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Background: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Results: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20–1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01–1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59–0.67) to 0.65 (95% CI, 0.62–0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=−4.82×10 −3 per year [95% CI, −6.49×10 −3 to −3.14×10 −3 ]; P =1.82×10 −8 ), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86–0.98]; P =0.0041). Conclusions: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.

Background: The “1-3-6-12-day rule” for starting direct oral anticoagulants (DOACs) in patients with nonvalvular atrial fibrillation after acute ischemic stroke or transient ischemic attack recommends timings that may be later than used in clinical practice. We investigated more practical optimal timing of DOAC initiation according to stroke severity. Methods: The combined data of prospective registries in Japan, Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-nonvalvular atrial fibrillation (September 2011 to March 2014) and RELAXED (February 2014 to April 2016) were used. Patients were divided into transient ischemic attack and 3 stroke subgroups by the National Institutes of Health Stroke Scale score: mild (0–7), moderate (8–15), and severe (≥16). The early treatment group was defined as patients starting DOACs earlier than the median initiation day in each subgroup. Outcomes included a composite of recurrent stroke or systemic embolism, ischemic stroke, and severe bleeding within 90 days. Six European prospective registries were used for validation. Results: In the 1797 derivation cohort patients, DOACs were started at median 2 days after transient ischemic attack and 3, 4, and 5 days after mild, moderate, and severe strokes, respectively. Stroke or systemic embolism was less common in Early Group (n=785)—initiating DOACS within 1, 2, 3, and 4 days, respectively—than Late Group (n=1012) (1.9% versus 3.9%; adjusted hazard ratio, 0.50 [95% CI, 0.27–0.89]), as was ischemic stroke (1.7% versus 3.2%, 0.54 [0.27–0.999]). Major bleeding was similarly common in the 2 groups (0.8% versus 1.0%). On validation, both ischemic stroke (2.4% versus 2.2%) and intracranial hemorrhage (0.2% versus 0.6%) were similarly common in Early (n=547) and Late (n=1483) Groups defined using derivation data. Conclusions: In Japanese and European populations, early DOAC initiation within 1, 2, 3, or 4 days according to stroke severity seemed to be feasible to decrease the risk of recurrent stroke or systemic embolism and no increase in major bleeding. These findings support ongoing randomized trials to better establish the optimal timing of DOAC initiation.

Background: Subclinical vascular brain lesions are highly prevalent in elderly patients with stroke. Little is known about predisposing factors and their impact on long-term outcome of patients with stroke at a young age. Methods: We quantified magnetic resonance-defined subclinical vascular brain lesions, including lacunes and white matter hyperintensities, perivascular spaces and cerebral microbleeds, and assessed total small-vessel disease (SVD) score in patients with first-ever acute ischemic stroke aged 18 to 45 years, and followed them up, as part of the multicentre Italian Project on Stroke in Young Adults. The primary end point was a composite of ischemic stroke, transient ischemic attack, myocardial infarction, or other arterial events. We assessed the predictive accuracy of magnetic resonance features and whether the addition of these markers improves outcome prediction over a validated clinical tool, such as the Italian Project on Stroke in Young Adults score. Results: Among 591 patients (males, 53.8%; mean age, 37.5±6.4 years), 117 (19.8%) had subclinical vascular brain lesions. Family history of stroke was associated with lacunes (odds ratio, 2.24 [95% CI, 1.30–3.84]) and total SVD score (odds ratio, 2.06 [95% CI, 1.20–3.53] for score≥1), hypertension with white matter hyperintensities (odds ratio, 2.29 [95% CI, 1.22–4.32]). After a median follow-up of 36.0 months (25th–75th percentile, 38.0), lacunes and total SVD score were associated with primary end point (hazard ratio, 2.13 [95% CI, 1.17–3.90] for lacunes; hazard ratio, 2.17 [95% CI, 1.20–3.90] for total SVD score ≥1), and the secondary end point brain ischemia (hazard ratio, 2.55 [95% CI, 1.36–4.75] for lacunes; hazard ratio, 2.61 [95% CI, 1.42–4.80] for total SVD score ≥1). The predictive performances of the models, including magnetic resonance features were comparable to those of the random model. Adding individual magnetic resonance features to the Italian Project on Stroke in Young Adults score did not improve model prediction. Conclusions: Subclinical vascular brain lesions affect ≈2 in 10 young adults with ischemic stroke. Although lacunes and total SVD score are associated with thrombotic recurrence, they do not improve accuracy of outcome prediction over validated clinical predictors.

Spontaneous cervical artery dissection (sCeAD) is the most common cause of ischemic stroke at a young age, but its pathogenetic mechanism and risk factors are not fully elucidated. It is reasonable to think that bleeding propensity, vascular risk factors such as hypertension and head or neck trauma, and constitutional weakness of the arterial wall together play a role in the pathogenesis of sCeAD. Hemophilia A is known to be an X-linked condition that leads to spontaneous bleeding in various tissues and organs. To date, a few cases of acute arterial dissection in patients with hemophilia have been reported, but the relationship between these two diseases has not been studied so far. In addition, there are no guidelines indicating the best antithrombotic treatment option in these patients. We report the case of a man with hemophilia A who developed sCeAD and transient oculo-pyramidal syndrome and was treated with acetylsalicylic acid. We also review previous published cases of arterial dissection in patients with hemophilia, discussing the potential pathogenetic mechanism underlying this rare association and potential antithrombotic therapeutic options.

Background: Cerebral venous thrombosis (CVT) is an uncommon cause of stroke in young adults. We aimed to determine the impact of age, gender and risk factors (including sex-specific) on CVT onset. Methods: We used data from the BEAST (Biorepository to Establish the Aetiology of Sinovenous Thrombosis), a multicentre multinational prospective observational study on CVT. Composite factors analysis (CFA) was performed to determine the impact on the age of CVT onset in males and females. Results: A total of 1309 CVT patients (75.3% females) aged ⩾18 years were recruited. The overall median (IQR-interquartile range) age for males and females was 46 (35–58) years and 37 (28–47) years ( p Conclusions: Women suffer CVT 9 years earlier in comparison to men. Female patients with multiple (⩾1) risk factors suffer CVT ~12 years earlier compared to those with no identifiable risk factors.

BackgroundPatients with stroke secondary to isolated anterior cerebral artery (ACA) occlusions have poor outcomes. Whether tandem occlusions (TO) of the extracranial internal carotid (ICA) and the ACA carry even worse outcomes that remain unknown.MethodsPatients with TO involving ICA and ACA occlusions were identified from 14 participating centers from the EndoVascular treatment And ThRombolysis in Ischemic Stroke Patients (EVATRISP) project which is a multicenter, observational, cohort study with prospective accrual of data followed by retrospective data analysis. Patients with isolated ACA stroke served as controls.ResultsIncluded were 92 patients with isolated ACA and 16 patients with ICA-ACA TO stroke. On univariate analyses, patients with TO had more severe strokes on admission [median NIHSS (IQR) 13.5 (9–21) vs. 8 (5–12), p = 0.003] and were more often treated with thrombectomy (81 vs. 40%, p = 0.002). Mortality rates were higher among TO patients (31 vs. 11%, p = 0.03). Rates of favorable functional outcomes were numerically lower among TO patients (38 vs. 60%) but the difference was not statistically significant (p = 0.09). On multivariate analyses, the presence of TO did not modify the chances for favorable outcomes.ConclusionTO stroke with ICA and isolated ACA involvement is rare and results in more severe initial neurological deficits and higher mortality compared to those seen in patients with isolated ACA stroke.

Background: The probability to receive intravenous thrombolysis (IVT) for treatment of acute ischemic stroke declines with increasing age and is consequently the lowest in very elderly patients. Safety concerns likely influence individual IVT treatment decisions. Using data from a large IVT registry, we aimed to provide more evidence on safety of IVT in the very elderly. Methods: In this prospective multicenter study from the TRISP (Thrombolysis in Ischemic Stroke Patients) registry, we compared patients ≥90 years with those Results: Of 16 974 eligible patients, 976 (5.7%) were ≥90 years. Patients ≥90 years had higher median National Institutes of Health Stroke Scale on admission (12 versus 8) and were more often dependent prior to the index stroke (prestroke modified Rankin Scale score of ≥3; 45.2% versus 7.4%). Occurrence of symptomatic intracranial hemorrhage (5.7% versus 4.4%, odds ratio adjusted 1.14 [0.83–1.57]) did not differ significantly between both groups. However, the probability of death (odds ratio adjusted 3.77 [3.14–4.53]) and poor functional outcome (odds ratio adjusted 2.63 [2.13–3.25]) was higher in patients aged ≥90 years. Results for the sample of centenarians (n=21) were similar. Conclusions: The probability of symptomatic intracranial hemorrhage after IVT in very elderly patients with stroke did not exceed that of their younger counterparts. The higher probability of death and poor functional outcome during follow-up in the very elderly seems not to be related to IVT treatment. Very high age itself should not be a reason to withhold IVT.

ObjectiveTo investigate the age-dependent impact of traditional stroke risk factors on the occurrence of intracerebral haemorrhage (ICH).MethodsWe performed a case–control analysis, comparing consecutive patients with ICH with age-matched and sex-matched stroke-free controls, enrolled in the setting of the Multicenter Study on Cerebral Hemorrhage in Italy (MUCH-Italy) between 2002 and 2014 by multivariable logistic regression model within subgroups stratified by age quartiles (Q1–Q4).ResultsWe analysed 3492 patients and 3492 controls. The impact of untreated hypertension on the risk of ICH was higher in the lower than in the upper age quartile (OR 11.64, 95% CI 7.68 to 17.63 in Q1 vs OR 6.05, 95% CI 3.09 to 11.85 in Q4 with intermediate ORs in Q2 and Q3), while the opposite trend was observed for untreated hypercholesterolaemia (OR 0.63, 95% CI 0.45 to 0.97 in Q1 vs OR 0.36, 95% CI 0.26 to 0.56 in Q4 with intermediate ORs in Q2 and Q3). The effect of untreated diabetes and excessive alcohol intake was detected only in the older age group (OR 3.63, 95% CI 1.22 to 10.73, and OR 1.69, 95% CI 1.13 to 2.51, respectively).ConclusionsOur findings provide evidence of age-dependent differences in the effects of susceptibility factors on the risk of ICH.

Supplemental Digital Content is available in the text., Background and Purpose: Timely reperfusion is an important goal in treatment of eligible patients with acute ischemic stroke. However, during the coronavirus disease 2019 (COVID-19) pandemic, prehospital and in-hospital emergency procedures faced unprecedented challenges, which might have caused a decline in the number of acute reperfusion therapy applied and led to a worsening of key quality measures for this treatment during lockdown. Methods: This prospective multicenter cohort study used data from the TRISP (Thrombolysis in Ischemic Stroke Patients) registry of patients with acute ischemic stroke treated with reperfusion therapies, that is, intravenous thrombolysis or endovascular therapy. We compared prehospital and in-hospital time-based performance measures (stroke-onset-to-admission, admission-to-treatment, admission-to-image, and image-to-treatment time) during the first 6 weeks after announcement of lockdown (lockdown period) with the same period in 2019 (reference period). Secondary outcomes included stroke severity (National Institutes of Health Stroke Scale) after 24 hours and occurrence of symptomatic intracranial hemorrhage (following the ECASS [European-Australasian Acute Stroke Study]-II criteria). Results: Across 20 stroke centers, 540 patients were treated with intravenous thrombolysis/endovascular therapy during lockdown period compared with 578 patients during reference period (−7% [95% CI, 5%–9%]). Performance measures did not change significantly during the lockdown period (2020/2019 minutes median: onset-to-admission 133/145; admission-to-treatment 51/48). Same was true for admission-to-image (20/19) and image-to-treatment (31/30) time in patients with available time of first image (n=871, 77.9%). Median National Institutes of Health Stroke Scale on admission (2020/2019: 11/11) and after 24 hours (2020/2019: 6/5) and percentage of symptomatic intracranial hemorrhage (2020/2019: 6.2/5.7) did not differ significantly between both periods. Conclusions: The COVID-19 pandemic lockdown resulted in a mild decline in the number of patients with stroke treated with acute reperfusion therapies. More importantly, the solid stability of key quality performance measures between the 2020 and 2019 period may indicate resilience of acute stroke care service during the lockdown, at least in well-established European stroke centers.

Background and Purpose: Clinical trials on stroke prevention in patients with atrial fibrillation have consistently shown clinical benefit from either warfarin or non–vitamin K antagonist oral anticoagulants (NOACs). NOAC-treated patients have consistently reported to be at lower risk for intracerebral hemorrhage (ICH) than warfarin-treated patients. The aims of this prospective, multicenter, multinational, unmatched, case-control study were (1) to investigate for risk factors that could predict ICH occurring in patients with atrial fibrillation during NOAC treatment and (2) to evaluate the role of CHA 2 DS 2 -VASc and HAS-BLED scores in the same setting. Methods: Cases were consecutive patients with atrial fibrillation who had ICH during NOAC treatment. Controls were consecutive patients with atrial fibrillation who did not have ICH during NOAC treatment. As within the CHA 2 DS 2 -VASc and HAS-BLED scores there are some risk factors in common, several multivariable logistic regression models were performed to identify independent prespecified predictors for ICH events. Results: Four hundred nineteen cases (mean age, 78.8±8.1 years) and 1526 controls (mean age, 76.0±10.3 years) were included in the study. From the different models performed, independent predictors of ICH were increasing age, concomitant use of antiplatelet agents, active malignancy, high risk of fall, hyperlipidemia, low clearance of creatinine, peripheral artery disease, and white matter changes. Low doses of NOACs (given according to label or not) and congestive heart failure were inversely associated with the risk of ICH. HAS-BLED and CHA 2 DS 2 -VASc scores performed poorly in predicting ICH with areas under the curves of 0.496 (95% CI, 0.468–0.525) and 0.530 (95% CI, 0.500–0.560), respectively. Conclusions: Several risk factors were associated to ICH in patients treated with NOACs for stroke prevention but not HAS-BLED and CHA 2 DS 2 -VASc scores.

Background: In patients with atrial fibrillation who suffered an ischemic stroke while on treatment with nonvitamin K antagonist oral anticoagulants, rates and determinants of recurrent ischemic events and major bleedings remain uncertain. Methods: This prospective multicenter observational study aimed to estimate the rates of ischemic and bleeding events and their determinants in the follow-up of consecutive patients with atrial fibrillation who suffered an acute cerebrovascular ischemic event while on nonvitamin K antagonist oral anticoagulant treatment. Afterwards, we compared the estimated risks of ischemic and bleeding events between the patients in whom anticoagulant therapy was changed to those who continued the original treatment. Results: After a mean follow-up time of 15.0±10.9 months, 192 out of 1240 patients (15.5%) had 207 ischemic or bleeding events corresponding to an annual rate of 13.4%. Among the events, 111 were ischemic strokes, 15 systemic embolisms, 24 intracranial bleedings, and 57 major extracranial bleedings. Predictive factors of recurrent ischemic events (strokes and systemic embolisms) included CHA 2 DS 2 -VASc score after the index event (odds ratio [OR], 1.2 [95% CI, 1.0–1.3] for each point increase; P =0.05) and hypertension (OR, 2.3 [95% CI, 1.0–5.1]; P =0.04). Predictive factors of bleeding events (intracranial and major extracranial bleedings) included age (OR, 1.1 [95% CI, 1.0–1.2] for each year increase; P =0.002), history of major bleeding (OR, 6.9 [95% CI, 3.4–14.2]; P =0.0001) and the concomitant administration of an antiplatelet agent (OR, 2.8 [95% CI, 1.4–5.5]; P =0.003). Rates of ischemic and bleeding events were no different in patients who changed or not changed the original nonvitamin K antagonist oral anticoagulants treatment (OR, 1.2 [95% CI, 0.8–1.7]). Conclusions: Patients suffering a stroke despite being on nonvitamin K antagonist oral anticoagulant therapy are at high risk of recurrent ischemic stroke and bleeding. In these patients, further research is needed to improve secondary prevention by investigating the mechanisms of recurrent ischemic stroke and bleeding.

As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic spreads, it is becoming increasingly evident that coronavirus disease 2019 (COVID-19) is not limited to the respiratory system, and that other organs can be affected. In particular, virus-related neurological manifestations are being reported more and more frequently in the scientific literature. In this article, we review the literature on the association between COVID-19 and neurological manifestations, present evidence from preclinical research suggesting that SARS-CoV-2 could be responsible for many of these manifestations, and summarize the biological pathways that could underlie each neurological symptom. Understanding the mechanisms that lead to neurological manifestations in patients with COVID-19 and how these manifestations correlate with clinical outcomes will be instrumental in guiding the optimal use of targeted therapeutic strategies., In this Perspective, Pezzini and Padovani critique the evidence for neurological manifestations of COVID-19, including epidemiological, neuropathological and neuroimaging data, and highlight the need for further work to establish whether SARS-CoV-2 is responsible for these symptoms.

Introduction The aim of this study in patients with acute posterior ischaemic stroke (PS) and atrial fibrillation (AF) was to evaluate (1) the risks of recurrent ischaemic event and severe bleeding and (2) these risks in relation with oral anticoagulant therapy (OAT) and its timing. Materials and Methods Patients with PS were prospectively included; the outcome events of these patients were compared with those of patients with anterior stroke (AS) which were taken from previous registries. The primary outcome was the composite of stroke recurrence, transient ischaemic attack, symptomatic systemic embolism, symptomatic cerebral bleeding and major extracranial bleeding occurring within 90 days from acute stroke. Results A total of 2470 patients were available for the analysis: 473 (19.1%) with PS and 1997 (80.9%) with AS. Over 90 days, 213 (8.6%) primary outcome events were recorded: 175 (8.7%) in patients with AS and 38 (8.0%) in those with PS. In patients who initiated OAT within 2 days, the primary outcome occurred in 5 out of 95 patients (5.3%) with PS compared to 21 out of 373 patients (4.3%) with AS (OR 1.07; 95% CI 0.39–2.94). In patients who initiated OAT between days 3 and 7, the primary outcome occurred in 3 out of 103 patients (2.9%) with PS compared to 26 out of 490 patients (5.3%) with AS (OR 0.54; 95% CI 0.16–1.80). Discussion our findings suggest that, when deciding the time to initiate oral anticoagulation, the location of stroke, either anterior or posterior, does not predict the risk of outcome events. Conclusions Patients with PS or AS and AF appear to have similar risks of ischaemic or haemorrhagic events at 90 days with no difference concerning the timing of initiation of OAT.

ObjectiveTo evaluate whether pretreatment with metformin (MET) is associated with less stroke severity and better outcome after IV thrombolysis (IVT), we analyzed a cohort of 1,919 patients with stroke with type 2 diabetes mellitus in a multicenter exploratory analysis.MethodsData from patients with diabetes and ischemic stroke treated with IVT were collected within the European Thrombolysis in Ischemic Stroke Patients (TRISP) collaboration. We applied propensity score matching (PSM) to obtain balanced baseline characteristics of patients treated with and without MET.ResultsOf 1,919 patients with stroke with type 2 diabetes who underwent IVT, 757 (39%) had received MET before stroke (MET+), whereas 1,162 (61%) had not (MET−). MET+ patients were younger with a male preponderance. Hypercholesterolemia and pretreatment with statins, antiplatelets, or antihypertensives were more common in the MET+ group. After PSM, the 2 groups were well balanced with respect to demographic and clinical aspects. Stroke severity on admission (NIH Stroke Scale 10.0 ± 6.7 vs 11.3 ± 6.5), 3-month degree of independence on modified Rankin Scale (2 [interquartile range (IQR) 1.0–4.0] vs 3 [IQR 1.0–4.0]), as well as mortality (12.5% vs 18%) were significantly lower in the MET+ group. The frequency of symptomatic intracerebral hemorrhages did not differ between groups. HbA1c levels were well-balanced between the groups.ConclusionsPatients with stroke and diabetes on treatment with MET receiving IVT had less severe strokes on admission and a better functional outcome at 3 months. This suggests a protective effect of MET resulting in less severe strokes as well as beneficial thrombolysis outcome.

Introduction Alterations in haemoglobin levels are frequent in stroke patients. The prognostic meaning of anaemia and polyglobulia on outcomes in patients treated with intravenous thrombolysis is ambiguous. Patients and methods In this prospective multicentre, intravenous thrombolysis register-based study, we compared haemoglobin levels on hospital admission with three-month poor outcome (modified Rankin Scale 3–6), mortality and symptomatic intracranial haemorrhage (European Cooperative Acute Stroke Study II-criteria (ECASS-II-criteria)). Haemoglobin level was used as continuous and categorical variable distinguishing anaemia (female: 15.5 g/dl; male: >17 g/dl). Anaemia was subdivided into mild and moderate/severe (female/male: Results Among 6866 intravenous thrombolysis-treated stroke patients, 5448 (79.3%) had normal haemoglobin level, 1232 (17.9%) anaemia – of those 903 (13.2%) had mild and 329 (4.8%) moderate/severe anaemia – and 186 (2.7%) polyglobulia. Anaemia was associated with poor outcome (ORadjusted 1.25 (1.05–1.48)) and mortality (ORadjusted 1.58 (1.27–1.95)). In anaemia subgroups, both mild and moderate/severe anaemia independently predicted poor outcome (ORadjusted 1.29 (1.07–1.55) and 1.48 (1.09–2.02)) and mortality (ORadjusted 1.45 (1.15–1.84) and ORadjusted 2.00 (1.46–2.75)). Each haemoglobin level decrease by 1 g/dl independently increased the risk of poor outcome (ORadjusted 1.07 (1.02–1.11)) and mortality (ORadjusted 1.08 (1.02–1.15)). Anaemia was not associated with occurrence of symptomatic intracranial haemorrhage. Polyglobulia did not change any outcome. Discussion The more severe the anaemia, the higher the probability of poor outcome and death. Severe anaemia might be a target for interventions in hyperacute stroke. Conclusion Anaemia on admission, but not polyglobulia, is a strong and independent predictor of poor outcome and mortality in intravenous thrombolysis-treated stroke patients.

Long-term consequences of cervical artery dissection (CeAD), a major cause of ischemic stroke in young people, have been poorly investigated. The Italian Project on Stroke at Young Age - Cervical Artery Dissection (IPSYS CeAD) project is a multicenter, hospital-based, consecutively recruiting, observational, cohort study aimed to address clinically important questions about long-term outcome of CeAD patients, which are not covered by other large-scale registries. Patients with radiologically diagnosed CeAD were consecutively included in the registry. Baseline demographic and clinical variables, as well as information on risk factors, were systematically collected for each eligible patient. Follow-up evaluations were conducted between 3 and 6 months after the initial event (t1) and then annually (t2 at 1 year, t3 at 2 years , and so on), in order to assess outcome events (long-term recurrent CeAD, any fatal/nonfatal ischemic stroke, transient ischemic attack (TIA), or other arterial thrombotic event, and death from any cause). Between 2000 and 2019, data from 1530 patients (age at diagnosis, 47.2 ± 11.5 years; women, 660 [43.1%]) have been collected at 39 Italian neurological centers. Dissection involved a single vessel in 1308 (85.5%) cases and caused brain ischemia in 1303 (85.1%) (190 TIA/1113 ischemic stroke). Longitudinal data are available for 1414 (92.4%) patients (median follow-up time in patients who did not experience recurrent events, 36.0 months [25th to 75th percentile, 63.0]). The collaborative IPSYS CeAD effort will provide novel information on the long-term outcome of CeAD patients. This could allow for tailored treatment approaches based on patients' individual characteristics.

Background and Purpose— We investigated whether subarachnoid extension (SAHE) of intracerebral hemorrhage (ICH) is associated with hematoma expansion (HE). Methods— Retrospective analysis of patients with primary spontaneous ICH admitted at 3 academic hospitals in Italy. The study population was divided into a development and a replication cohort. SAHE was rated on baseline noncontrast computed tomography by investigators blinded to clinical data. The main outcome of interest was HE, defined as ICH growth >33% mL and/or >6 mL. Predictors of HE were explored with multivariable logistic regression stratified by ICH location (lobar versus nonlobar). Results— A total of 360 and 192 patients were included in the development and replication cohort, respectively. SAHE was identified with good interrater reliability ( K =0.82), and its frequency was 27.8% in the development and 24.5% in the replication cohort. In univariate analysis, HE was more common in patients with SAHE (52.0% versus 27.3%; P P =0.001) whereas there was no association with HE in nonlobar ICH (odds ratio, 0.55 [95% CI, 0.17–1.84]; P =0.334). The increased risk of HE in lobar ICH with SAHE was confirmed in the replication cohort (odds ratio, 3.46 [95% CI, 1.07–11.20]; P =0.038). Conclusions— SAHE predicts HE in lobar ICH. This may improve the stratification of HE risk in clinical practice or future trials targeting HE. Further research is needed to confirm our findings and characterize the underlying biological mechanisms.

ObjectiveTo explore the impact of antithrombotic therapy discontinuation in the postacute phase of cervical artery dissection (CeAD) on the mid-term outcome of these patients.MethodsIn a cohort of consecutive patients with first-ever CeAD, enrolled in the setting of the multicentre Italian Project on Stroke in Young Adults Cervical Artery Dissection, we compared postacute (beyond 6 months since the index CeAD) outcomes between patients who discontinued antithrombotic therapy and patients who continued taking antithrombotic agents during follow-up. Primary outcome was a composite of ischaemic stroke and transient ischaemic attack. Secondary outcomes were (1) Brain ischaemia ipsilateral to the dissected vessel and (2) Recurrent CeAD. Associations with the outcome of interest were assessed by the propensity score (PS) method.ResultsOf the 1390 patients whose data were available for the outcome analysis (median follow-up time in patients who did not experience outcome events, 36.0 months (25th–75th percentile, 62.0)), 201 (14.4%) discontinued antithrombotic treatment. Primary outcome occurred in 48 patients in the postacute phase of CeAD. In PS-matched samples (201 vs 201), the incidence of primary outcomes among patients taking antithrombotics was comparable with that among patients who discontinued antithrombotics during follow-up (5.0% vs 4.5%; p(log rank test)=0.526), and so was the incidence of the secondary outcomes ipsilateral brain ischaemia (4.5% vs 2.5%; p(log rank test)=0.132) and recurrent CeAD (1.0% vs 1.5%; p(log rank test)=0.798).ConclusionsDiscontinuation of antithrombotic therapy in the postacute phase of CeAD does not appear to increase the risk of brain ischaemia during follow-up.

Purpose Intracerebral hemorrhage (ICH) is an uncommon but deadly event in patients with COVID-19 and its imaging features remain poorly characterized. We aimed to describe the clinical and imaging features of COVID-19-associated ICH. Methods Multicenter, retrospective, case–control analysis comparing ICH in COVID-19 patients (COV19 +) versus controls without COVID-19 (COV19 −). Clinical presentation, laboratory markers, and severity of COVID-19 disease were recorded. Non-contrast computed tomography (NCCT) markers (intrahematoma hypodensity, heterogeneous density, blend sign, irregular shape fluid level), ICH location, and hematoma volume (ABC/2 method) were analyzed. The outcome of interest was ultraearly hematoma growth (uHG) (defined as NCCT baseline ICH volume/onset-to-imaging time), whose predictors were explored with multivariable linear regression. Results A total of 33 COV19 + patients and 321 COV19 − controls with ICH were included. Demographic characteristics and vascular risk factors were similar in the two groups. Multifocal ICH and NCCT markers were significantly more common in the COV19 + population. uHG was significantly higher among COV19 + patients (median 6.2 mL/h vs 3.1 mL/h, p = 0.027), and this finding remained significant after adjustment for confounding factors (systolic blood pressure, antiplatelet and anticoagulant therapy), in linear regression (B(SE) = 0.31 (0.11), p = 0.005). This association remained consistent also after the exclusion of patients under anticoagulant treatment (B(SE) = 0.29 (0.13), p = 0.026). Conclusions ICH in COV19 + patients has distinct NCCT imaging features and a higher speed of bleeding. This association is not mediated by antithrombotic therapy and deserves further research to characterize the underlying biological mechanisms.

Objective Cerebral venous thrombosis (CVT) is an uncommon form of stroke affecting mostly young individuals. Although genetic factors are thought to play a role in this cerebrovascular condition, its genetic etiology is not well understood. Methods A genome-wide association study was performed to identify genetic variants influencing susceptibility to CVT. A 2-stage genome-wide study was undertaken in 882 Europeans diagnosed with CVT and 1,205 ethnicity-matched control subjects divided into discovery and independent replication datasets. Results In the overall case-control cohort, we identified highly significant associations with 37 single nucleotide polymorphisms (SNPs) within the 9q34.2 region. The strongest association was with rs8176645 (combined p = 9.15 x 10(-24); odds ratio [OR] = 2.01, 95% confidence interval [CI] = 1.76-2.31). The discovery set findings were validated across an independent European cohort. Genetic risk score for this 9q34.2 region increases CVT risk by a pooled estimate OR = 2.65 (95% CI = 2.21-3.20, p = 2.00 x 10(-16)). SNPs within this region were in strong linkage disequilibrium (LD) with coding regions of the ABO gene. The ABO blood group was determined using allele combination of SNPs rs8176746 and rs8176645. Blood groups A, B, or AB, were at 2.85 times (95% CI = 2.32-3.52, p = 2.00 x 10(-16)) increased risk of CVT compared with individuals with blood group O. Interpretation We present the first chromosomal region to robustly associate with a genetic susceptibility to CVT. This region more than doubles the likelihood of CVT, a risk greater than any previously identified thrombophilia genetic risk marker. That the identified variant is in strong LD with the coding region of the ABO gene with differences in blood group prevalence provides important new insights into the pathophysiology of CVT. ANN NEUROL 2021

International audience; The aim of the present European Stroke Organisation guideline is to provide clinically useful evidence-based recommendations on the management of extracranial artery dissection (EAD) and intracranial artery dissection (IAD). EAD and IAD represent leading causes of stroke in the young, but are uncommon in the general population, thus making it challenging to conduct clinical trials and large observational studies. The guidelines were prepared following the Standard Operational Procedure for European Stroke Organisation guidelines and according to GRADE methodology. Our four recommendations result from a thorough analysis of the literature comprising two randomized clinical trials (RCTs) comparing anticoagulants to anti-platelets in the acute phase of ischemic stroke and twenty-six comparative observational studies. In EAD patients with acute ischemic stroke we recommend using intravenous thrombolysis (IVT) with alteplase within 4.5 hours of onset if standard inclusion/exclusion criteria are met, and mechanical thrombectomy in patients with large vessel occlusion of the anterior circulation. We further recommend early endovascular or surgical intervention for IAD patients with subarachnoid hemorrhage (SAH). Based on evidence from two phase 2 RCTs that have shown no difference between the benefits and risks of anticoagulants versus anti-platelets in the acute phase of symptomatic EAD, we strongly recommend that clinicians can prescribe either option. In post-acute EAD patients with residual stenosis or dissecting aneurysms and in symptomatic IAD patients with an intracranial dissecting aneurysm and isolated headache, there is insufficient data to provide a recommendation on the benefits and risks of endovascular/surgical treatment. Finally, nine expert consensus statements, adopted by 8 to 11 of the 11 experts involved, propose guidance for clinicians when the quality of evidence was too low to provide recommendations. Some of these pertain to the management of IAD (use of IVT, endovascular treatment, and antiplatelets versus anticoagulation in IAD with ischemic stroke and use of endovascular or surgical interventions for IAD with headache only). Other expert consensus statements address the use of direct anticoagulants and dual antiplatelet therapy in EAD-related cerebral ischemia, endovascular treatment of the EAD/IAD lesion and multidisciplinary assessment of the best therapeutic approaches in specific situations.

Background and PURPOSE Migraine has been shown to increase cerebral excitability, promote rapid infarct expansion into tissue with perfusion deficits, and result in larger infarcts in animal models of focal cerebral ischemia. Whether these effects occur in humans has never been properly investigated. METHODS In a series of consecutive patients with acute ischemic stroke, enrolled in the setting of the Italian Project on Stroke at Young Age, we assessed acute as well as chronic infarct volumes by volumetric magnetic resonance imaging, and compared these among different subgroups identified by migraine status. RESULTS A cohort of 591 patients (male, 53.8%; mean age, 37.5±6.4 years) qualified for the analysis. Migraineurs had larger acute infarcts than non-migraineurs (median, 5.9 cm3 [interquartile range (IQR), 1.4 to 15.5] vs. 2.6 cm3 [IQR, 0.8 to 10.1], P

Background and Purpose— Despite treatment with oral anticoagulants, patients with nonvalvular atrial fibrillation (AF) may experience ischemic cerebrovascular events. The aims of this case-control study in patients with AF were to identify the pathogenesis of and the risk factors for cerebrovascular ischemic events occurring during non–vitamin K antagonist oral anticoagulants (NOACs) therapy for stroke prevention. Methods— Cases were consecutive patients with AF who had acute cerebrovascular ischemic events during NOAC treatment. Controls were consecutive patients with AF who did not have cerebrovascular events during NOACs treatment. Results— Overall, 713 cases (641 ischemic strokes and 72 transient ischemic attacks; median age, 80.0 years; interquartile range, 12; median National Institutes of Health Stroke Scale on admission, 6.0; interquartile range, 10) and 700 controls (median age, 72.0 years; interquartile range, 8) were included in the study. Recurrent stroke was classified as cardioembolic in 455 cases (63.9%) according to the A-S-C-O-D (A, atherosclerosis; S, small vessel disease; C, cardiac pathology; O, other causes; D, dissection) classification. On multivariable analysis, off-label low dose of NOACs (odds ratio [OR], 3.18; 95% CI, 1.95–5.85), atrial enlargement (OR, 6.64; 95% CI, 4.63–9.52), hyperlipidemia (OR, 2.40; 95% CI, 1.83–3.16), and CHA 2 DS 2 -VASc score (OR, 1.72 for each point increase; 95% CI, 1.58–1.88) were associated with ischemic events. Among the CHA 2 DS 2 -VASc components, age was older and presence of diabetes mellitus, congestive heart failure, and history of stroke or transient ischemic attack more common in patients who had acute cerebrovascular ischemic events. Paroxysmal AF was inversely associated with ischemic events (OR, 0.45; 95% CI, 0.33–0.61). Conclusions— In patients with AF treated with NOACs who had a cerebrovascular event, mostly but not exclusively of cardioembolic pathogenesis, off-label low dose, atrial enlargement, hyperlipidemia, and high CHA 2 DS 2 -VASc score were associated with increased risk of cerebrovascular events.

Background and Purpose— Bridging therapy with low-molecular-weight heparin reportedly leads to a worse outcome for acute cardioembolic stroke patients because of a higher incidence of intracerebral bleeding. However, this practice is common in clinical settings. This observational study aimed to compare (1) the clinical profiles of patients receiving and not receiving bridging therapy, (2) overall group outcomes, and (3) outcomes according to the type of anticoagulant prescribed. Methods— We analyzed data of patients from the prospective RAF and RAF-NOACs studies. The primary outcome was defined as the composite of ischemic stroke, transient ischemic attack, systemic embolism, symptomatic cerebral bleeding, and major extracerebral bleeding observed at 90 days after the acute stroke. Results— Of 1810 patients who initiated oral anticoagulant therapy, 371 (20%) underwent bridging therapy with full-dose low-molecular-weight heparin. Older age and the presence of leukoaraiosis were inversely correlated with the use of bridging therapy. Forty-two bridged patients (11.3%) reached the combined outcome versus 72 (5.0%) of the nonbridged patients ( P =0.0001). At multivariable analysis, bridging therapy was associated with the composite end point (odds ratio, 2.3; 95% CI, 1.4–3.7; P P =0.005) and hemorrhagic (odds ratio, 2.4; 95% CI, 1.2–4.9; P =0.01) end points separately. Conclusions— Our findings suggest that patients receiving low-molecular-weight heparin have a higher risk of early ischemic recurrence and hemorrhagic transformation compared with nonbridged patients.

Introduction To describe clinical, neuroimaging, and laboratory features of a large cohort of Italian patients with reversible cerebral vasoconstriction syndrome. Methods In the setting of the multicenter Italian Project on Stroke at Young Age (IPSYS), we retrospectively enrolled patients with a diagnosis of definite reversible cerebral vasoconstriction syndrome according to the International Classification of Headache Disorders (ICHD)-3 beta criteria (6.7.3 Headache attributed to reversible cerebral vasoconstriction syndrome, imaging-proven). Clinical manifestations, neuroimaging, treatment, and clinical outcomes were evaluated in all patients. Characteristics of reversible cerebral vasoconstriction syndrome without typical causes (“idiopathic reversible cerebral vasoconstriction syndrome”) were compared with those of reversible cerebral vasoconstriction syndrome related to putative causative factors (“secondary reversible cerebral vasoconstriction syndrome”). Results A total of 102 patients (mean age, 47.2 ± 13.9 years; females, 85 [83.3%]) qualified for the analysis. Thunderclap headache at presentation was reported in 69 (67.6%) patients, and it typically recurred in 42 (60.9%). Compared to reversible cerebral vasoconstriction syndrome cases related to putative etiologic conditions (n = 21 [20.6%]), patients with idiopathic reversible cerebral vasoconstriction syndrome (n = 81 [79.4%]) were significantly older (49.2 ± 13.9 vs. 39.5 ± 11.4 years), had more frequently typical thunderclap headache (77.8% vs. 28.6%) and less frequently neurological complications (epileptic seizures, 11.1% vs. 38.1%; cerebral infarction, 6.1% vs. 33.3%), as well as concomitant reversible brain edema (25.9% vs. 47.6%). Conclusions Clinical manifestations and putative etiologies of reversible cerebral vasoconstriction syndrome in our series are slightly different from those observed in previous cohorts. This variability might be partly related to the coexistence of precipitating conditions with a putative etiologic role on disease occurrence.

Background and Purpose endovascular therapy (ET) is the standard of care for anterior circulation acute ischemic stroke (AIS) caused by large vessel occlusion (LVO). The role of adjunctive intravenous thrombolysis (IVT) in these patients is still unclear. The present study aims to test whether IVT plus ET (CoT, combined therapy) provides additional benefits over direct ET for anterior circulation AIS by LVO. Methods we performed a single center retrospective observational study of patients with AIS caused by anterior circulation LVO, referred to our center between January 2014 and January 2017 and treated with ET. The patients were divided in 2 groups based on the treatment they received: CoT and, if IVT contraindicated, direct ET. We compared functional recovery (modified Rankin at 3-months follow-up), recanalization rate (thrombolysis in cerebral infarction [TICI] score) and time, early follow-up infarct volume (EFIV) (for recanalized patients only) as well as safety profile, defined as symptomatic intracerebral hemorrhage (sICH) and 3-month mortality, between groups. Results 145 subjects were included in the study, 70 in direct ET group and 75 in CoT group. Patients who received CoT presented more frequently a functional independence at 3-months follow-up compared to patients who received direct ET (mRS score 0-1: 48.5% vs 18.6%; P

BACKGROUND AND PURPOSE Because of their potential to alter the integrity of collagen and other components of the extracellular matrix, fluoroquinolone antibiotics might be involved in the pathogenesis of spontaneous cervical artery dissection (sCeAD). METHODS In the setting of a single-centre case-control study, whether fluoroquinolone use in the 30-day period before the index event is associated with sCeAD (cases) in comparison with a group of age- and sex-matched patients who suffered a first-ever acute cerebral infarction from a cause other than CeAD (non-CeAD IS, controls) was assessed. RESULTS Overall, 284 cases (mean age 43.2 ± 10.4 years; 58.5% men) and 568 controls qualified for the analysis. Thirty (10.6%) patients in the sCeAD group and 16 (2.8%) in the non-CeAD IS group were fluoroquinolone users (P ≤ 0.001). The use of these antibiotics was associated with a more than two-fold increased risk of sCeAD [odds ratio (OR) 2.31; 95% confidence interval (CI) 1.00-5.30] after adjusting for confounders. The risk was more substantial in the subgroup of patients with dissection involving the carotid artery (OR 2.78; 95% CI 1.14-6.78), in females (OR 4.58; 95% CI 1.04-20.1) and compared to that conferred by other antibiotics (OR 2.42; 95% CI 1.02-5.75). CONCLUSIONS Fluoroquinolones may represent a novel contributing factor involved in the pathogenesis of sCeAD.

Background and Purpose— We sought to explore the effect of genetic imbalance on functional outcome after ischemic stroke (IS). Methods— Copy number variation was identified in high-density single-nucleotide polymorphism microarray data of IS patients from the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) and SiGN (Stroke Genetics Network)/GISCOME (Genetics of Ischaemic Stroke Functional Outcome) networks. Genetic imbalance, defined as total number of protein-coding genes affected by copy number variations in an individual, was compared between patients with favorable (modified Rankin Scale score of 0–2) and unfavorable (modified Rankin Scale score of ≥3) outcome after 3 months. Subgroup analyses were confined to patients with imbalance affecting ohnologs—a class of dose-sensitive genes, or to those with imbalance not affecting ohnologs. The association of imbalance with outcome was analyzed by logistic regression analysis, adjusted for age, sex, stroke subtype, stroke severity, and ancestry. Results— The study sample comprised 816 CADISP patients (age 44.2±10.3 years) and 2498 SiGN/GISCOME patients (age 67.7±14.2 years). Outcome was unfavorable in 122 CADISP and 889 SiGN/GISCOME patients. Multivariate logistic regression analysis revealed that increased genetic imbalance was associated with less favorable outcome in both samples (CADISP: P =0.0007; odds ratio=0.89; 95% CI, 0.82–0.95 and SiGN/GISCOME: P =0.0036; odds ratio=0.94; 95% CI, 0.91–0.98). The association was independent of age, sex, stroke severity on admission, stroke subtype, and ancestry. On subgroup analysis, imbalance affecting ohnologs was associated with outcome (CADISP: odds ratio=0.88; 95% CI, 0.80–0.95 and SiGN/GISCOME: odds ratio=0.93; 95% CI, 0.89–0.98) whereas imbalance without ohnologs lacked such an association. Conclusions— Increased genetic imbalance was associated with poorer functional outcome after IS in both study populations. Subgroup analysis revealed that this association was driven by presence of ohnologs in the respective copy number variations, suggesting a causal role of the deleterious effects of genetic imbalance.

Background and ObjectivesThere is a worldwide increase in the incidence of stroke in young adults, with major regional and ethnic differences. Advancing knowledge of ethnic and regional variation in causes and outcomes will be beneficial in implementation of regional health care services. We studied the global distribution of risk factors, causes, and 3-month mortality of young patients with ischemic stroke, by performing a patient data meta-analysis from different cohorts worldwide.MethodsWe performed a pooled analysis of individual patient data from cohort studies that included consecutive patients with ischemic stroke aged 18–50 years. We studied differences in prevalence of risk factors and causes of ischemic stroke between different ethnic and racial groups, geographic regions, and countries with different income levels. We investigated differences in 3-month mortality by mixed-effects multivariable logistic regression.ResultsWe included 17,663 patients from 32 cohorts in 29 countries. Hypertension and diabetes were most prevalent in Black (hypertension, 52.1%; diabetes, 20.7%) and Asian patients (hypertension 46.1%, diabetes, 20.9%). Large vessel atherosclerosis and small vessel disease were more often the cause of stroke in high-income countries (HICs; both p < 0.001), whereas “other determined stroke” and “undetermined stroke” were higher in low and middle-income countries (LMICs; both p < 0.001). Patients in LMICs were younger, had less vascular risk factors, and despite this, more often died within 3 months than those from HICs (odds ratio 2.49; 95% confidence interval 1.42–4.36).DiscussionEthnoracial and regional differences in risk factors and causes of stroke at young age provide an understanding of ethnic and racial and regional differences in incidence of ischemic stroke. Our results also highlight the dissimilarities in outcome after stroke in young adults that exist between LMICs and HICs, which should serve as call to action to improve health care facilities in LMICs.

Background and purpose Whether the reported association between migraine with aura (MA) and cardioembolic stroke may be explained by a higher rate of atrial fibrillation (AF) or by other potential cardiac sources of cerebral embolism remains to be determined.Methods In the setting of a single centre cohort study of consecutive patients with acute brain ischaemia stratified by migraine status, the association between AF as well as patent foramen ovale (PFO) and migraine was explored.Results In all, 1738 patients (1017 [58.5%] men, mean age 67.9 +/- 14.9 years) qualified for the analysis. Aging was inversely associated with migraine, whilst women had a >3-fold increased disease risk (odds ratio [OR] 3.82, 95% confidence interval [CI] 2.58-5.66). No association between AF and history of migraine or its pathogenic subtypes was detected. Conversely, migraine was associated with PFO, both in the entire cohort (OR 1.84, 95% CI 1.07-3.16) and in patients aged

Objective To characterize patients with acute ischemic stroke related to SARS-CoV-2 infection and assess the classification performance of clinical and laboratory parameters in predicting in-hospital outcome of these patients. Methods In the setting of the STROKOVID study including patients with acute ischemic stroke consecutively admitted to the ten hub hospitals in Lombardy, Italy, between March 8 and April 30, 2020, we compared clinical features of patients with confirmed infection and non-infected patients by logistic regression models and survival analysis. Then, we trained and tested a random forest (RF) binary classifier for the prediction of in-hospital death among patients with COVID-19. Results Among 1013 patients, 160 (15.8%) had SARS-CoV-2 infection. Male sex (OR 1.53; 95% CI 1.06–2.27) and atrial fibrillation (OR 1.60; 95% CI 1.05–2.43) were independently associated with COVID-19 status. Patients with COVID-19 had increased stroke severity at admission [median NIHSS score, 9 (25th to75th percentile, 13) vs 6 (25th to75th percentile, 9)] and increased risk of in-hospital death (38.1% deaths vs 7.2%; HR 3.30; 95% CI 2.17–5.02). The RF model based on six clinical and laboratory parameters exhibited high cross-validated classification accuracy (0.86) and precision (0.87), good recall (0.72) and F1-score (0.79) in predicting in-hospital death. Conclusions Ischemic strokes in COVID-19 patients have distinctive risk factor profile and etiology, increased clinical severity and higher in-hospital mortality rate compared to non-COVID-19 patients. A simple model based on clinical and routine laboratory parameters may be useful in identifying ischemic stroke patients with SARS-CoV-2 infection who are unlikely to survive the acute phase.

ObjectiveTo investigate the prevalence, predictors, and prognostic effect of hematoma expansion (HE) in patients with intracerebral hemorrhage (ICH) with unclear symptom onset (USO).MethodsWe performed a retrospective analysis of patients with primary spontaneous ICH admitted at 5 academic medical centers in the United States and Italy. HE (volume increase >6 mL or >33% from baseline to follow-up noncontrast CT [NCCT]) and mortality at 30 days were the outcomes of interest. Baseline NCCT was also analyzed for presence of hypodensities (any hypodense region within the hematoma margins). Predictors of HE and mortality were explored with multivariable logistic regression.ResultsWe enrolled 2,165 participants, 1,022 in the development cohort and 1,143 in the replication cohort, of whom 352 (34.4%) and 407 (35.6%) had ICH with USO, respectively. When compared with participants having a clear symptom onset, patients with USO had a similar frequency of HE (25.0% vs 21.9%, p = 0.269 and 29.9% vs 31.5%, p = 0.423). Among patients with USO, HE was independently associated with mortality after adjustment for confounders (odds ratio [OR] 2.64, 95% confidence interval [CI] 1.43–4.89, p = 0.002). This finding was similar in the replication cohort (OR 3.46, 95% CI 1.86–6.44, p < 0.001). The presence of NCCT hypodensities in patients with USO was an independent predictor of HE in the development (OR 2.59, 95% CI 1.27–5.28, p = 0.009) and replication (OR 2.43, 95% CI 1.42–4.17, p = 0.001) population.ConclusionHE is common in patients with USO and independently associated with worse outcome. These findings suggest that patients with USO may be enrolled in clinical trials of medical treatments targeting HE.

Background and Purpose: Observational studies have suggested a link between fibromuscular dysplasia and spontaneous cervical artery dissection (sCeAD). However, whether patients with coexistence of the two conditions have distinctive clinical characteristics has not been extensively investigated. Methods: In a cohort of consecutive patients with first-ever sCeAD, enrolled in the setting of the multicenter IPSYS CeAD study (Italian Project on Stroke in Young Adults Cervical Artery Dissection) between January 2000 and June 2019, we compared demographic and clinical characteristics, risk factor profile, vascular pathology, and midterm outcome of patients with coexistent cerebrovascular fibromuscular dysplasia (cFMD; cFMD+) with those of patients without cFMD (cFMD–). Results: A total of 1283 sCeAD patients (mean age, 47.8±11.4 years; women, 545 [42.5%]) qualified for the analysis, of whom 103 (8.0%) were diagnosed with cFMD+. In multivariable analysis, history of migraine (odds ratio, 1.78 [95% CI, 1.13–2.79]), the presence of intracranial aneurysms (odds ratio, 8.71 [95% CI, 4.06–18.68]), and the occurrence of minor traumas before the event (odds ratio, 0.48 [95% CI, 0.26–0.89]) were associated with cFMD. After a median follow-up of 34.0 months (25th to 75th percentile, 60.0), 39 (3.3%) patients had recurrent sCeAD events. cFMD+ and history of migraine predicted independently the risk of recurrent sCeAD (hazard ratio, 3.40 [95% CI, 1.58–7.31] and 2.07 [95% CI, 1.06–4.03], respectively) in multivariable Cox proportional hazards analysis. Conclusions: Risk factor profile of sCeAD patients with cFMD differs from that of patients without cFMD. cFMD and migraine are independent predictors of midterm risk of sCeAD recurrence.

ObjectiveAim of this study was to analyse the impact of COVID-19 on clinical and laboratory findings and outcome of neurological patients consecutively admitted to the emergency department (ED) of a tertiary hub center.MethodsAll adult patients consecutively admitted to the ED for neurological manifestations from February 20th through April 30th 2020 at Spedali Civili of Brescia entered the study. Demographic, clinical, and laboratory data were extracted from medical records and compared between patients with and without COVID-19.ResultsOut of 505 consecutively patients evaluated at ED with neurological symptoms, 147 (29.1%) tested positive for SARS-CoV-2. These patients displayed at triage higher values of CRP, AST, ALT, and fibrinogen but not lymphopenia (pConclusionsCOVID-19 impacts on clinical presentation of neurological disorders, with higher frequency of stroke, encephalitis and delirium, and was strongly associated with increased hospitalisation, mortality and disability.

International audience; Cervical artery dissection (CeAD) occurring in the context of sports is a matter of concern for CeAD patients. They seek advice on the role of sports in CeAD and on the safety of resuming sports after CeAD. The scarcity of studies and guidelines addressing these issues poses a challenge. We aimed at summarizing the current knowledge about CeAD and sports in order to provide an informed, comprehensive opinion for counseling CeAD patients. We took into account pathophysiological considerations, observations of cases reports, series, and registries, and conclusions by analogy from aortic dissection or inherited connective tissue syndromes. In summary, practicing active sports as the cause of CeAD seems uncommon. It seems recommendable to refrain from any kind of sports activities for at least 1 month, which can be extended in case of an unfavorable clinical or neurovascular course. We recommend starting with sport activities at low intensity-preferably with types of endurance sports-and to gradually increase the pace in an individually tailored manner, taking into circumstances of the occurrences of the CeAD in the individual patient (particularly in relation to sports), the meaning of sports activities for the individual well-being, the presence or absence of comorbidities and of neurological sequela, neurovascular findings, and whether there are signs of an underlying connective tissue alteration. Major limitations and several forms of bias are acknowledged. Still, in the absence of any better data, the summarized observations and considerations might help clinicians in advising and counseling patients with CeAD in clinical practice.

Italy was the first European country to be affected by the Covid-19 epidemic, with the outbreak estimated to have started in late February, 2020. Currently, Italy has reported more than 228000 Covid-19-positive cases, 14326 of which in the province of Brescia, Lombardy. Although emerging studies have shown a profound hypercoagulable state in Covid-19, it is still highly debated if Covid-19 increases the risk of cerebrovascular disorders. Some reports have shown high frequency of stroke in patients with Covid-191-3 while collaterally there was a decrease of approximately 39% of patients evaluated for stroke in U.S. hospitals,4 possibly due to the fear of seeking care in the midst of the pandemic.

Objective To assess the association between migraine and cryptogenic ischemic stroke (CIS) in young adults, with subgroup analyses stratified by sex and presence of patent foramen ovale (PFO). Methods We prospectively enrolled 347 consecutive patients aged 18 to 49 years with a recent CIS and 347 age- and sex-matched (+/- 5 years) stroke-free controls. Any migraine and migraine with (MA) and migraine without aura (MO) were identified by a screener, which we validated against a headache neurologist. We used conditional logistic regression adjusting for age, education, hypertension, diabetes, waist-to-hip ratio, physical inactivity, current smoking, heavy drinking, and oral estrogen use to assess independent association between migraine and CIS. The effect of PFO on the association between migraine and CIS was analyzed with logistic regression in a subgroup investigated with transcranial Doppler bubble screen. Results The screener performance was excellent (Cohen kappa > 0.75) in patients and controls. Compared with nonmigraineurs, any migraine (odds ratio [OR] = 2.48, 95% confidence interval [CI] = 1.63-3.76) and MA (OR = 3.50, 95% CI = 2.19-5.61) were associated with CIS, whereas MO was not. The association emerged in both women (OR = 2.97 for any migraine, 95% CI = 1.61-5.47; OR = 4.32 for MA, 95% CI = 2.16-8.65) and men (OR = 2.47 for any migraine, 95% CI = 1.32-4.61; OR = 3.61 for MA, 95% CI = 1.75-7.45). Specifically for MA, the association with CIS remained significant irrespective of PFO. MA prevalence increased with increasing magnitude of the right-to-left shunt in patients with PFO. Interpretation MA has a strong association with CIS in young patients, independent of vascular risk factors and presence of PFO. ANN NEUROL 2020

[Background] Cerebral venous thrombosis (CVT) is associated with intracranial hemorrhage., [Aim] To identify clinical and imaging features of CVT-associated intracranial hemorrhage. We hypothesized that higher clot burden would be associated with a higher risk of intracranial hemorrhage., [Methods] We performed a retrospective analysis of an international, multicenter cohort of patients with confirmed cerebral venous thrombosis who underwent computed tomography within 2 weeks of symptom onset. Clinical and imaging features were compared between patients with and without intracranial hemorrhage. Clot burden was assessed by counting the number of thrombosed venous sinuses and veins on confirmatory imaging., [Results] We enrolled 260 patients from 10 institutions in Europe and Mexico. The mean age was 42 years and 74% were female. Intracranial hemorrhage was found in 102 (39%). Among them parenchymal hemorrhage occurred in 64 (63%), in addition, small juxta-cortical hemorrhage was found in 30 (29%), subarachnoid hemorrhage in 24 (24%) and subdural hemorrhage in 11 (11%). Multiple concomitant types of hemorrhage occurred in 23 (23%). Older age and superior sagittal thrombosis involvement were associated with presence of hemorrhage. The number of thrombosed venous sinuses was not associated with intracranial hemorrhage (median number IQRInterquartile ratio] of sinuses/veins involved with hemorrhage 2 (1–3) vs. 2 (1–3) without hemorrhage, p = 0.4)., [Conclusion] The high rate of intracranial hemorrhage in cerebral venous thrombosis is not explained by widespread involvement of the venous sinuses. Superior sagittal sinus involvement is associated with higher bleeding risk.

Background and purpose Most recurrent cervical artery dissection (CeAD) events occur shortly after the acute first CeAD. This study compared the characteristics of recurrent and first CeAD events and searched for associations between subsequent events of an individual person. Methods Cervical artery dissection patients with a new CeAD event occurring during a 3-6 month follow-up were retrospectively selected in seven specialized stroke centers. Clinical and vascular characteristics of the initial and the recurrent CeADs were compared. Results The study sample included 76 patients. Recurrent CeADs were occlusive in one (1.3%) patient, caused cerebral ischaemia in 13 (17.1%) and were asymptomatic in 39 (51.3%) patients, compared to 29 (38.2%) occlusive, 42 (55.3%) ischaemic and no asymptomatic first CeAD events. In 52 (68.4%) patients, recurrent dissections affected both internal carotid arteries or both vertebral arteries, whilst 24 (31.6%) patients had subsequent dissections in both types of artery. Twelve (28.6%) of 42 patients with an ischaemic first dissection had ischaemic symptoms due to the recurrent CeADs, too. However, only one (1.3%) of 34 patients with a non-ischaemic first CeAD suffered ischaemia upon recurrence. Conclusion Recurrent CeAD typically affects the same site of artery. It causes ischaemic events less often than the first CeAD. The risk that patients who presented with solely non-ischaemic symptoms of a first CeAD will have ischaemic symptoms in the case of a recurrent CeAD seems very small.

Background: In this randomized trial, currently utilized standard treatments were compared with enoxaparin for the prevention of venous thromboembolism (VTE) in patients with intracerebral hemorrhage (ICH). Methods: Enoxaparin (0.4 mg daily for 10 days) was started after 72 h from the onset of ICH. The primary outcome was symptomatic or asymptomatic deep venous thrombosis as assessed by ultrasound at the end of study treatment. The safety of enoxaparin was also assessed. We included the results of this study in a meta-analysis of all relevant studies comparing anticoagulants with standard treatments or placebo. Results: PREVENTIHS was prematurely stopped after the randomization of 73 patients, due to the low recruitment rate. The prevalence of any VTE at 10 days was 15.8% in the enoxaparin group and 20.0% in the control group (RR 0.79 [95% CI 0.29–2.12]); 2.6% of enoxaparin and 8.6% of standard therapy patients had severe bleedings (RR 0.31 [95% CI 0.03–2.82]). When these results were meta-analyzed with the results of the selected studies (4,609 patients; 194 from randomized trials), anticoagulants were associated with a nonsignificant reduction in any VTE (OR 0.81; 95% CI 0.43–1.51), in pulmonary embolism (OR 0.53; 95% CI, 0.17–1.60), and in mortality (OR 0.85; 95% CI 0.64–1.12) without increase in hematoma enlargement (OR 0.97; 95% CI, 0.31–3.04). Conclusions: In patients with acute ICH, the use of anticoagulants to prevent VTE was safe but the overall level of evidence was low due to the low number of patients included in randomized clinical trials.

Coronavirus disease 2019 (COVID-19) infection has the potential for targeting the central nervous system, and several neurological symptoms have been described in patients with severe respiratory distress. Here, we described the case of a 60-year-old patient with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection but only mild respiratory abnormalities who developed an akinetic mutism attributable to encephalitis. Magnetic resonance imaging was negative, whereas electroencephalography showed generalized theta slowing. Cerebrospinal fluid analyses during the acute stage were negative for SARS-CoV-2, positive for pleocytosis and hyperproteinorrachia, and showed increased interleukin-8 and tumor necrosis factor-α concentrations. Other infectious or autoimmune disorders were excluded. A progressive clinical improvement along with a reduction of cerebrospinal fluid parameters was observed after high-dose steroid treatment, thus arguing for an inflammatory-mediated brain involvement related to COVID-19. ANN NEUROL 2020;88:423-427.

ObjectiveTo report clinical and laboratory characteristics, treatment, and clinical outcomes of patients admitted for neurologic diseases with and without coronavirus disease 2019 (COVID-19).MethodsIn this retrospective, single-center cohort study, we included all adult inpatients with confirmed COVID-19 admitted to a neuro-COVID unit beginning February 21, 2020, who had been discharged or died by April 5, 2020. Demographic, clinical, treatment, and laboratory data were extracted from medical records and compared (false discovery rate corrected) to those of neurologic patients without COVID-19 admitted in the same period.ResultsOne hundred seventy-three patients were included in this study, of whom 56 were positive and 117 were negative for COVID-19. Patients with COVID-19 were older (77.0 years, interquartile range [IQR] 67.0–83.8 years vs 70.1 years, IQR 52.9–78.6 years, p = 0.006), had a different distribution regarding admission diagnoses, including cerebrovascular disorders (n = 43, 76.8% vs n = 68, 58.1%), and had a higher quick Sequential Organ Failure Assessment (qSOFA) score on admission (0.9, IQR 0.7–1.1 vs 0.5, IQR 0.4–0.6, p = 0.006). In-hospital mortality rates (n = 21, 37.5% vs n = 5, 4.3%, p < 0.001) and incident delirium (n = 15, 26.8% vs n = 9, 7.7%, p = 0.003) were significantly higher in the COVID-19 group. Patients with COVID-19 and without COVID with stroke had similar baseline characteristics, but patients with COVID-19 had higher modified Rankin Scale scores at discharge (5.0, IQR 2.0–6.0 vs 2.0, IQR 1.0–3.0, p < 0.001), with a significantly lower number of patients with a good outcome (n = 11, 25.6% vs n = 48, 70.6%, p < 0.001). In patients with COVID-19, multivariable regressions showed increasing odds of in-hospital death associated with higher qSOFA scores (odds ratio [OR] 4.47, 95% confidence interval [CI] 1.21–16.5, p = 0.025), lower platelet count (OR 0.98, 95% CI 0.97–0.99, p = 0.005), and higher lactate dehydrogenase (OR 1.01, 95% CI 1.00–1.03, p = 0.009) on admission.ConclusionsPatients with COVID-19 admitted with neurologic disease, including stroke, have a significantly higher in-hospital mortality and incident delirium and higher disability than patients without COVID-19.

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Background and Purpose: The optimal timing for starting oral anticoagulant after an ischemic stroke related to atrial fibrillation remains a challenge, mainly in patients treated with systemic thrombolysis or mechanical thrombectomy. We aimed at assessing the incidence of early recurrence and major bleeding in patients with acute ischemic stroke and atrial fibrillation treated with thrombolytic therapy and/or thrombectomy, who then received oral anticoagulants for secondary prevention. Methods: We combined the dataset of the RAF and the RAF-NOACs (Early Recurrence and Major Bleeding in Patients With Acute Ischemic Stroke and Atrial Fibrillation Treated With Non–Vitamin K Oral Anticoagulants) studies, which were prospective observational studies carried out from January 2012 to March 2014 and April 2014 to June 2016, respectively. We included consecutive patients with acute ischemic stroke and atrial fibrillation treated with either vitamin K antagonists or nonvitamin K oral anticoagulants. Primary outcome was the composite of stroke, transient ischemic attack, symptomatic systemic embolism, symptomatic cerebral bleeding, and major extracerebral bleeding within 90 days from the inclusion. Treated-patients were propensity matched to untreated-patients in a 1:1 ratio after stratification by baseline clinical features. Results: A total of 2159 patients were included, 564 (26%) patients received acute reperfusion therapies. After the index event, 505 (90%) patients treated with acute reperfusion therapies and 1287 of 1595 (81%) patients untreated started oral anticoagulation. Timing of starting oral anticoagulant was similar in reperfusion-treated and untreated patients (median 7.5 versus 7.0 days, respectively). At 90 days, the primary study outcome occurred in 37 (7%) patients treated with reperfusion and in 146 (9%) untreated patients (odds ratio, 0.74 [95% CI, 0.50–1.07]). After propensity score matching, risk of primary outcome was comparable between the 2 groups (odds ratio, 1.06 [95% CI, 0.53–2.02]). Conclusions: Acute reperfusion treatment did not influence the risk of early recurrence and major bleeding in patients with atrial fibrillation–related acute ischemic stroke, who started on oral anticoagulant.

Background and ObjectivesMigraine, stroke, and cervical artery dissection (CeAD) represent a triad of cerebrovascular disorders with pairwise comorbid relationships and vascular involvement. Larger samples and recent advances in methodology invite systematic exploration of their shared genetics.MethodsGenetic analyses leveraged summary statistics from genome-wide association studies of the largest available samples of each disorder, including subtypes of stroke (ischemic stroke, large artery stroke, small vessel stroke, and cardioembolic stroke) and migraine (with aura and without aura). For each pair of disorders, genetic correlation was assessed both on a genome-wide basis and within independent segments across the genome including known specific loci for each disorder. A cross-trait meta-analysis was used to identify novel candidate loci. Finally, potential causality of migraine susceptibility on stroke and CeAD was assessed by Mendelian randomization.ResultsAmong all pairs of disorders, genome-wide genetic correlation was observed only between CeAD and migraine, particularly MO. Local genetic correlations were more extensive between migraine and CeAD than those between migraine and stroke or CeAD and stroke and revealed evidence for novel CeAD associations at rs6693567 (ADAMTSL4/ECM1), rs11187838 (PLCE1), and rs7940646 (MRVI1) while strengthening prior subthreshold evidence at rs9486725 (FHL5) and rs650724 (LRP1). At known migraine loci, novel associations with stroke had concordant risk alleles for small vessel stroke at rs191602009 (CARF) and for cardioembolic stroke at rs55884259 (NKX2-5). Known migraine loci also revealed novel associations but with opposite risk alleles for all stroke, ischemic stroke, and small vessel stroke at rs55928386 (HTRA1), for large artery stroke at rs11172113 (LRP1), and for all stroke and ischemic stroke at rs1535791 and rs4942561 (both LRCH1), respectively. rs182923402 (near PTCH1) was a novel concordant locus for migraine and cardioembolic stroke. Mendelian randomization supported potential causal influences of migraine on CeAD (odds ratio [95% confidence interval] per doubling migraine prevalence = 1.69 [1.24–2.3], p = 0.0009) with concordant risk, but with opposite risk on large artery stroke (0.86 [0.76–0.96], p = 0.0067).DiscussionThe findings emphasize shared genetic risk between migraine and CeAD while identifying loci with likely vascular function in migraine and shared but opposite genetic risk between migraine and stroke subtypes, and a central role of LRP1 in all 3 cerebrovascular disorders.

Background and Purpose— Women have a worse outcome after stroke compared with men, although in intravenous thrombolysis (IVT)–treated patients, women seem to benefit more. Besides sex differences, age has also a possible effect on functional outcome. The interaction of sex on the functional outcome in IVT-treated patients in relation to age remains complex. The purpose of this study was to compare outcome after IVT between women and men with regard to age in a large multicenter European cohort reflecting daily clinical practice of acute stroke care. Methods— Data were obtained from IVT registries of 12 European tertiary hospitals. The primary outcome was poor functional outcome, defined as a modified Rankin scale score of 3 to 6 at 3 months. We stratified outcome by age in decades. Safety measures were symptomatic intracranial hemorrhage and mortality at 3 months. Results— In this cohort, 9495 patients were treated with IVT, and 4170 (43.9%) were women with a mean age of 71.9 years. After adjustments for baseline differences, female sex remained associated with poor functional outcome (odds ratio, 1.15; 95% confidence interval, 1.02–1.31). There was no association between sex and functional outcome when data were stratified by age. Symptomatic intracranial hemorrhage rate was similar in both sexes (adjusted odds ratio, 0.93; 95% confidence interval, 0.73–1.19), whereas mortality was lower among women (adjusted odds ratio, 0.83; 95% confidence interval, 0.70–0.99). Conclusions— In this large cohort of IVT-treated patients, women more often had poor functional outcome compared with men. This difference was not dependent on age.

Futile recanalization occurs when successful recanalization fails to improve clinical outcome in acute ischemic stroke patients. Predictors of futile recanalization are still debated and may help in selecting patients for reperfusion strategies. We aim to determine whether leukoaraiosis may be useful in predicting futile recanalization in acute ischemic stroke patients treated by endovascular mechanical thrombectomy. We included in the analysis patients with acute ischemic stroke due to anterior circulation large vessel occlusion undergoing endovascular mechanical thrombectomy obtaining complete vessel recanalization. Demographics, vascular risk factors, baseline National Institutes of Health Stroke Scale score, time from symptoms onset to recanalization, Alberta Stroke Program Early CT Score, and leukoaraiosis graded on a 4-point van Swieten scale were collected. We dichotomized patients into those with moderate–severe leukoaraiosis (2–4) versus those with absent-slight leukoaraiosis (0, 1). Outcome measures were symptomatic intracranial hemorrhage, and modified Rankin scale score at 90 days. The relationships among radiological parameters and clinical data with outcome measures were studied with univariate and multivariable analyses. Sixty-eight patients were identified. Recanalization was futile in 32.4% of cases. On multivariable logistic regression analysis, the presence of moderate–severe LA was independent predictors of FR (P = 0.01). Furthermore, higher NIHSS score at baseline (P