Statin use and long-term risk of recurrent intracerebral haemorrhage: the MUCH-Italy.

BACKGROUND: Whether statin use after spontaneous intracerebral haemorrhage (ICH) increases the risk of recurrent ICH is uncertain. METHODS: In the setting of the Multicentric Study on Cerebral Haemorrhage in Italy we followed up a cohort of 30-day ICH survivors, consecutively admitted from January 2002 to July 2014, to assess whether the use of statins after the acute event is associated with recurrent cerebral bleeding. RESULTS: 1623 patients (mean age, 73.9±10.3 years; males, 55.9%) qualified for the analysis. After a median follow-up of 40.5 months (25th to 75th percentile, 67.7) statin use was not associated with increased risk of recurrent ICH either in the whole study group (adjusted HR, 0.99; 95% CI 0.64 to 1.53) or in the subgroups defined by haematoma location (deep ICH, adjusted HR, 0.74; 95% CI 0.35 to 1.57; lobar ICH, adjusted HR, 1.09; 95% CI 0.62 to 1.90), intensity of statins (low-moderate intensity statins, adjusted HR, 0.93; 95% CI 0.58 to 1.49; high-intensity statins, adjusted HR, 1.48; 95% CI 0.66 to 3.31) and use of statins before the index event (adjusted HR, 0.66; 95% CI 0.38 to 1.17). CONCLUSIONS: Statin use appears to be unrelated to the risk of ICH recurrence.

The Italian hub-and-spoke network for the emergency neurology management.

OBJECTIVE: The aim of the present study was to assess emergency neurology management in Italy by comparing patients admitted to the hub and spoke hospitals. METHODS: Data obtained from the annual Italian national survey (NEUDay) investigating the activity and facilities of neurology in the emergency room conducted in November 2021 were considered. Information for each patient who received a neurologic consultation after accessing the emergency room was acquired. Data on facilities were also gathered, including hospital classification (hub vs spoke), number of consultations, presence of neurology and stroke unit, number of beds, availability of neurologist, radiologist, neuroradiologist, and instrumental diagnostic accessibility. RESULTS: Overall, 1,111 patients were admitted to the emergency room and had neurological consultation across 153 facilities (out of the 260 Italian ones). Hub hospitals had significantly more beds, availability of neurological staff, and instrumental diagnostic accessibility. Patients admitted to hub hospital had a greater need for assistance (higher number of yellow/red codes at neurologist triage). A higher propensity to be admitted to hub centers for cerebrovascular problems and to receive a diagnosis of stroke was observed. CONCLUSIONS: The identification of hub and spoke hospitals is strongly characterized by the presence of beds and instrumentation mainly dedicated to acute cerebrovascular pathologies. Moreover, the similarity in the number and type of accesses between hub and spoke hospitals suggests the need to look for adequate identification of all the neurological pathologies requiring urgent treatment.

Models of care in emergency neurology: from the Neuro Fast Track to the emergency neurologist-a position paper of the Italian Association for Emergency Neurology (ANEU).

I n the context of an adequate health care organization, the figure of the neurologist as an emergency operator (in the emergency room-ER-and/or in a dedicated outpatient clinic) is crucial for an effective functional connection with the territory (and therefore with general practitioners), a reduction in inappropriate ER accesses, specific diagnostic and therapeutic approaches to neurological emergencies in the ER and a reduction in nonspecific or even unnecessary instrumental investigations. In this position paper of the Italian Association of Emergency Neurology (ANEU: Associazione Neurologia dell'Emergenza Urgenza), these issues are addressed, and two important organizational solutions are proposed: 1) The Neuro Fast Track, as an outpatient organization approach strongly linked to general practitioners and non-neurological specialists and dedicated to cases with deferrable urgency (to be assessed within 72 h) 2) The identification of an emergency neurologist, who is engaged in ER assessments as a consultant and involved in the management of the semi-intensive care unit of the emergency neurology and the stroke unit according to an appropriate rotation, as well as in consultations for patients with neurological emergencies in inpatient wards The possibility of computerizing the screening of patients with deferrable urgency in the Neuro Fast Track is described. A dedicated app represents an important tool that can facilitate the identification of patients for whom deferred assessment is appropriate, the scheduling of neurological examinations and reductions in the booking time through a more rapid approach to specialist assessment and subsequent investigations.

Antithrombotic therapy in the postacute phase of cervical artery dissection: the Italian Project on Stroke in Young Adults Cervical Artery Dissection.

OBJECTIVE: To explore the impact of antithrombotic therapy discontinuation in the postacute phase of cervical artery dissection (CeAD) on the mid-term outcome of these patients. METHODS: In 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. RESULTS: Of 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). CONCLUSIONS: Discontinuation of antithrombotic therapy in the postacute phase of CeAD does not appear to increase the risk of brain ischaemia during follow-up.

Risk Factors for Intracerebral Hemorrhage in Patients With Atrial Fibrillation on Non-Vitamin K Antagonist Oral Anticoagulants for Stroke Prevention.

[Figure: see text].

Clinical phenotypes of embolic strokes of undetermined source.

BACKGROUND AND PURPOSE: The embolic stroke of undetermined source (ESUS) represents a heterogeneous clinical entity. The aim of this study was to investigate whether distinct clinical phenotypes may be identified in the ESUS population. METHODS: We retrospectively identified consecutive patients hospitalized for acute ischemic stroke who met the ESUS diagnostic criteria. Baseline characteristics and diagnostic workup findings were collected. Hierarchical cluster analysis was carried out to classify clinical features and identify different groups of ESUS patients. RESULTS: One hundred twenty-seven patients with a mean age of 68.6 (12.5) years were included. Three main clusters were identified. The first cluster associated young age, male sex, presence of patent foramen ovale, and posterior circulation infarct. The second phenotype linked hypertension, severe stroke, left atrial cardiopathy, diabetes mellitus, and involvement of multiple vascular territories. The third cluster gathered smoking, dyslipidemia, ipsilateral vulnerable sub-stenotic carotid plaque, and infarct of anterior vascular territory. CONCLUSIONS: Distinct clinical phenotypes have been identified within the ESUS population, which may supply clues to the underlying pathogenic mechanisms.

Discovering the Italian phenotype of cerebral amyloid angiopathy (CAA): the SENECA project.

Cerebral amyloid angiopathy (CAA) is one of the major types of cerebral small vessel disease, and a leading cause of spontaneous intracerebral hemorrhage and cognitive decline in elderly patients. Although increasingly detected, a number of aspects including the pathophysiology, the clinical and neuroradiological phenotype, and the disease course are still under investigation. The incomplete knowledge of the disease limits the implementation of evidence-based guidelines on patient's clinical management and the development of treatments able to prevent or reduce disease progression. The SENECA (SEarchiNg biomarkErs of Cerebral Angiopathy) project is the first Italian multicenter cohort study aimed at better defining the disease natural history and identifying clinical and neuroradiological markers of disease progression. By a multidisciplinary approach and the collection of a large and well-phenotyped series and biorepository of CAA patients, the study is ultimately expected to improve the diagnosis and the knowledge of CAA pathophysiological mechanisms.

Prediction of Outcome in Embolic Strokes of Undetermined Source.

BACKGROUND AND AIM: Predicting outcome after stroke is a major goal and research field. The Embolic Stroke of Undetermined Source (ESUS) is a recently introduced clinical construct, and the prediction of outcome in this population has to be further explored. The aim of the study was to evaluate the prognostic validity and accuracy of the Acute Stroke Registry and Analysis of Lausanne (ASTRAL) score in patients with ESUS. METHODS: Consecutive patients hospitalized for acute ischemic stroke who met the ESUS diagnostic criteria were identified and the ASTRAL scores estimated. The study endpoint was the 3-month unfavorable outcome (modified Rankin Scale>2). Predictive performance was investigated through logistic regression analysis and discrimination and calibration tests. RESULTS: Among 202 patients with ESUS, 67 (33.2%) had unfavourable 3-month outcome. The ASTRAL score was an independent predictor of poor outcome [adjOR = 1.44, 95% confidence interval (CI) 1.30-1.60, P < .001], showed good discriminatory power (area under the receiver operating characteristic curve .913, 95% CI .871-.956) and was well calibrated (Hosmer-Lemeshow test P = .496). CONCLUSIONS: The ASTRAL score was an independent predictor of 3-month functional outcome and showed high predictive accuracy in patients with ESUS.

Vascular Remodeling in Moyamoya Angiopathy: From Peripheral Blood Mononuclear Cells to Endothelial Cells.

The pathophysiological mechanisms of Moyamoya angiopathy (MA), which is a rare cerebrovascular condition characterized by recurrent ischemic/hemorrhagic strokes, are still largely unknown. An imbalance of vasculogenic/angiogenic mechanisms has been proposed as one possible disease aspect. Circulating endothelial progenitor cells (cEPCs) have been hypothesized to contribute to vascular remodeling of MA, but it remains unclear whether they might be considered a disease effect or have a role in disease pathogenesis. The aim of the present study was to provide a morphological, phenotypical, and functional characterization of the cEPCs from MA patients to uncover their role in the disease pathophysiology. cEPCs were identified from whole blood as CD45dimCD34+CD133+ mononuclear cells. Morphological, biochemical, and functional assays were performed to characterize cEPCs. A significant reduced level of cEPCs was found in blood samples collected from a homogeneous group of adult (mean age 46.86 ± 11.7; 86.36% females), Caucasian, non-operated MA patients with respect to healthy donors (HD; p = 0.032). Since no difference in cEPC characteristics and functionality was observed between MA patients and HD, a defective recruitment mechanism could be involved in the disease pathophysiology. Collectively, our results suggest that cEPC level more than endothelial progenitor cell (EPC) functionality seems to be a potential marker of MA. The validation of our results on a larger population and the correlation with clinical data as well as the use of more complex cellular model could help our understanding of EPC role in MA pathophysiology.

Causes and Risk Factors of Cerebral Ischemic Events in Patients With Atrial Fibrillation Treated With Non-Vitamin K Antagonist Oral Anticoagulants for Stroke Prevention.

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 CHA2DS2-VASc score (OR, 1.72 for each point increase; 95% CI, 1.58-1.88) were associated with ischemic events. Among the CHA2DS2-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 CHA2DS2-VASc score were associated with increased risk of cerebrovascular events.

GEN-O-MA project: an Italian network studying clinical course and pathogenic pathways of moyamoya disease-study protocol and preliminary results.

BACKGROUND: GENetics of mOyaMoyA (GEN-O-MA) project is a multicenter observational study implemented in Italy aimed at creating a network of centers involved in moyamoya angiopathy (MA) care and research and at collecting a large series and bio-repository of MA patients, finally aimed at describing the disease phenotype and clinical course as well as at identifying biological or cellular markers for disease progression. The present paper resumes the most important study methodological issues and preliminary results. METHODS: Nineteen centers are participating to the study. Patients with both bilateral and unilateral radiologically defined MA are included in the study. For each patient, detailed demographic and clinical as well as neuroimaging data are being collected. When available, biological samples (blood, DNA, CSF, middle cerebral artery samples) are being also collected for biological and cellular studies. RESULTS: Ninety-eight patients (age of onset mean ± SD 35.5 ± 19.6 years; 68.4% females) have been collected so far. 65.3% of patients presented ischemic (50%) and haemorrhagic (15.3%) stroke. A higher female predominance concomitantly with a similar age of onset and clinical features to what was reported in previous studies on Western patients has been confirmed. CONCLUSION: An accurate and detailed clinical and neuroimaging classification represents the best strategy to provide the characterization of the disease phenotype and clinical course. The collection of a large number of biological samples will permit the identification of biological markers and genetic factors associated with the disease susceptibility in Italy.

Impact on Prehospital Delay of a Stroke Preparedness Campaign: A SW-RCT (Stepped-Wedge Cluster Randomized Controlled Trial).

BACKGROUND AND PURPOSE: Public campaigns to increase stroke preparedness have been tested in different contexts, showing contradictory results. We evaluated the effectiveness of a stroke campaign, designed specifically for the Italian population in reducing prehospital delay. METHODS: According to an SW-RCT (Stepped-Wedge Cluster Randomized Controlled Trial) design, the campaign was launched in 4 provinces in the northern part of the region Emilia Romagna at 3-month intervals in randomized sequence. The units of analysis were the patients admitted to hospital, with stroke and transient ischemic attack, over a time period of 15 months, beginning 3 months before the intervention was launched in the first province to allow for baseline data collection. The proportion of early arrivals (within 2 hours of symptom onset) was the primary outcome. Thrombolysis rate and some behavioral end points were the secondary outcomes. Data were analyzed using a fixed-effect model, adjusting for cluster and time trends. RESULTS: We enrolled 1622 patients, 912 exposed and 710 nonexposed to the campaign. The proportion of early access was nonsignificantly lower in exposed patients (354 [38.8%] versus 315 [44.4%]; adjusted odds ratio, 0.81; 95% confidence interval, 0.60-1.08; P=0.15). As for secondary end points, an increase was found for stroke recognition, which approximated but did not reach statistical significance (P=0.07). CONCLUSIONS: Our campaign was not effective in reducing prehospital delay. Even if some limitations of the intervention, mainly in terms of duration, are taken into account, our study demonstrates that new communication strategies should be tested before large-scale implementation. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01881152.

Development of an education campaign to reduce delays in pre-hospital response to stroke.

BACKGROUND: Systematic reviews call for well-designed trials with clearly described intervention components to support the effectiveness of educational campaigns to reduce patient delay in stroke presentation. We herein describe the systematic development process of a campaign aimed to increase stroke awareness and preparedness. METHODS: Campaign development followed Intervention Mapping (IM), a theory- and evidence-based tool, and was articulated in two phases: needs assessment and intervention development. In phase 1, two cross-sectional surveys were performed, one aiming to measure stroke awareness in the target population and the other to analyze the behavioral determinants of prehospital delay. In phase 2, a matrix of proximal program objectives was developed, theory-based intervention methods and practical strategies were selected and program components and materials produced. RESULTS: In phase 1, the survey on 202 citizens highlighted underestimation of symptom severity, as in only 44% of stroke situations respondents would choose to call the emergency service (EMS). In the survey on 393 consecutive patients, 55% presented over 2 hours after symptom onset; major determinants were deciding to call the general practitioner first and the reaction of the first person the patient called. In phase 2, adult individuals were identified as the target of the intervention, both as potential "patients" and witnesses of stroke. The low educational level found in the patient survey called for a narrative approach in cartoon form. The family setting was chosen for the message because 42% of patients who presented within 2 hours had been advised by a family member to call EMS. To act on people's tendency to view stroke as an untreatable disease, it was decided to avoid fear-arousal appeals and use a positive message providing instructions and hope. Focus groups were used to test educational products and identify the most suitable sites for message dissemination. CONCLUSIONS: The IM approach allowed to develop a stroke campaign integrating theories, scientific evidence and information collected from the target population, and enabled to provide clear explanations for the reasons behind key decisions during the intervention development process. TRIAL REGISTRATION: NCT01881152 . Retrospectively registered June 7 2013.

Feasibility and usefulness of ultrasonography in idiopathic intracranial hypertension or secondary intracranial hypertension.

BACKGROUND: Transorbital sonography (TOS) has been proven to be able to non-invasively detect elevated intracranial pressure. In this condition TOS shows an increase in optic nerve sheath diameter (ONSD). It has been suggested that internal jugular vein valve insufficiency (IJVVI) may represent a factor contributing to the pathogenesis of idiopathic intracranial hypertension (IIH). The aim of this study was to investigate whether patients with IIH or secondary IH have higher ONSD values and higher frequency of IJVVI compared to subjects without IH. METHODS: Twenty-one patients with newly diagnosed IIH or secondary IH were prospectively evaluated and compared with 21 age, gender and BMI-matched controls. Experienced vascular sonographers used B-mode TOS to evaluate ONSD, optic nerve diameter (OND) and IJVVI. CSF opening pressures were also measured. RESULTS: ONSD values were significantly higher in patients (6.50 ± 0.67) than controls (5.73 ± 0.66; p < 0.0001). No differences were found in OND values between patients (2.99 ± 0.26) and controls (2.93 ± 0.41; p = 0.574). No correlation was demonstrated between ONSD and CSF opening pressure (r = 0,086) (p = 0.73). No difference in frequency of IJVVI between patients (11/42 valves, 26 %) and controls (9/42, 21 %) was observed (p = 0.777). CONCLUSIONS: Increased ONSD values detected by TOS support the diagnosis of IH. Our results do not support the hypothesis of a venous congestion as a potential factor contributing to the pathogenesis of IIH. TRIAL REGISTRATION: Not applicable. Observational, non-interventional study.

Italian symptomatic intracranial atherosclerosis study (ISIDE) : A multicenter transcranial ultrasound evaluation.

There are currently no data available on the prevalence of symptomatic intracranial atherosclerosis (ICAS) in Italy. The aim of this prospective, multicenter, hospital-based, transcranial ultrasound study was to establish the prevalence of ICAS among patients hospitalized with acute ischemic stroke. At 11 stroke centers across Italy, patients consecutively admitted for their first ever acute ischemic stroke were assessed prospectively over a 24-month period either with transcranial color-coded Doppler sonography (TCCS) or transcranial Doppler (TCD) according to validated criteria. ICAS was diagnosed when there was an evidence of a cerebral infarction in the territory of a ≥50 % stenosis detected by TCCS/TCD and confirmed by magnetic resonance angiography or computed tomography angiography. A total of 1134 patients were enrolled, 665 of them (58.6 %) men, with a mean age of 71.2 ± 13.3 years. ICAS was recorded in 99 patients (8.7 % of the whole sample, 8.9 % among Caucasians), most commonly located in the anterior circulation (63 of 99, 5.5 %). After adjusting for potential confounders, multivariate analysis identified carotid/vertebral ≥50 % stenosis [odds ratio (OR) 2.59, 95 % (confidence interval) CI 1.77-6.33; P = 0.02] and hypercholesterolemia (OR 1.38, 95 % CI 1.02-1.89; P = 0.02) as being independently associated with ICAS. ICAS is a surprisingly relevant cause of ischemic stroke in Italy, identified in almost 9 % of first-ever stroke patients. It is more prevalent in the anterior circulation and independently associated with hemodynamically significant cervical vessel atherosclerosis and hypercholesterolemia. These findings support the systematic use of transcranial ultrasound to identify ICAS in patients presenting with acute ischemic stroke and in cases with ≥50 % cervical vessel stenoses.

The "SALPARE study" of spontaneous intracerebral hemorrhage: part 1.

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) is a devastating type of stroke with a huge impact on patients and families. Expanded use of oral anticoagulants and ageing population might contribute to an epidemiological change. In view of these trends, we planned a study to obtain a contemporary picture and identify early prognostic factors to improve secondary prevention. METHODS: This multicenter prospective cohort study included consecutive adult patients with non-traumatic ICH admitted to three academic Italian hospitals (Salerno, Padova, Reggio Emilia) over a 2-year period. Demographic characteristics, vascular risk profile, clinical data and main radiological characteristics were correlated to 90-day clinical outcome. RESULTS: Out of 682 patients [mean age: 73 ± 14 years; 316 (46.3%) females] enrolled in this study, 40% died [86/180 (47.8%) in Salerno, 120/320 (37.5%) in Padova, 67/182 (36.8%) in Reggio Emilia; p < 0.05)] and 36% were severely disabled at 90 days. Several factors were associated with a higher risk of poor functional outcome such as antithrombotic drug use, hyperglycemia, previous cerebrovascular accident, low platelet count, and pontine/massive/intraventricular hemorrhage. However, at multivariate analysis only pre-ICH mRS score (OR 30.84), GCS score at presentation (OR 11.88), initial hematoma volume (OR 29.71), and NIHSS score at presentation (OR 25.89) were independent predictors of death and poor functional outcome. CONCLUSION: Despite the heterogeneity among centers, this study on ICH has identified four simple prognostic factors that can independently predict patients outcome, stratify their risk, and guide their management.

The "SALPARE study" of spontaneous intracerebral haemorrhage-part 2-early CT predictors of outcome in ICH: keeping it simple.

BACKGROUND: The aim of this study was to investigate the prognostic role of hematoma characteristics and hematoma expansion (HE) in patients with spontaneous intracerebral hemorrhage (ICH). METHODS: This multicenter prospective cohort study enrolled consecutive adult patients with non-traumatic ICH admitted to three Italian academic hospitals (Salerno, Padova, Reggio Emilia) over a 2-year period. Early noncontrast CT (NCCT) features of the hematoma, including markers of HE, and 3-month outcome were recorded. Multivariable logistic regression analysis was performed to identify predictors of poor outcome. RESULTS: A total of 682 patients were included in the study [mean age: 73 ± 14 years; 316 (46.3%) females]. Pontine and massive hemorrhage, intraventricular bleeding, baseline hematoma volume > 15 mL, blend sign, swirl sign, margin irregularity ≥ 4, density heterogeneity ≥ 3, hypodensity ≥ 1, island sign, satellite sign, and black hole sign were associated with a higher risk of mortality and disability. However, at multivariate analysis only initial hematoma volume (OR 29.71) proved to be an independent predictor of poor functional outcome at 3 months. CONCLUSION: Simple hematoma volume measured on baseline CT best identifies patients with a worse outcome, while early NCCT markers of HE do not seem to add any clinically significant information.

European Stroke Organisation (ESO) Guidelines on Moyamoya angiopathy Endorsed by Vascular European Reference Network (VASCERN).

The European Stroke Organisation (ESO) guidelines on Moyamoya Angiopathy (MMA), developed according to ESO standard operating procedure and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology, were compiled to assist clinicians in managing patients with MMA in their decision making. A working group involving neurologists, neurosurgeons, a geneticist and methodologists identified nine relevant clinical questions, performed systematic literature reviews and, whenever possible, meta-analyses. Quality assessment of the available evidence was made with specific recommendations. In the absence of sufficient evidence to provide recommendations, Expert Consensus Statements were formulated. Based on low quality evidence from one RCT, we recommend direct bypass surgery in adult patients with haemorrhagic presentation. For ischaemic adult patients and children, we suggest revascularization surgery using direct or combined technique rather than indirect, in the presence of haemodynamic impairment and with an interval of 6-12 weeks between the last cerebrovascular event and surgery. In the absence of robust trial, an Expert Consensus was reached recommending long-term antiplatelet therapy in non-haemorrhagic MMA, as it may reduce risk of embolic stroke. We also agreed on the utility of performing pre- and post- operative haemodynamic and posterior cerebral artery assessment. There were insufficient data to recommend systematic variant screening of RNF213 p.R4810K. Additionally, we suggest that long-term MMA neuroimaging follow up may guide therapeutic decision making by assessing the disease progression. We believe that this guideline, which is the first comprehensive European guideline on MMA management using GRADE methods will assist clinicians to choose the most effective management strategy for MMA.

Thrombolysis after dabigatran reversal: A nation-wide Italian multicentre study, systematic review and meta-analysis.

Introduction: Recent anticoagulant intake represents a contraindication for thrombolysis in acute ischemic stroke. Idarucizumab reverses the anticoagulant effect of dabigatran, potentially allowing for thrombolysis. This nation-wide observational cohort study, systematic review, and meta-analysis evaluated the efficacy and safety of thrombolysis preceded by dabigatran-reversal in people with acute ischemic stroke. Patients and methods: We recruited people undergoing thrombolysis following dabigatran-reversal at 17 stroke centers in Italy (reversal-group), people on dabigatran treated with thrombolysis without reversal (no-reversal group), and age, sex, hypertension, stroke severity, and reperfusion treatment-matched controls in 1:7 ratio (control-group). We compared groups for symptomatic intracranial hemorrhage (sICH, main outcome), any brain hemorrhage, good functional outcome (mRS 0-2 at 3 months), and death. The systematic review followed a predefined protocol (CRD42017060274), and odds ratio (OR) meta-analysis was implemented to compare groups. Results: Thirty-nine patients in dabigatran-reversal group and 300 matched controls were included. Reversal was associated with a non-significant increase in sICH (10.3% vs 6%, aOR = 1.32, 95% CI = 0.39-4.52), death (17.9% vs 10%, aOR = 0.77, 95% CI = 0.12-4.93) and good functional outcome (64.1% vs 52.8%, aOR = 1.41, 95% CI = 0.63-3.19). No hemorrhagic events or deaths were registered in no-reversal group (n = 12). Pooling data from 3 studies after systematic review (n = 1879), reversal carried a non-significant trend for sICH (OR = 1.53, 95% CI = 0.67-3.50), death (OR = 1.53, 95% CI = 0.73-3.24) and good functional outcome (OR = 2.46, 95% CI = 0.85-7.16). Discussion and conclusion: People treated with reperfusion strategies after dabigatran reversal with idarucizumab seem to have a marginal increase in the risk of sICH but comparable functional recovery to matched patients with stroke. Further studies are needed to define treatment cost-effectiveness and potential thresholds in plasma dabigatran concentration for reversal.