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Introduction: Cervical artery dissection (CeAD) is considered a non-atherosclerotic arteriopathy, but atherosclerosis of the cervical arteries may co-exist. We explored the frequency and clinical importance of co-existent atherosclerosis in patients with CeAD., Patients and Methods: Single-center exploratory study from the Stroke Center Basel, Switzerland. We re-reviewed duplex ultrasound images at (i) baseline and (ii) last follow-up visit for the presence versus absence of the following atherosclerotic manifestations in the carotid arteries: (i) abnormal carotid intima-media thickness, (ii) plaques, and (iii) atherosclerotic stenosis. We investigated whether CeAD patients with versus without co-existing atherosclerosis differ regarding (a) recurrence of CeAD and (b) occurrence of vascular events (myocardial infarction, peripheral artery disease, or ischemic stroke) using logistic regression with adjustment for age and follow-up time., Results: Among 294 CeAD patients (median age 46 [IQR 37-53], 41.8% women), 35 (12%) had any atherosclerotic signs at baseline. Among 196 patients with available follow-up, another 21/196 (11%) patients developed atherosclerosis during a median follow-up of 55.7 months. Patients with atherosclerosis had decreased odds of recurrent CeADs when compared to patients without atherosclerosis (OR 0.03, 95% CI = 0.00-0.30). During follow-up, 6 (15%) vascular events occurred among 40 CeAD patients with atherosclerosis and 13 (8.5%) among 153 patients without atherosclerosis (OR 1.38, 95% CI = 0.39-4.55, data for 3 patients were missing)., Discussion and Conclusion: Signs of atherosclerosis in the carotid artery were detectable in 12% of CeAD patient at baseline. Additionally, 11% of CeAD patients developed new signs of atherosclerosis within the following 5 years. The presence of atherosclerosis may suggest a lower risk for recurrent CeAD. Whether it might indicate an increased risk for late clinical vascular events deserves further studies., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Data on the impact of competing stroke etiologies in stroke patients with atrial fibrillation (AF) are scarce., Methods: We used prospectively obtained data from an observational registry (Novel-Oral-Anticoagulants-in-Ischemic-Stroke-Patients-(NOACISP)-LONGTERM) of consecutive AF-stroke patients treated with oral anticoagulants. We compared the frequency of (i) the composite outcome of recurrent ischemic stroke (IS), intracerebral hemorrhage (ICH) or all-cause death as well as (ii) recurrent IS alone among AF-stroke patients with versus without competing stroke etiologies according to the TOAST classification. We performed cox proportional hazards regression modeling adjusted for potential confounders. Furthermore, the etiology of recurrent IS was assessed., Results: Among 907 patients (median age 81, 45.6% female), 184 patients (20.3%) had competing etiologies, while 723 (79.7%) had cardioembolism as the only plausible etiology. During 1587 patient-years of follow-up, patients with additional large-artery atherosclerosis had higher rates of the composite outcome (adjusted HR [95% CI] 1.64 [1.11, 2.40], p  = 0.017) and recurrent IS (aHR 2.96 [1.65, 5.35 ], p  < 0.001), compared to patients with cardioembolism as the only plausible etiology. Overall 71 patients had recurrent IS (7.8%) of whom 26.7% had a different etiology than the index IS with large-artery-atherosclerosis (19.7%) being the most common non-cardioembolic cause., Conclusion: In stroke patients with AF, causes other than cardioembolism as competing etiologies were common in index or recurrent IS. Concomitant presence of large-artery-atherosclerosis seems to indicate an increased risk for recurrences suggesting that stroke preventive means might be more effective if they also address competing stroke etiologies in AF-stroke patients., Clinical Trial Registration: NCT03826927.

Background: Data on the safety and effectiveness of once-daily (QD) versus twice-daily (BID) direct oral anticoagulants (DOAC) in comparison to vitamin K antagonists (VKA) and to one another in patients with atrial fibrillation (AF) and recent stroke are scarce., Patients and Methods: Based on prospectively obtained data from the observational registry Novel-Oral-Anticoagulants-in-Ischemic-Stroke-Patients(NOACISP)-LONGTERM (NCT03826927) from Basel, Switzerland, we compared the occurrence of the primary outcome - the composite of recurrent ischemic stroke, major bleeding, and all-cause death - among consecutive AF patients treated with either VKA, QD DOAC, or BID DOAC following a recent stroke using Cox proportional hazards regression including adjustment for potential confounders., Results: We analyzed 956 patients (median age 80 years, 46% female), of whom 128 received VKA (13.4%), 264 QD DOAC (27.6%), and 564 BID DOAC (59%). Over a total follow-up of 1596 patient-years, both QD DOAC and BID DOAC showed a lower hazard for the composite outcome compared to VKA (adjusted HR [95% CI] 0.69 [0.48, 1.01] and 0.66 [0.47, 0.91], respectively). Upon direct comparison, the hazard for the composite outcome did not differ between patients treated with QD versus BID DOAC (adjusted HR [95% CI] 0.94 [0.70, 1.26]). Secondary analyses focusing on the individual components of the composite outcome revealed no clear differences in the risk-benefit profile of QD versus BID DOAC., Discussion and Conclusion: The overall benefit of DOAC over VKA seems to apply to both QD and BID DOAC in AF patients with a recent stroke, without clear evidence that one DOAC dosing regimen is more advantageous than the other., Competing Interests: Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AP: research support from the Swiss Academy of Medical Sciences/Bangerter-Rhyner Foundation and the Swiss Heart Foundation; CT: travel honoraria from Bayer; research support from the Swiss Heart Foundation, Freiwillige Akademische Gesellschaft Basel, Bangerter-Rhyner Foundation, University of Basel, Novartis Foundation for Medical and Biological Research; ST: travel grants from BMS/Pfizer; DJS: research support from the Science Funds and Stroke Funds University Hospital Basel, Swiss National Science Foundation, Swiss Society of Neurology, Bangerter-Rhyner Foundation, Daiichi-Sankyo; Thrombosis research prize from Bayer Foundation; compensation for educational efforts from Stago; advisory board fees from Portola/Alexion, Bayer, Pfizer; NP: research support from the Swiss National Science Foundation, Swiss Heart Foundation; advisory boards for AstraZeneca and Daiichi-Sankyo; speaker honoraria from Vifor and OMPharma Suisse; GMDM: support from the Swiss National Science Foundation; Spezialprogramm Nachwuchsförderung Klinische Forschung, University of Basel; Science Funds (Wissenschaftspool) University Hospital Basel; Swiss Heart Foundation; ProPatient Foundation Basel; Bangerter-Rhyner-Stiftung; Swisslife Jubiläumsstiftung for Medical Research; Swiss Neurological Society; Fondazione Dr Ettore Balli; De Quervain research grant; Thermo Fisher GmbH; travel honoraria by Bayer and BMS/Pfizer; speaker honoraria by Bayer and Medtronic; consultant honoraria by Bayer and Novartis; member of the Steering Committee of PACIFIC Stroke; Industry payments are made to the research fund of the University Hospital Basel; LHB: research support from the Swiss Heart Foundation, Swiss National Science Foundation, Stiftung zur Förderung der gastroenterologischen und allgemeinen klinischen Forschung sowie der medizinischen Bildauswertung; unrestricted research grant from AstraZeneca, personal fees from Amgen, Claret Medical, InnovHeart; HG: research support from the Swiss National Science Foundation; advisory board honoraria from Daiichi-Sankyo; funding for travel from BMS/Pfizer and AbbVie; STE: research support from the Swiss National Science Foundation, Swiss Heart Foundation, Freiwillige Akademische Gesellschaft Basel, Science Fund Rehabilitation, Felix Platter Basel, the Stroke Fund and Scientific Fund of the University Hospital Basel, Pfizer, Daiichi-Sankyo; compensation from Stago for educational material; travel or speaker honoraria from Bayer, Boehringer-Ingelheim, BMS, Daiichi-Sankyo; advisory boards for Bayer, Boehringer-Ingelheim, BMS; PAL: research support from the Swiss National Science Foundation, Swiss Heart Foundation, Research Funds Neurology University Hospital Basel; advisory board compensation from Boehringer-Ingelheim, Bayer, Recordati SA, Daiichi-Sankyo; travel support from Pfizer. The remaining authors declare no relevant conflicts., (© European Stroke Organisation 2022.)

Introduction: The type of antithrombotic treatment in cervical artery dissection patients is still a matter of debate. Most physicians prefer anticoagulants over antiplatelet agents for stroke prevention. However, this approach is not evidence-based and antiplatelets might be as safe and as effective. The 'Biomarkers and Antithrombotic Treatment in Cervical Artery Dissection' ('TREAT-CAD') trial (clinicaltrials.gov: NCT02046460) compares Aspirin to oral anticoagulants (vitamin K antagonists) with regard to efficacy and safety by using both clinical and imaging surrogate outcome measures. TREAT-CAD tests the hypothesis, that aspirin is as safe and effective as vitamin K antagonists., Patients and Methods: TREAD-CAD is a P rospective, R andomised controlled, O pen-labelled, multicentre, non-inferiority trial with B linded assessment of outcome E vents (PROBE-design). Key eligibility criteria are (i) clinical symptoms attributable to cervical artery dissection and (ii) verification of the cervical artery dissection diagnosis by established magnetic resonance imaging criteria. Patients are randomised to receive either Aspirin 300 mg daily or vitamin K antagonists for 90 days., Results: Primary outcomes are assessed at 14 ± 10 days (magnetic resonance imaging and clinical examination) and at 90 ± 30 days (clinical examinations). The primary endpoint is a composite outcome measure - labelled C erebrovascular I schemia, major H emorrhagic events or D eath (CIHD) - and includes (i) occurrence of any stroke (including retinal infarction), (ii) new ischaemic lesions on diffusion-weighted magnetic resonance imaging, (iii) any major extracranial haemorrhage, (iv) any symptomatic intracranial haemorrhage, (v) any new haemorrhagic lesion visible on paramagnetic-susceptible sequences and (vi) death., Discussion: After database closure, (i) central verification of cervical artery dissection diagnosis will be done by two experienced raters, (ii) adjudication of outcome events will be performed by independent adjudication committees, separately for clinical and imaging outcomes. The primary analysis will be done on the per protocol data set. The targeted sample size consists of 169 evaluable patients in the per protocol data set., Conclusion: TREAT-CAD is testing the non-inferiority of Aspirin versus vitamin K antagonists treatment in patients with symptomatic cervical artery dissection by combined clinical and magnetic resonance imaging outcomes., (© European Stroke Organisation 2020.)

Introduction: Cerebral small vessel disease is an important cause for both ischaemic stroke and intracranial haemorrhage. To date, knowledge on the impact of small vessel disease on the clinical course in stroke patients treated with oral anticoagulation for atrial fibrillation is limited., Patients and Methods: Registry-based prospective observational study of 320 patients (aged 78.2 ± 9.2 years) treated with anticoagulation following atrial fibrillation stroke. Patients underwent standardised magnetic-resonance-imaging assessing measures of small vessel disease, including cerebral microbleeds and white matter hyperintensities. Median follow-up was 754 (interquartile range = [708-828]) days. Using adjusted logistic and Cox regression, we assessed the association of imaging measures with clinical outcome including recurrent ischaemic stroke, intracranial haemorrhage and death and assessed disability (modified Rankin Scale)., Results: Overall, recurrent ischaemic stroke was more common than intracranial haemorrhage (22 versus 8, respectively). Cerebral microbleeds were related to an increased risk of the composite endpoint (ischaemic stroke, intracranial haemorrhage, death: odds ratio (OR) 2.05, 95% confidence interval (CI) 1.27-3.31; P  = 0.003), as were white matter hyperintensities (OR 2.00, 95%CI 1.23-3.27, P  = 0.005). This was also true in time-to-event analysis (cerebral microbleeds: HR 2.31, 95%CI 1.39-3.52; P  < 0.001; white matter hyperintensities: HR 1.99, 95%CI 1.20-3.17; P  = 0.007). Both measures were associated with an increased risk for recurrent ischaemic stroke (cerebral microbleeds: HR 4.42, 95%CI 1.07-18.20; P  = 0.04; white matter hyperintensities: HR 5.27, 95%CI 1.08-25.79, P  = 0.04) and intracranial haemorrhage (cerebral microbleeds: HR 2.43, 95%CI 1.04-5.69; P  = 0.04; white matter hyperintensities: HR 2.57, 95%CI 1.11-5.98, P  = 0.03). Furthermore, confluent white matter hyperintensities were associated with increased disability (OR 4.03; 95%CI 2.16-7.52; P  < 0.001) and mortality (HR 1.81, 95%CI 1.04-3.14, P  = 0.04)., Discussion and Conclusion: In atrial fibrillation stroke patients treated with oral anticoagulation, small vessel disease is associated with an unfavourable outcome. The presence of microbleeds indicated a risk higher for recurrent ischaemic stroke than for intracranial haemorrhage., (© European Stroke Organisation 2019.)

Introduction: The potential role of genetic alterations in cervical artery dissection (CeAD) pathogenesis is poorly understood. We aimed to identify pathogenic genetic variants associated with cervical artery dissection by using whole exome sequencing., Patients and Methods: CeAD-patients with either a family history of cervical artery dissection (f-CeAD) or recurrent cervical artery dissection (r-CeAD) from the CeAD-databases of two experienced stroke centres were analysed by whole exome sequencing.Variants with allele frequency <0.05 and classified as pathogenic by predicting algorithms (SIFT or Polyphen-2) or the ClinVar database were explored. First, we analysed a panel of 30 candidate genes associated with arterial dissection (any site) or aneurysm according to the OMIM (online Mendelian Inheritance of Men) database. Second, we performed a genome-wide search for pathogenic variants causing other vascular phenotypes possibly related to cervical artery dissection.Findings were classified as CeAD-causing (pathogenic variants in genes from the arterial dissection or aneurysm panel) or suggestive (pathogenic variants in genes associated with other vascular phenotypes and variants of unknown significance in genes from the arterial dissection or aneurysm panel). All other variants were classified as benign/uncertain., Results: Among 43 CeAD-patients, 28 patients (17 pedigrees) had f-CeAD and 15 had r-CeAD. No CeAD-causing variants were identified in r-CeAD patients. Among f-CeAD-patients, 5/17 pedigrees carried CeAD-causing variants in COL3A1, COL4A1, COL4A3, COL4A4, COL5A1, COL5A2 and FBN1. Suggestive variants in ABCC6, COL3A1, COL5A2, MEF2A, and RNF213 were detected in three pedigrees with f-CeAD and six patients with r-CeAD. Discussion and conclusion: CeAD-causing variants were rare and exclusively found in f-CeAD-patients, suggesting differences between the genetic architectures of f-CeAD and r-CeAD. The identified variants indicate a high genetic heterogeneity of the study sample., (© European Stroke Organisation 2019.)

Aim: To investigate whether lesions on diffusion-weighted imaging (DWI+) after carotid artery stenting (CAS) or endarterectomy (CEA) might provide a surrogate outcome measure for procedural stroke., Materials and Methods: Systematic MedLine® database search with selection of all studies published up to the end of 2016 in which DWI scans were obtained before and within seven days after CAS or CEA. The correlation between the underlying log odds of stroke and of DWI+ across all treatment groups (i.e. CAS or CEA groups) from included studies was estimated using a bivariate random effects logistic regression model. Relative risks of DWI+ and stroke in studies comparing CAS vs. CEA were estimated using fixed-effect Mantel-Haenszel models., Results: We included data of 4871 CAS and 2099 CEA procedures (85 studies). Across all treatment groups (CAS and CEA), the log odds for DWI+ was significantly associated with the log odds for clinically manifest stroke (correlation coefficient 0.61 (95% CI 0.27 to 0.87), p = 0.0012). Across all carotid artery stenting groups, the correlation coefficient was 0.19 (p = 0.074). There were too few CEA groups to reliably estimate a correlation coefficient in this subset alone. In 19 studies comparing CAS vs. CEA, the relative risks (95% confidence intervals) of DWI+ and stroke were 3.83 (3.17-4.63, p < 0.00001) and 2.38 (1.44-3.94, p = 0.0007), respectively., Discussion: This systematic meta-analysis demonstrates a correlation between the occurrence of silent brain infarcts on diffusion-weighted imaging and the risk of clinically manifest stroke in carotid revascularisation procedures., Conclusion: Our findings strengthen the evidence base for the use of DWI as a surrogate outcome measure for procedural stroke in carotid revascularisation procedures. Further randomised studies comparing treatment effects on DWI lesions and clinical stroke are needed to fully establish surrogacy.

Introduction: In patients with stroke attributable to cervical artery dissection, we compared endovascular therapy to intravenous thrombolysis regarding three-month outcome, recanalisation and complications., Materials and Methods: In a multicentre intravenous thrombolysis/endovascular therapy-register-based cohort study, all consecutive cervical artery dissection patients with intracranial artery occlusion treated within 6 h were eligible for analysis. Endovascular therapy patients (with or without prior intravenous thrombolysis) were compared to intravenous thrombolysis patients regarding (i) excellent three-month outcome (modified Rankin Scale score 0-1), (ii) symptomatic intracranial haemorrhage, (iii) recanalisation of the occluded intracranial artery and (iv) death. Upon a systematic literature review, we performed a meta-analysis comparing endovascular therapy to intravenous thrombolysis in cervical artery dissection patients regarding three-month outcome using a random-effects Mantel-Haenszel model., Results: Among 62 cervical artery dissection patients (median age 48.8 years), 24 received intravenous thrombolysis and 38 received endovascular therapy. Excellent three-month outcome occurred in 23.7% endovascular therapy and 20.8% with intravenous thrombolysis patients. Symptomatic intracranial haemorrhage occurred solely among endovascular therapy patients (5/38 patients, 13.2%) while four (80%) of these patients had bridging therapy; 6/38 endovascular therapy and 0/24 intravenous thrombolysis patients died. Four of these 6 endovascular therapy patients had bridging therapy. Recanalisation was achieved in 84.2% endovascular therapy patients and 66.7% intravenous thrombolysis patients (odds ratio 3.2, 95% confidence interval [0.9-11.38]). Sensitivity analyses in a subgroup treated within 4.5 h revealed a higher recanalisation rate among endovascular therapy patients (odds ratio 3.87, 95% confidence interval [1.00-14.95]), but no change in the key clinical findings. In a meta-analysis across eight studies (n = 212 patients), cervical artery dissection patients (110 intravenous thrombolysis and 102 endovascular therapy) showed identical odds for favourable outcome (odds ratio 0.97, 95% confidence interval [0.38-2.44]) among endovascular therapy patients and intravenous thrombolysis patients., Discussion and Conclusion: In this cohort study, there was no clear signal of superiority of endovascular therapy over intravenous thrombolysis in cervical artery dissection patients, which - given the limitation of our sample size - does not prove that endovascular therapy in these patients cannot be superior in future studies. The observation that symptomatic intracranial haemorrhage and deaths in the endovascular therapy group occurred predominantly in bridging patients requires further investigation., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The cause of cervical artery dissection is not well understood. We test the hypothesis that mutations in genes associated with known arterial connective tissue disorders are enriched in patients with familial cervical artery dissection., Patients and Methods: Patient duos from nine pedigrees with familial cervical artery dissection were analyzed by whole exome sequencing. Single nucleotide variants in a panel of 11 candidate genes (ACTA2, MYH11, FBN1, TGFBR1, TGFBR2, TGFB2, COL3A1, COL4A1, SMAD3, MYLK and SLC2A10) were prioritized according to functionality (stop-loss, nonsense, and missense variants with polyphen-2 score ≥0.95). Variants classified as "benign" or "likely benign" in the ClinVar database were excluded from further analysis. For comparison, non-benign stop-loss, nonsense and missense variants with polyphen-2 score ≥0.95 in the same panel of candidate genes were identified in the European non-Finnish population of the ExAC database ( n  = 33,370)., Results: Non-benign Single nucleotide variants in both affected patients were identified in four of the nine cervical artery dissection families (COL3A1; Gly324Ser, FBN1: Arg2554Trp, COL4A1: Pro116Leu, and TGFBR2: Ala292Thr) yielding an allele frequency of 22.2% (4/18). In the comparison group, 1782 variants were present in 33,370 subjects from the ExAC database (allele frequency: 1782/66,740 = 2.7%; p  = 0.0008; odds ratio = 14.2; 95% confidence interval = 3.8-52.9)., Conclusion: Cervical artery dissection families showed enrichment for non-benign variants in genes associated with arterial connective tissue disorders. The observation that findings differed across families indicates genetic heterogeneity of familial cervical artery dissection., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.