline (p = 0.0001), and after three (p = 0.004) and six (p = 0.03) months of DMF treatment. Consequently, low baseline sNfL values (≤ 12 pg/ml) increased the probability of NEDA (OR 5.8; CI 1.82-15.6; p = 0.002, after correcting by disease activity in the previous year), and associated with significant reductions of central memory CD4+ T lymphocytes, interferon-gamma+ CD8+ T lymphocytes, Natural Killer T cells, and memory B cells upon DMF treatment, being the highest differences in memory B cells (p < 0.0001). This shows that low baseline sNfL values identify MS patients with higher probability of optimal response to DMF and of a reduction in effector immune cells.

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.)

Despite the increasing evidence of the benefit of corticosteroids for the treatment of moderate-severe coronavirus disease 2019 (COVID-19) patients, no data are available about the potential role of high doses of steroids for these patients. We evaluated the mortality, the risk of need for mechanical ventilation (MV), or death and the risk of developing a severe acute respiratory distress syndrome (ARDS) between high (HD) and standard doses (SD) among patients with a severe COVID-19. All consecutive confirmed COVID-19 patients admitted to a single center were selected, including those treated with steroids and an ARDS. Patients were allocated to the HD (≥ 250 mg/day of methylprednisolone) of corticosteroids or the SD (≤ 1.5 mg/kg/day of methylprednisolone) at discretion of treating physician. Five hundred seventy-three patients were included: 428 (74.7%) men, with a median (IQR) age of 64 (54-73) years. In the HD group, a worse baseline respiratory situation was observed and male gender, older age, and comorbidities were significantly more common. After adjusting by baseline characteristics, HDs were associated with a higher mortality than SD (adjusted OR 2.46, 95% CI 1.59-3.81, p < 0.001) and with an increased risk of needing MV or death (adjusted OR 2.35, p = 0.001). Conversely, the risk of developing a severe ARDS was similar between groups. Interaction analysis showed that HD increased mortality exclusively in elderly patients. Our real-world experience advises against exceeding 1-1.5 mg/kg/day of corticosteroids for severe COVID-19 with an ARDS, especially in older subjects. This reinforces the rationale of modulating rather than suppressing immune responses in these patients.

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.)

Introduction: Spinal cord infarction is a rare disease with a high rate of morbidity. Its diagnosis can be challenging and controversy remains regarding the best treatment. Few case series have been published., Methods: We conducted a retrospective review of cases of spinal cord infarction attended in a tertiary hospital from 1999 to 2020. Aetiology and clinical, imaging, and prognostic features were assessed., Results: Forty-one patients (58.5% men, mean [standard deviation] age 61 [17] years) were included in the study. Thirty-one patients (75.6%) presented vascular risk factors. Motor deficits were recorded in 39 (95.1%), pain in 20 (48.8%), sensory deficits in 33 (80.4%), and autonomic dysfunction in 24 (58.5%). MRI was performed in 37 (90.2%) patients. Diffusion-weighted images were available for 12 patients, with 10 showing diffusion restriction. The thoracic region was the most frequently affected (68.2%). Vascular imaging studies were performed in 33 patients (80.4%). The most frequent aetiologies were aortic dissection (6 cases), atherosclerosis demonstrated by vascular imaging (6 cases), fibrocartilaginous embolism (6 cases), surgery (5 cases), and hypotension (4 cases). Aetiology was undetermined in 12 patients (29.3%), although 9 of these presented vascular risk factors. At the end of the follow-up period (median, 24 months; interquartile range, 3-70), 12 patients (29.2%) were able to walk without assistance. Vascular risk factors and paraparesis were significantly associated with poorer prognosis (P<.05)., Discussion: Spinal cord infarction may present diverse aetiologies, with the cause remaining undetermined in many patients. Long-term functional prognosis is poor, and depends on baseline characteristics and clinical presentation. MRI, and especially diffusion-weighted sequences, is useful for early diagnosis., (Copyright © 2021 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.)

Introduction: Thrombectomy in the carotid artery territory was recently shown to be effective up to 24hours after symptoms onset., Methods: We conducted a retrospective review of a prospective registry of patients treated at our stroke reference centre between November 2016 and April 2019 in order to assess the safety and effectiveness of mechanical thrombectomy performed beyond 6hours after symptoms onset in patients with acute ischaemic stroke and large vessel occlusion in the carotid artery territory., Results: Data were gathered from 59 patients (55.9% women; median age, 71 years). In 33 cases, stroke was detected upon awakening; 57.6% of patients were transferred from another hospital. Median baseline NIHSS score was 16, and median ASPECTS score was 8, with 94.9% of patients presenting>50% of salvageable tissue. Satisfactory recanalisation was achieved in 88.1% of patients, beyond 24hours after onset in 5 cases. At 90 days of follow-up, 67.8% were functionally independent; those who were not were older and presented higher prevalence of atrial fibrillation, greater puncture-to-recanalisation time, and higher NIHSS scores, both at baseline and at discharge., Conclusion: In our experience, mechanical thrombectomy beyond 6hours was associated with good 90-day functional outcomes. Age, NIHSS score, puncture-to-recanalisation time, and presence of atrial fibrillation affected functional prognosis. The efficacy of the treatment beyond 24hours after onset merits study., (Copyright © 2020 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.)

Immunosuppression (IS) and autoimmune disease (AD) are prevalent in patients with severe coronavirus disease 2019 (COVID-19), but their impact on its clinical course is unknown. We investigated relationships between IS, AD, and outcomes in patients hospitalized with COVID-19. Data on consecutive admissions for COVID-19 were extracted retrospectively from medical records. Patients were assigned to one of four cohorts, according to whether or not they had an AD (AD and NAD) or were immunosuppressed (IS and NIS). The primary endpoint was development of severe acute respiratory distress syndrome (ARDS); secondary endpoints included death, and a composite of mechanical ventilation (MV) or death. A total of 789 patients were included: 569 (72.1%) male, 76 (9.6%) with an AD, and 63 (8.0%) with IS. Relative to the NIS-NAD cohort, patients in the IS-AD cohort had a significantly reduced risk of severe ARDS (adjusted hazard ratio [aHR] 0.42; 95% confidence interval [CI] 0.23-0.80; p = 0.008). No significant relationships between IS or AD status and either death or the composite of MV and death were identified, although a trend towards higher mortality was identified in the IS-NAD cohort (aHR vs NIS-NAD 1.71; 95% CI 0.94-3.12; p = 0.081). Patients in this cohort also had higher median serum levels of interleukin-6 compared with IS-AD patients (98.2 vs 21.6 pg/mL; p = 0.0328) and NIS-NAD patients (29.1 pg/mL; p = 0.0057). In conclusion, among patients hospitalized with COVID-19, those receiving immunosuppressive treatment for an AD may have a reduced risk of developing severe ARDS.

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.)

Background and Purpose: This study aimed to determine the maximum tolerated dose and to evaluate the overall safety and tolerability of single doses of PF-05230907 in subjects with acute intracerebral hemorrhage., Methods: Individuals presenting with intracerebral hemorrhage were enrolled in a phase 1, multicenter, open-label clinical trial. A Bayesian modified continual reassessment method design based on treatment-emergent thromboembolic or ischemic events was adopted. Sequential dosing, an external data monitoring committee, and prespecified stopping rules were incorporated as safeguards., Results: Twenty-one subjects received PF-05230907. The mean (±SD) age in years and intracerebral hemorrhage volume in mL at baseline were 62 (±9) and 18 (±11), respectively. Two treatment-emergent thromboembolic or ischemic events occurred (deep vein thrombosis and cerebral ischemia), in the 30 μg/kg dose group. There were no other clear drug-related toxicities at dose levels ranging from 5 to 30 μg/kg. At the time of study termination, the maximum tolerated dose was estimated to be 24 μg/kg, with a mean fitted dose-toxicity estimate of 11.9% (95% CI, 1.2%-27.4%)., Conclusions: Single doses of PF-05230907 appeared to be tolerated across a range of doses in the intracerebral hemorrhage population, with thrombotic events observed only at the highest dose level tested. Recruitment within the recommended therapeutic window of opportunity remains a challenge. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02687191.

Introduction: There is little control of cardiovascular (CV) risk factors in secondary prevention after an ischaemic stroke, in part due to a lack of adherence to treatment. The CV polypill may contribute to proper treatment adherence, which is necessary for CV disease prevention. This study aimed to establish how and in what cases the CV polypill should be administered., Methods: A group of 8 neurologists drafted consensus recommendations using structured brainstorming and based on their experience and a literature review., Results: These recommendations are based on the opinion of the participating experts. The use of the CV polypill is beneficial for patients, healthcare professionals, and the health system. Its use is most appropriate for atherothrombotic stroke, lacunar stroke, stroke associated with cognitive impairment, cryptogenic stroke with CV risk factors, and silent cerebrovascular disease. It is the preferred treatment in cases of suspected poor adherence, polymedicated patients, elderly people, patients with polyvascular disease or severe atherothrombosis, young patients in active work, and patients who express a preference for the CV polypill. Administration options include switching from individual drugs to the CV polypill, starting treatment with the CV polypill in the acute phase in particular cases, use in patients receiving another statin or an angiotensin ii receptor antagonist, or de novo use if there is suspicion of poor adherence. Nevertheless, use of the CV polypill requires follow-up on the achievement of the therapeutic objectives to make dose adjustments., Conclusions: This document is the first to establish recommendations for the use of the CV polypill in cerebrovascular disease, beyond its advantages in terms of treatment adherence., (Copyright © 2017 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Intracerebral hemorrhage (ICH) is 7- to 10-fold higher in anticoagulated patients. Given the more extended use of oral anticoagulants, an increase in the prevalence of ICH associated with oral anticoagulation (ICH-OAC) could be expected. However, there is no previous study that assesses the time trends of ICH-OAC in Spain., Methods: We conducted a combined data analysis after creating a joint database of the 3 most important epidemiological studies on ICH-OAC of our country: the EPICES study (2008-2009), the TAC Registry (TR) study (2012-2013) and the TAC Registry 2 (TR2) study (2015). We finally included 65, 235, and 366 patients from the EPICES, TR, and TR2 studies, respectively., Results: We have observed a 3.73-fold increase in the crude annual incidence of ICH-OAC throughout the period of study, with proportion of ICH-OAC out of total ICH increasing from 8.4% in 2008 to 18.2% in 2015. Age, dyslipidemia, and prior antiplatelet treatment increased during the study, but we found no statistically significant differences in other risk factors for ICH-OAC., Conclusions: The incidence of ICH-OAC is increasing in our country. It might at least be partly explained by aging of the population, with mean age at presentation being higher in the last years., (© 2020 S. Karger AG, Basel.)

In the context of COVID-19 infection, 0.5-2% of affected patients will suffer a stroke. The strokes are usually severe with an unfavourable prognosis. Most patients suffer from occlusion of the large brain-supplying arteries caused by the COVID-19 induced coagulation disorders. In the context of COVID-19 infection, there has been a dramatic temporary decrease in the number of stroke patients treated in stroke units., (Published on behalf of the European Society of Cardiology. © The Author(s) 2020.)

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 and Objective: Oral anticoagulation (OAC) for secondary stroke prevention is recommended in atrial fibrillation (AF) and other sources of cardioembolic stroke. Our objectives were to explore the differences in ischemic and hemorrhagic events when using OAC for secondary stroke prevention according to the type of anticoagulant treatment and to analyze the number and reasons for OAC switches during long-term follow-up. Methods: Ischemic stroke (IS) patients who were discharged on OAC for secondary stroke prevention from January 2014 to October 2017 were recruited in a prospective, multicenter, hospital-based registry. Follow-up at 3 months was scheduled at the outpatient clinic with subsequent annual phone interviews for 3 years. Patients were classified into three study groups according to OAC at discharge: Vitamin K antagonist (VKA), Factor Xa inhibitor (FXa), or direct thrombin inhibitor (DTI). We compared stroke recurrences, intracranial hemorrhage, major bleeding, and all-cause mortality during the follow-up. We recorded any switches in OAC and the main reasons for the change. Results: A total of 241 patients were included. An anticoagulant was indicated in the presence of a source of cardioembolic stroke in 240 patients (99.6%) and lupus plus antiphospholipid syndrome in one patient. Up to 86 patients (35.6%) were on OAC before the index stroke; in 71 (82.5%) of them, this was VKA. At hospital discharge, 105 were treated with FXa (43.8%), 96 with VKA (39.6%), and 40 with DTI (16.6%). The cumulative incidences at 3 years were 17% for stroke recurrence, 1.6% for intracranial hemorrhage, 4.9% for major hemorrhage, and 22.8% for all-cause mortality, with no differences among the OAC groups in any outcomes. During the follow-up, 40 OAC switches were recorded (63% of them to FXa), mostly due to stroke recurrence. Conclusion: Long-term OAC in secondary stroke prevention is associated with a lower frequency of bleeding complications than stroke recurrences. No differences between anticoagulant drugs were found in any of the analyzed outcomes. The main cause for OAC switch during follow-up was stroke recurrence., (Copyright © 2020 Gutiérrez-Zúñiga, Rigual, Torres-Iglesias, Sánchez-Velasco, Alonso de Leciñana, Masjuan, Álvarez Velasco, Navas, Izquierdo-Esteban, Fernández-Ferro, Rodríguez-Pardo, Ruiz-Ares, Zapata-Wainberg, Fuentes and Díez-Tejedor.)

Recent case-series of small size implied a pathophysiological association between coronavirus disease 2019 (COVID-19) and severe large-vessel acute ischemic stroke. Given that severe strokes are typically associated with poor prognosis and can be very efficiently treated with recanalization techniques, confirmation of this putative association is urgently warranted in a large representative patient cohort to alert stroke clinicians, and inform pre- and in-hospital acute stroke patient pathways. We pooled all consecutive patients hospitalized with laboratory-confirmed COVID-19 and acute ischemic stroke in 28 sites from 16 countries. To assess whether stroke severity and outcomes (assessed at discharge or at the latest assessment for those patients still hospitalized) in patients with acute ischemic stroke are different between patients with COVID-19 and non-COVID-19, we performed 1:1 propensity score matching analyses of our COVID-19 patients with non-COVID-19 patients registered in the Acute Stroke Registry and Analysis of Lausanne Registry between 2003 and 2019. Between January 27, 2020, and May 19, 2020, 174 patients (median age 71.2 years; 37.9% females) with COVID-19 and acute ischemic stroke were hospitalized (median of 12 patients per site). The median National Institutes of Health Stroke Scale was 10 (interquartile range [IQR], 4-18). In the 1:1 matched sample of 336 patients with COVID-19 and non-COVID-19, the median National Institutes of Health Stroke Scale was higher in patients with COVID-19 (10 [IQR, 4-18] versus 6 [IQR, 3-14]), P =0.03; (odds ratio, 1.69 [95% CI, 1.08-2.65] for higher National Institutes of Health Stroke Scale score). There were 48 (27.6%) deaths, of which 22 were attributed to COVID-19 and 26 to stroke. Among 96 survivors with available information about disability status, 49 (51%) had severe disability at discharge. In the propensity score-matched population (n=330), patients with COVID-19 had higher risk for severe disability (median mRS 4 [IQR, 2-6] versus 2 [IQR, 1-4], P <0.001) and death (odds ratio, 4.3 [95% CI, 2.22-8.30]) compared with patients without COVID-19. Our findings suggest that COVID-19 associated ischemic strokes are more severe with worse functional outcome and higher mortality than non-COVID-19 ischemic strokes.

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.)

Introduction: An increased incidence of stroke in HIV-infected patients has already been reported, suggesting that HIV infection may be a cerebrovascular risk factor. The objective of this study was to assess temporal trends in the proportion of HIV infection among patients with stroke in Spain., Methods: Data were obtained from the minimum basic dataset (MBDS) of all patients hospitalized in Spain between 1997 and 2012 with a primary or secondary diagnosis of stroke. The annual proportion of HIV infection and time trends (stratifying by type of stroke and HIV stage) were calculated, and predictors of HIV infection and the social and economic impact of HIV-infected (HIV+) and non-infected (HIV-) patients were analyzed., Results: Of 857,371 patients hospitalized with an incident stroke, 2134 (0.25%) had HIV infection. A 2.5% year-on-year increase (OR 1.025, 95% CI 1.015-1.036, p<0.0001) of the proportion of HIV-infected patients was observed due to an increase in the asymptomatic stage of the infection (per year OR 1.077, 95% CI 1.057-1.097, p<0.0001), as the proportion of patients with AIDS remained stable. Factors independently associated with HIV infection and stroke were active smoking, stimulating drugs and hepatitis C virus (HCV) infection. A higher mortality rate, longer hospital stay and a higher cost per hospitalized patient was observed among HIV+ patients., Conclusions: From 1997 to 2012, there was an increase in the proportion of HIV infection among patients hospitalized with stroke irrespective of the classical vascular risk factors, reinforcing the role of HIV infection as a cerebrovascular risk factor., (Copyright © 2019 Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.)

Objective: Current prehospital scales used to detect large vessel occlusion reveal very low endovascular thrombectomy (EVT) rates among selected patients. We developed a novel prehospital scale, the Madrid-Direct Referral to Endovascular Center (M-DIRECT), to identify EVT candidates for direct transfer to EVT-capable centers (EVT-Cs). The scale evaluated clinical examination, systolic blood pressure, and age. Since March 2017, patients closer to a stroke unit without EVT capabilities and an M-DIRECT positive score have been transferred to the nearest EVT-C. To test the performance of the scale-based routing protocol, we compared its outcomes with those of a simultaneous cohort of patients directly transferred to an EVT-C., Methods: In this prospective observational study of consecutive patients with stroke code seen by emergency medical services, we compared diagnoses, treatments, and outcomes of patients who were closer to an EVT-C (mothership cohort) with those transferred according to the M-DIRECT score (M-DIRECT cohort)., Results: The M-DIRECT cohort included 327 patients and the mothership cohort 214 patients. In the M-DIRECT cohort, 227 patients were negative and 100 were positive. Twenty-four (10.6%) patients required secondary transfer, leaving 124 (38%) patients from the M-DIRECT cohort admitted to an EVT-C. EVT rates were similar for patients with ischemic stroke in both cohorts (30.9% vs 31.5%). The M-DIRECT scale had 79% sensitivity, 82% specificity, and 53% positive predictive value for EVT. Recanalization and independence rates at 3 months did not differ between the cohorts., Conclusions: The M-DIRECT scale was highly accurate for EVT, with treatment rates and outcomes similar to those of a mothership paradigm, thereby avoiding EVT-C overload with a low rate of secondary transfers., (© 2020 American Academy of Neurology.)

Introduction: Organisational capacity in terms of resources and care circuits to shorten response times in new stroke cases is key to obtaining positive outcomes. This study compares therapeutic approaches and treatment outcomes between traditional care centres (with stroke teams and no stroke unit) and centres with stroke units., Methods: We conducted a prospective, quasi-experimental study (without randomisation of the units analysed) to draw comparisons between 2 centres with stroke units and 4 centres providing traditional care through the neurology department, analysing a selection of agreed indicators for monitoring quality of stroke care. A total of 225 patients participated in the study. In addition, self-administered questionnaires were used to collect patients' evaluations of the service and healthcare received., Results: Centres with stroke units showed shorter response times after symptom onset, both in the time taken to arrive at the centre and in the time elapsed from patient's arrival at the hospital to diagnostic imaging. Hospitals with stroke units had greater capacity to respond through the application of intravenous thrombolysis than centres delivering traditional neurological care., Conclusion: Centres with stroke units showed a better fit to the reference standards for stroke response time, as calculated in the Quick study, than centres providing traditional care through the neurology department., (Copyright © 2017 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.)

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.)

Introduction: Substantia nigra hyperechogenicity (SN+) in transcranial sonography (TCS) is frequent in Parkinson's disease (PD), while lenticular nucleus hyperechogenicity (LN+) and 3rd ventricle enlargement (3V+) are typical of Atypical Parkinsonisms (AP). However, there are no studies assessing the diagnostic yield of all TCS biomarkers in the three AP (progressive supranuclear palsy, PSP, multiple system atrophy, MSA, corticobasal degeneration, CBD). Previous references lack homogeneous criteria and data are incomprehensive., Methods: Analysis of TCS performed in routine clinical practice in AP and PD patients from two tertiary hospitals. Expert recommendations were strictly followed. Previous literature was critically analysed., Results: 155 AP (98 PSP, 40 MSA, 14 CBD), 254 PD, 145 control subjects were included. We confirmed good sensitivity for SN+ in PD (80%), but specificity was lower than reported (61%). LN+ and 3V + had moderate sensitivity for AP and PSP diagnosis respectively (65%, 63%), but specificity was higher than reported (87%, 91%). We confirmed high specificity and positive predictive value of the combination SN/LN (98%, 93% AP; 83%, 86% PD). The combinations of two or three echofeatures, previously unreported, showed high specificity but lower sensitivity (SN/3V: 75% sensitivity, 87% specificity PD; 42% sensitivity, 98% specificity PSP) (SN + LN+: 79% sensitivity, 86% specificity CBD) (SN/3V/LN: 67% sensitivity, 89% specificity PD; 29% sensitivity, 99% specificity PSP; 41% sensitivity, 95% specificity MSA; 57% sensitivity 91% specificity CBD)., Conclusions: We present a large comprehensive study of TCS, confirming its usefulness and certain limitations in AP diagnosis. Adherence to consensus criteria is critical to implement TCS for clinical and research purposes., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: This study proposes a set of quality indicators for care outcomes in patients with acute cerebral infarction. These indicators are understandable and relevant from a clinical viewpoint, as well as being acceptable and feasible in terms of time required, ease of data capture, and interpretability., Method: The method consisted of reaching consensus among doctors after having reviewed the literature on quality indicators in stroke. We then designed and conducted a field study to assess the understandability and feasibility of the set of indicators., Results: Consensus yielded 8 structural indicators, 5 process indicators, and 12 result indicators. Additionally, standards of reference were established for each indicator., Conclusion: This set of indicators can be used to monitor the quality care for stroke patients, identify strengths, and potentially to identify areas needing improvement., (Copyright © 2017 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Cryptogenic strokes constitute 20 to 30% of ischemic strokes, and most cryptogenic strokes are considered to be embolic and of undetermined source. An earlier randomized trial showed that rivaroxaban is no more effective than aspirin in preventing recurrent stroke after a presumed embolic stroke from an undetermined source. Whether dabigatran would be effective in preventing recurrent strokes after this type of stroke was unclear., Methods: We conducted a multicenter, randomized, double-blind trial of dabigatran at a dose of 150 mg or 110 mg twice daily as compared with aspirin at a dose of 100 mg once daily in patients who had had an embolic stroke of undetermined source. The primary outcome was recurrent stroke. The primary safety outcome was major bleeding., Results: A total of 5390 patients were enrolled at 564 sites and were randomly assigned to receive dabigatran (2695 patients) or aspirin (2695 patients). During a median follow-up of 19 months, recurrent strokes occurred in 177 patients (6.6%) in the dabigatran group (4.1% per year) and in 207 patients (7.7%) in the aspirin group (4.8% per year) (hazard ratio, 0.85; 95% confidence interval [CI], 0.69 to 1.03; P = 0.10). Ischemic strokes occurred in 172 patients (4.0% per year) and 203 patients (4.7% per year), respectively (hazard ratio, 0.84; 95% CI, 0.68 to 1.03). Major bleeding occurred in 77 patients (1.7% per year) in the dabigatran group and in 64 patients (1.4% per year) in the aspirin group (hazard ratio, 1.19; 95% CI, 0.85 to 1.66). Clinically relevant nonmajor bleeding occurred in 70 patients (1.6% per year) and 41 patients (0.9% per year), respectively., Conclusions: In patients with a recent history of embolic stroke of undetermined source, dabigatran was not superior to aspirin in preventing recurrent stroke. The incidence of major bleeding was not greater in the dabigatran group than in the aspirin group, but there were more clinically relevant nonmajor bleeding events in the dabigatran group. (Funded by Boehringer Ingelheim; RE-SPECT ESUS ClinicalTrials.gov number, NCT02239120.)., (Copyright © 2019 Massachusetts Medical Society.)

Background and Purpose: There are no recommendations regarding how to treat cardioembolic recurrent strokes when patients are well anticoagulated. We evaluated the safety and efficacy of combining oral anticoagulation (OAC) with percutaneous left atrial appendage closure (LAAC) in patients with well-anticoagulated atrial fibrillation (AF) with recurrent strokes., Methods: In an explorative, prospective, observational study, LAAC was performed in patients with AF with at least two ischaemic strokes in the previous year, despite good anticoagulation using the Amplatzer Cardiac Plug (St Jude Medical, St Paul, MN, USA) or Amulet Abbot device (Abbot Vascular, Santa Clara, CA, USA). We recorded age, type of AF, CHA 2 DS 2 -VASC and HAS-BLED scores, types of OAC and risk factors. After closure, treatment with aspirin (100 mg/day) was continued for 3 months in combination with indefinite OAC. Clinical status, recurrent embolisms and bleeding complications were recorded during follow-up., Results: A total of 19 patients were included (mean age, 72.1 ± 9.6 years; mean CHA 2 DS 2 -VASC score, 5.3 ± 1.48; mean number of previous strokes, 2.78 ± 1.15). Thirteen had spontaneous echocardiographic contrast and all had dilatation of the left atrium. Eighteen patients had a multilobulated left atrial appendage, 17 with 'chicken-wing' morphology and one patient had a left atrial appendage thrombus. There were no complications during the procedure. Only one patient had a transient ischaemic attack and no major bleeding occurred during a mean follow-up of 17.4 ± 11.5 months., Conclusion: Combination therapy with indefinite OAC plus LAAC in patients with AF with recurrent strokes despite good anticoagulation should be considered in order to prevent a new stroke., (© 2018 EAN.)

Introduction: Isolated acute amnesia is an exceptional presenting symptom of thalamic stroke. This study analyses the clinical profile, the diagnosis, the treatment and the prognosis of these patients., Case Reports: We conducted a retrospective review of the cases of thalamic infarct that presented exclusively as acute amnesia in our university tertiary hospital (n = 3) and a review of similar cases in PubMed (n = 20). 48% presented at least one risk factor of stroke (arterial hypertension, dyslipidaemia, diabetes mellitus, atrial fibrillation or a previous stroke). Amnesia was anterograde in three cases (13%) and global in the remaining 20 (87%). The infarct was detected in neuroimaging studies carried out within the first 24 hours in one patient (4%) and later in all the others; the average time until a diagnosis was established was 11 days. The initial CT scan was normal in five patients (22%). Eight cases (35%) required magnetic resonance imaging to detect the infarct. Of these, four subjects were studied directly with MR imaging. Amnesia clearly improved in eight patients (35%), and three of them (13%) made a full recovery. Fifteen patients (65%) presented mnemonic sequelae that interfered with their functional capacity. The clinical picture lasted less than 24 hours in two patients (9%). None of the cases received revasculisation therapy in the acute phase., Conclusion: The diagnosis of thalamic infarcts that begin exclusively with amnesia is very difficult and this has negative repercussions on their treatment in the acute phase. These infarcts can produce a functionally disabling memory deficit in a high percentage of patients.

Introduction: Cervical artery dissection (CAD) is responsible for up to 20% of all ischaemic strokes in patients younger than 45. The benefits of acute-phase reperfusion therapy in these patients have yet to be confirmed., Methods: We conducted a retrospective review of patients with CAD admitted to a comprehensive stroke centre between 2010 and 2015. We recorded baseline clinical characteristics, treatments, functional outcomes, and mortality., Results: We identified 35 cases of CAD (23 carotid/12 vertebral); mean age was 43.5 ± 9.5 years and 67.7% were men. Ten patients (32.3%) had a history of trauma. The most frequent risk factors were arterial hypertension (29%) and smoking (35.5%). The most common clinical presentation was ischaemic stroke (29 patients, 93.5%). The median baseline National Institute of Health Stroke Scale score was 6 (range, 0-41). The most frequently used diagnostic method was CT angiography (74.2%), followed by MRI (64.5%) and digital subtraction angiography (45.6%). Seven patients (22.6%) were treated with intravenous fibrinolysis and 11 (35.5%) with endovascular treatment plus intravenous fibrinolysis; at 3 months, functional independence (modified Rankin Scale scores 0-2) was achieved by 57.1% and 63.6% of these cases, respectively. One patient died (3.2%)., Conclusions: In our sample, the most common form of presentation of CAD was ischaemic stroke. Reperfusion therapy seems to be a safe and effective option for these patients, and outcomes resemble those of other patients with ischaemic stroke. Larger comparative studies are necessary to better assess response to reperfusion therapy in acute ischaemic stroke., (Copyright © 2016 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background and Purpose: The aim of this study was to describe the clinical and epidemiological characteristics of acute ischaemic stroke (AIS) in patients with atrial fibrillation (AF) previously treated with oral anticoagulants (OACs) according to the type of OAC prescribed. Also, to analyze the outcomes of the patients and the therapeutic approach adopted by the neurologist in the acute phase and for secondary prevention., Methods: We performed a multicenter, observational study based on prospective registries. We included patients with AF treated with OACs admitted for AIS over a 1-year period. Detailed clinical data and functional outcome at 3 months (modified Rankin Scale score) were collected. Patients were divided into two groups according to their pre-AIS anticoagulant therapy: vitamin K antagonists (AIS-VKA) and direct-acting OACs (AIS-DOAC)., Results: We recruited 1240 patients (80.4% AIS-VKA and 19.6% AIS-DOAC). In the AIS-DOAC group, transient ischaemic attack was more frequent (18.1% vs. 10.8%; P = 0.001), symptomatic hemorrhagic transformation was less frequent (1.6% vs. 4.6%; P = 0.035) and hospital stay was shorter (median 6 vs. 7 days; P = 0.03). Intravenous thrombolysis was more commonly used in AIS-VKA (9.2% vs. 1.6%; P < 0.001). There were no differences between the groups with respect to mechanical thrombectomy, mortality and modified Rankin Scale score at 3 months. At 3 months, 54% of patients required a DOAC as antithrombotic treatment for secondary prevention., Conclusions: Patients with AF treated with DOACs who experienced AIS more frequently had transient symptoms (transient ischaemic attack), less symptomatic hemorrhagic transformation and a shorter mean stay than those treated with VKAs. Most patients who had been previously anticoagulated with AIS received long-term treatment with DOACs., (© 2018 EAN.)

Background: In-hospital stroke death rate is an important sanitary issue. Despite advances in the acute phase management of stroke patients, mortality and disability rates remain high. In aging populations and with different mortality between the sexes in general, the study of sex- and age-related differences becomes increasingly relevant for optimization of post-acute clinical care of stroke patients., Methods: We designed a cohort follow-up study with 13,932 consecutive ischemic stroke (IS) patients from 19 Spanish hospitals. Data was obtained from the Spanish Stroke Registry; transient ischemic attacks and ages <18 years were excluded. Patients were organised by age group and sex. We compared female and male patient cohorts within and across age groups univariately and used multivariable logistic regression to adjust for confounders in differential in-hospital mortality., Results: The median (percentiles 2.5 and 97.5%) age was 78 (41-92) years old for women and 71 (41-92) for men. IS women were more likely to be older, to exhibit cardio-embolic aetiology, and less likely to have been admitted to a stroke unit or to have had a stroke code activated. Both pre-stroke modified Rankin Scale and National Institute of Health Stroke Scale (NIHSS) scores at admission increased significantly with age and were higher in women than those in men. Differences in distributions of common risk factors for IS and of in-hospital outcomes between women and men actually changed with patient's age. It is to be noted here that although there were no statistically significant differences (p > 0.05) between the sexes within any age group, in-hospital mortality appeared significantly higher in women than that in men when analysed overall, due to confounding. Death was more closely related to stroke in women than in men and occurred earlier. Although there were some age-specific sex differences between the predictors for in-hospital mortality, stroke severity measured by NIHSS was the main predictor of in-hospital mortality for both sexes. Topographic classifications - partial anterior circulatory infarct and total anterior circulatory infarct - were significant prognostic factors for men aged <60 years and for those in the 60-69 years range respectively., Conclusion: Although most of our findings were consistent with previous studies, it is important to take into account and highlight differences in in-hospital mortality between the sex and age group. Not to account for age-related differences between the sexes can give false results that may mislead management decisions. As most deaths in women were related to stroke, it is important to improve their early management, stroke code activation, access to stroke units and/or revascularisation therapies, especially in the older age groups., (© 2019 S. Karger AG, Basel.)

Objectives: Substantia nigra hyperechogenicity (SN+) detected by transcranial ultrasound (TUS) is useful for Parkinson's disease (PD) diagnosis. Approximately 15% false negative results of unknown significance are reported. However, most TUS studies are transversal, and diagnosis of PD may change during follow-up., Methods: Analysis of our prospective registry of TUS in clinical practice, selecting patients with sufficient bone window, to whom TUS was performed because of suspected PD, and a minimum of 3-year follow-up. Subjects were classified regarding SN echogenicity (SN+/SN-)., Results: 172 patients (122 SN+, 50 SN-), mean age 71 years (25-90), were included. At the end of follow-up, PD diagnosis was retained by 91% SN+ vs. 54% SN- subjects (p < 0.0001), while final diagnosis of atypical parkinsonism (3%SN+ vs. 16%SN-, p:0.0059) was more frequent in SN-. Dopaminergic therapy response was associated with SN+ (88% SN+ vs. 50% SN-, p < 0.0001), as were abnormal DaTSCANs (90%SN+ vs. 56%SN-, p 0.0027). SN echogenicity had 80% sensitivity and 68% specificity for PD diagnosis, while SPECT had 91% and 73%, respectively. SN+ was the only baseline predictor of keeping PD diagnosis at the end of follow-up, with an odds ratio of 12 (95% CI 3-42) (p < 0.001)., Conclusions: In our sample of patients with suspected PD, SN hyperechogenicity predicted PD diagnosis in the long term with a high odds ratio. Conversely, a baseline normal SN echogenicity was associated with a poorer response to PD therapy and change to a different diagnosis from PD. Normal SN appears to be a caveat for clinicians to check for atypical parkinsonism features during follow-up.

Stroke continues to be one of the leading causes of death and disability in the world. One of the main problems with a patient who has survived from a stroke is the possibility of developing a new vascular episode again. Hypertension is the modifiable vascular risk factor with the greatest impact for both primary prevention and stroke recurrence. The Group for the study of Hypertension and Brain (GEHYC) from the Spanish Society of Hypertension aims to spread the importance of strict control of blood pressure in order to prevent cerebrovascular diseases. In this article, this multidisciplinary Group reviews the latest evidence regarding antihypertensive treatment and secondary prevention of ischemic stroke., (Copyright © 2018 SEH-LELHA. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background and Purpose: To investigate the efficacy and safety of mechanical thrombectomy in patients with acute ischemic stroke according to the oral anticoagulation medication taken at the time of stroke onset., Materials and Methods: A retrospective multicenter study of prospectively collected data based on data from the registry the Madrid Stroke Network was performed. We included consecutive patients with acute ischemic stroke treated with mechanical thrombectomy and compared the frequency of intracranial hemorrhage and the modified Rankin Scale (mRS) score at 3 months according to anticoagulation status., Results: The study population comprised 502 patients, of whom 389 (77.5%) were not anticoagulated, 104 (20.7%) were taking vitamin K antagonists, and 9 (1.8%) were taking direct oral anticoagulants. Intravenous thrombolysis had been performed in 59.8% and 15.0% of non-anticoagulated and anticoagulated patients, respectively. Rates of intracranial hemorrhage after treatment were similar between non-anticoagulated and anticoagulated patients, as were rates of recanalization. After 3 months of follow-up, the mRS score was ≤2 in 56.3% and 55.7% of non-anticoagulated and anticoagulated patients, respectively (P=NS). Mortality rates were similar in the two groups (13.1%and12.4%, respectively). Among anticoagulated patients, no differences were found for intracranial bleeding, mRS score, or mortality rates between patients taking vitamin K antagonists and those taking direct oral anticoagulants., Conclusions: Mechanical thrombectomy is feasible in anticoagulated patients with acute ischemic stroke. The outcomes and safety profile are similar to those of patients with no prior anticoagulation therapy., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Introduction: Intracranial haemorrhages (ICH) represent a severe and frequently lethal complication in patients treated with vitamin K antagonists (VKA). The purpose of our study is to describe the factors and clinical features associated with mortality in these patients., Methods: We conducted an observational, retrospective, multi-centre study based on prospective stroke registries in Spain. We included all patients admitted to neurology departments during a one-year period who met the following inclusion criteria: being 18 or older, having a diagnosis of ICH, and receiving VKA. Clinical and radiological parameters and 3-month outcomes were analysed., Results: A total of 235 patients from 21 hospitals were included. Mortality rate at 90 days was 42.6%. Bivariate analysis showed a significant association between death and the following factors: median NIHSS score at admission (5 [IQR = 9] vs 17 [IQR = 14] points, P<.01) and presence of an extensive hemispheric haemorrhage (4.9% vs 35%, P < .01; χ 2 ). Extensive hemispheric haemorrhages, in addition to being the most lethal type, were associated with a shorter time to death (mean of 16.5 days; 95% CI: 7.1-26). A logistic regression model showed that only baseline NIHSS scores independently predicted death (odds ratio=1.13 [95% CI: 1.08-1.17] for each point in the scale)., Conclusion: ICH in patients treated with VKA is associated with high mortality rates; mortality in these patients is mainly and independently associated with the clinical situation at stroke onset., (Copyright © 2016 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.)

Introduction: Patients treated with vitamin K antagonists (VKA) are at increased risk of intracranial haemorrhage (ICH). The purpose of our study was to determine the quality of previous anticoagulation control in patients with VKA-associated ICH., Materials and Methods: We prospectively assessed every consecutive patient admitted to our stroke unit with VKA-associated ICH between 2013 and 2016. Demographic, clinical, and radiological variables, as well as consecutive international normalized ratios (INR) during 7 previous months, were extracted. Time in therapeutic range (TTR), time over range (TOR), time below range (TBR), and percentage of INR within range (PINRR) were calculated., Results and Discussion: The study population comprised 53 patients. Mean age was 79 years; 42% were women. Forty-eight patients had atrial fibrillation (AF) and 5 mechanical prosthetic valves. Therapeutic or infratherapeutic INR on arrival was detected in 64.4% of patients (95% CI 2.7 to 3.2). TTR was 67.8% (95% CI: 60.2 to 75.6 %) and PINRR was 75% (95% CI: 49.9-100). TOR was 17.2% (95% CI: 10.4 to 23.9% ) and TBR was 17% (95% CI: 10.6 to 23.9%)., Conclusion: VKA-associated ICH happens usually in the context of good chronic anticoagulation control. Newer risk assessment methods are required.

Objective: To describe the milestones in the anticoagulant care process of atrial fibrillation patients (AF), as well as quality and safety indicators, in order to establish an integrated care process of these patients in the Community of Madrid., Methods: A consensus conference technique was applied, with the participation of 21 professionals (seven in the Steering Group and 14 known experts), from the specialties of Emergency, Internal Medicine, Cardiology, Neurology, Haematology, Family Medicine, Nursing, and Quality. Hospitals and Primary Care were represented. Milestones, elements and barriers/limitations were agreed upon in the care process of anticoagulated AF patients. A minimum set of indicators were also defined to assess the quality of care., Results: Four milestones (stratification of thromboembolism and bleeding risk, evaluation for anticoagulant treatment, follow-up of direct-acting oral anticoagulants, and follow-up of treatment with vitamin K antagonists) were identified. A total of 14 barriers/limitations were also prioritised. In total, six indicators were defined (two structural-related, two processes-related, and two outcomes-related)., Conclusions: Milestones and critical activities, together with a set of indicators, have been agreed for the development of guidelines with which to achieve a better therapeutic approach for anticoagulated AF patients., (Copyright © 2018 FECA. Publicado por Elsevier España, S.L.U. All rights reserved.)

Introduction: The clinical problems of patients with movement disorders (MD) are complex, and the duration and frequency of face-to-face consultations may be insufficient to meet their needs. We analysed the implementation of an e-mail-based query service for our MD unit's patients and their primary care physicians (PCPs)., Methods: We retrospectively reviewed all consecutive emails sent and received over a period of 4 months, one year after implementation of the e-mail inquiry system. All patients received the during consultations, and PCPs, during scheduled informative meetings. We recorded and later analysed the profile of the questioner, patients' demographic and clinical data, number of queries, reason for consultation, and actions taken., Results: From 1 January 2015 to 30 April 2015, the service received 137 emails from 63 patients (43% male, mean age 71±10.5) diagnosed with Parkinson's disease (76%), atypical parkinsonism (10%), and others (14%); 116 responses were sent. Twenty (32%) emails were written by patients, 38 (60%) by their caregivers, and 5 (8%) by their PCPs. The reasons for consultation were clinical in 50 cases (80%): 16 (32%) described clinical deterioration, 14 (28%) onset of new symptoms, and 20 (40%) side effects or concerns about medications. In 13 cases (20%), the query was bureaucratic: 11 were related to appointments (85%) and 2 were requests for clinical reports (15%). In response, new appointments were scheduled in 9 cases (14%), while the rest of the questions were answered by email. Patients were satisfied overall and the additional care burden on specialists was not excessive., Conclusions: Implementing an e-mail-based consultation system is feasible in MD units. It facilitates both communication between neurologists and patients and continued care in the primary care setting., (Copyright © 2016 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background and Purpose: The aim of this article was to analyze the likelihood of receiving informal care after a stroke and to study the burden and risk of burnout of primary caregivers in Spain., Methods: The CONOCES study is an epidemiological, observational, prospective, multicenter study of patients diagnosed with stroke and admitted to a Stroke Unit in the Spanish healthcare system. At 3 and 12 months post-event, we estimated the time spent caring for the patient and the burden borne by primary caregivers. Several multivariate models were applied to estimate the likelihood of receiving informal caregiving, the burden, and the likelihood of caregivers being at a high risk of burnout., Results: Eighty percent of those still alive at 3 and 12 months poststroke were receiving informal care. More than 40% of those receiving care needed a secondary caregiver at 3 months poststroke. The likelihood of receiving informal care was associated with stroke severity and the individual's health-related quality of life. When informal care was provided, both the burden borne by caregivers and the likelihood of caregivers being at a high risk of burnout was associated with (1) caregiving hours; (2) the patient's health-related quality of life; (3) the severity of the stroke measured at discharge; (4) the patient having atrial fibrillation; and (5) the degree of dependence., Conclusions: This study reveals the heavy burden borne by the caregivers of stroke survivors. Our analysis also identifies explanatory and predictive variables for the likelihood of receiving informal care, caregiver burden, and high risk of burnout., (© 2017 American Heart Association, Inc.)

Background and Purpose: The benefits of mechanical thrombectomy (MT) in basilar artery occlusions (BAO) have not been explored in recent clinical trials. We compared outcomes and procedural complications of MT in BAO with anterior circulation occlusions., Methods: Data from the Madrid Stroke Network multicenter prospective registry were analyzed, including baseline characteristics, procedure times, procedural complications, symptomatic intracranial hemorrhage (SICH), modified Rankin Scale (mRS), and mortality at 3 months., Results: Of 479 patients treated with MT, 52 (11%) had BAO. The onset to reperfusion time lapse was longer in patients with BAO (median (IQR) 385 min (320-540) vs 315 min (240-415), p<0.001), as was the duration of the procedures (100 min (40-130) vs 60 min (39-90), p=0.006). Moreover, the recanalization rate was lower (75% vs 84%, p=0.01). A trend toward more procedural complications was observed in patients with BAO (32% vs 21%, p=0.075). The frequency of SICH was 2% vs 5% (p=0.25). At 3 months, patients with BAO had a lower rate of independence (mRS 0-2) (40% vs 58%, p=0.016) and higher mortality (33% vs 12%, p<0.001). The rate of futile recanalization was 50% in BAO versus 35% in anterior circulation occlusions (p=0.05). Age and duration of the procedure were significant predictors of futile recanalization in BAO., Conclusions: MT is more laborious and shows more procedural complications in BAO than in anterior circulation strokes. The likelihood of futile recanalization is higher in BAO and is associated with greater age and longer procedure duration. A refinement of endovascular procedures for BAO might help optimize the results., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Patients with atrial fibrillation and prior stroke or transient ischemic attack exhibit a very high risk of recurrence. Secondary prevention with oral anticoagulants is mandatory. Overall, clinical guidelines recommend the use of target-specific oral anticoagulants over vitamin K antagonists for secondary prevention of stroke in patients with atrial fibrillation. However, many patients with atrial fibrillation and previous stroke are not receiving the appropriate antithrombotic treatment, perhaps due to the perceived risks of anticoagulation including the risk of hemorrhagic transformation of an ischemic stroke. The ENGAGE AF-TIMI 48 trial showed that although edoxaban 60 mg and warfarin reduced the risk of stroke to a similar extent, edoxaban exhibited a lesser risk of bleeding, particularly intracranial hemorrhage. Importantly, these data were independent of the presence of prior stroke or transient ischemic attack. Therefore, edoxaban can be used in both primary and secondary prevention of stroke in patients with non-valvular atrial fibrillation. The aim of this review was to update the available evidence about edoxaban in the clinical management of secondary prevention in individuals with non-valvular atrial fibrillation.