European Stroke Journal

Practical suggestions on clinical decisions about vascular disease management in patients with cognitive impairment are proposed.

The document was produced by the Dementia Committee of the European Stroke Organisation (ESO) based on the evidence from the literature where available and on the clinical experience of the Committee members. This paper was endorsed by the ESO.

Vascular risk factors and cerebrovascular disease are frequent in patients with cognitive impairment. While acute stroke treatment has evolved substantially in last decades, evidence of management of cerebrovascular pathology beyond stroke in patients with cognitive impairment and dementia is quite limited. Additionally, trials to test some daily-life clinical decisions are likely to be complex, difficult to undertake and take many years to provide sufficient evidence to produce recommendations. This document was conceived to provide some suggestions until data from field trials are available. It was conceived for the use of clinicians from memory clinics or involved specifically in cognitive disorders, addressing practical aspects on diagnostic tools, vascular risk management and suggestions on some therapeutic options.

The authors did not aim to do an exhaustive or systematic review or to cover all current evidence. The document approach in a very practical way frequent issues concerning cerebrovascular disease in patients with known cognitive impairment.

The initiation and conduct of randomised clinical trials are complicated by multiple barriers, including delays in obtaining regulatory approvals. Quantitative data on the extent of the delays due to national or local review in randomised clinical trials is scarce.

We assessed the times needed to obtain regulatory approval and to initiate a trial site for an academic, EU-funded, phase III, randomised clinical trial of pharmacological prevention of complications in patients with acute stroke in over 80 sites in nine European countries. The primary outcome was the time from the first submission to a regulatory authority to initiation of a trial site. Secondary outcomes included time needed to complete each individual preparatory requirement and the number of patients recruited by each site in the first 6 and 12 months.

The median time from the first submission to a regulatory authority to initiation of a trial site was 784 days (IQR: 586–1102). The single most time-consuming step was the conclusion of a clinical trial agreement between the national coordinator and the trial site, which took a median of 194 days (IQR: 93–293). A longer time to site initiation was associated with a lower patient recruitment rate in the first six months after initiation (B = –0.002; p = 0.02).

In this EU-funded clinical trial, approximately 26 months were needed to initiate a trial site for patient recruitment. The conclusion of a contract with a trial site was the most time-consuming activity. To simplify and speed up the process, we suggest that the level of detail of contracts for academic trials should be proportional to the risks and commercial interests of these trials.

Hyperintense acute reperfusion marker (HARM) is an indicator of early disruption of the blood-brain-barrier. Our aim was to investigate the incidence of HARM in patients with a diffusion weighted imaging (DWI) - fluid attenuated inversion recovery (FLAIR) mismatch and determine the association between this marker and hemorrhagic complications as well as clinical outcome.

We included patients from the Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial who underwent baseline perfusion weighted imaging (PWI). HARM was defined as a hyperintense signal in the cerebrospinal fluid space on FLAIR imaging at 24 h after baseline imaging. We compared baseline characteristics in patients with and without HARM and investigated the association between HARM and any hemorrhagic transformation (HT) and parenchymal hematoma (PH) in a multivariate logistic regression. We also explored HARM as an independent predictor of poor outcome, defined as a modified Rankin Scale of 3–6 at 90 days.

HARM was present in 14 of 223 (6%) patients with a DWI-FLAIR mismatch and baseline characteristics were similar in patients with vs without HARM. HARM showed an independent relationship with any HT (OR 6.67; 95%CI 1.72–26.58) and any PH (OR 6.92; 95%CI 1.34–29.49). The rate of HARM was similar in patients with good and poor outcome (5%, p = 0.90).

In the WAKE-UP trial, the incidence of HARM was only 6% at 24 h. An association was present between HARM and hemorrhagic complications, but no relationship with functional outcome was observed.

The role of surgery in spontaneous intracerebral haemorrhage (sICH) remains controversial. This leads to variation in the percentage of patients who are treated with surgery between countries.

We sent an online survey to all neurosurgeons (n = 140) and to a sample of neurologists (n = 378) in Dutch hospitals, with questions on management in supratentorial sICH in general, and on treatment in six patients, to explore current variation in medical and neurosurgical management. We assessed patient and haemorrhage characteristics influencing treatment decisions.

Twenty-nine (21%) neurosurgeons and 92 (24%) neurologists responded. Prior to surgery, neurosurgeons would more frequently administer platelet-transfusion in patients on clopidogrel (64% versus 13%; p = 0.000) or acetylsalicylic acid (61% versus 11%; p = 0.000) than neurologists. In the cases, neurosurgeons and neurologists were similar in their choice for surgery as initial treatment (24% and 31%; p = 0.12), however variation existed amongst physicians in specific cases. Neurosurgeons preferred craniotomy with haematoma evacuation (74%) above minimally-invasive techniques (5%). Age, Glasgow Coma Scale score and ICH location were important factors influencing decisions on treatment for neurosurgeons and neurologists. 69% of neurosurgeons and 80% of neurologists would randomise patients in a trial evaluating the effect of minimally-invasive surgery on functional outcome.

Our results reflect the lack of evidence about the right treatment strategy in patients with sICH.

New high quality evidence is needed to guide treatment decisions for patients with ICH. The willingness to randomise patients into a clinical trial on minimally-invasive surgery, contributes to the feasibility of such studies in the future.

Non-vitamin K-antagonist oral anticoagulants (NOAC) have become first choice oral anticoagulant (OAC) with decreasing use of vitamin K antagonists (VKA), partly due to lower risk of intracerebral hemorrhage (ICH). Aim: to identify trends in sale of OACs and relate them to trends in OAC-related ICH (OAC-ICH).

Study was based on the population in the Capital Region of Denmark (1.8 million inhabitants). We identified all patients admitted with a non-traumatic OAC-ICH in 2010–2017 and ascertained diagnosis and drug use through medical charts. We used information available in the public domain on sale of defined daily doses (DDD) of OAC in the Capital Region of Denmark.

453 patients with OAC-ICH out of a total of 2877 ICH-events were identified. From 2010 to 2017 sale of NOAC rose from 0.1 to 11.8 DDD/1000 inhabitants/day (p < 0.001); while VKA sale decreased from 7.6 to 5.2 DDD/1000 inhabitants/day (p < 0.001). The total number of ICH events was stable between 2010 and 2017, but the proportion of OAC-ICH events increased from 13% in 2010 to 22% in 2017 (p < 0.001). The proportion of ICH events related to NOAC had a significant increasing trend (p < 0.001), whereas a decreasing trend was observed for VKA (p = 0.04).

In Denmark, the population on OACs has increased; resulting from increased use of NOACs. Parallel to this development, the proportion of OAC-ICH overall has increased based on an increasing trend in NOAC-related ICH.

Our findings document a need for further research on prevention and treatment of this complication.

Knowledge of the implementation gap would facilitate the use of intravenous thrombolysis in stroke, which is still low in many countries. The study was conducted to identify national implementation targets for the utilisation and logistics of intravenous thrombolysis.

Multicomponent interventions by stakeholders in health care to optimise prehospital and hospital management with the goal of fast and accessible intravenous thrombolysis for every candidate. Implementation results were documented from prospectively collected cases in all 45 stroke centres nationally. The thrombolytic rate was calculated from the total number of all ischemic strokes in the population of the Czech Republic since 2004.

Thrombolytic rates of 1.3 (95%CI 1.1 to 1.4), 5.4 (95%CI 5.1 to 5.7), 13.6 (95%CI 13.1 to 14.0), 23.3 (95%CI 22.8 to 23.9), and 23.5% (95%CI 23.0 to 24.1%) were achieved in 2005, 2009, 2014, 2017, and 2018, respectively. National median door-to-needle times were 60–70 minutes before 2012 and then decreased progressively every year to 25 minutes (IQR 17 to 36) in 2018. In 2018, 33% of both university and non-university hospitals achieved median door-to-needle time ≤20 minutes. In 2018, door-to-needle times ≤20, ≤45, and ≤60 minutes were achieved in 39, 85, and 93% of patients.

Thrombolysis can be provided to ≥ 20% of all ischemic strokes nationwide and it is realistic to achieve median door-to-needle time 20 minutes.

Stroke 20–20 could serve as national implementation target for intravenous thrombolysis and country specific implementation policies should be applied to achieve such target.

The Oxfordshire Community Stroke Project (OCSP) proposed a clinical classification for Stroke patients. This classification has proved helpful to predict the risk of neurological complications. However, the OCSP was initially based on findings on the neurological assesment, which can pose difficulties for classifying patients. We aimed to describe the development and the validation step of a computer-based algorithm based on the OCSP classification.

A flow-chart was created which was reviewed by five board-certified vascular neurologists from which a computer-based algorithm (COMPACT) was developed. Neurology residents from 12 centers were invited to participate in a randomized trial to assess the effect of using COMPACT. They answered a 20-item questionnaire for classifying the vignettes according to the OCSP classification. Each correct answer has been attributed to 1-point for calculating the final score.

Six-two participants agreed to participate and answered the questionnaire. Thirty-two were randomly allocated to use our algorithm, and thirty were allocated to adopt a list of symptoms alone. The group who adopted our algorithm had a median score of correct answers of 16.5[14.5, 17]/20 versus 15[13, 16]/20 points, p = 0.014. The use of our algorithm was associated with the overall rate of correct scores (p = 0.03).

Our algorithm seemed a useful tool for any postgraduate year Neurology resident. A computer-based algorithm may save time and improve the accuracy to classify these patients.

An easy-to-use computer-based algorithm improved the accuracy of the OCSP classification, with the possible benefit of further improvement of the prediction of neurological complications and prognostication.

To assess the association between 24 h blood pressure variability (BPV) on functional outcome and treatment effect of intravenous alteplase in acute ischaemic stroke.

In all patients with acute ischaemic stroke of unknown onset randomised in the WAKE-UP (Efficacy and Safety of magnetic resonance imaging [MRI]-based Thrombolysis in Wake-Up Stroke) trial, blood pressure (BP) was measured before randomisation and after initiation of treatment at regular intervals up to 24 hours. Individual BPV was measured by coefficient of variation (CV) of all BP values. Primary outcome measure was favourable outcome defined by a modified Rankin Scale (mRS) score 0 or 1 at 90 days after stroke.

BP measurements were available for 498 of 503 patients randomised (177 women [35.5%], mean age [SD] of 65.2 [11.5] years). Systolic BPV was not associated with the treatment effect of thrombolysis (test for interaction, p = 0.46). The adjusted odds ratio (aOR) for favourable outcome with alteplase, adjusted for age, stroke severity and baseline BP on admission, did not show an association across the quintiles of increasing systolic BPV with an aOR 1.89 (95% confidence interval [CI], 0.76–4.70) in the lowest quintile to aOR 1.05 (95% CI, 0.43–2.56) in the highest quintile. Higher mean systolic BP was associated with a smaller treatment effect of thrombolysis with a significant interaction (p = 0.033). The aOR for favourable outcome with alteplase decreased with quintiles of increasing mean systolic BP from aOR 3.16 (95% CI, 1.26–7.93) in the lowest quintile to aOR 0.84 (95% CI, 0.34–2.10) in in the highest quintile.

There was a significant interaction between mean systolic BP and treatment effect of thrombolysis with higher mean systolic BP being associated with poorer outcome. BPV was not associated with outcome after thrombolysis.

ClinicalTrials.gov identifier NCT01525290.

Despite a high burden of stroke, access to rapid brain imaging is limited in many middle- and low-income countries. Previous studies have described the astroglial protein GFAP (glial fibrillary acidic protein) as a biomarker of intracerebral hemorrhage. The aim of this study was to test the diagnostic accuracy of GFAP for ruling out intracranial hemorrhage in a prospective cohort of Indian stroke patients.

This study was conducted in an Indian tertiary hospital (Christian Medical College, Ludhiana). Patients with symptoms suggestive of acute stroke admitted within 12 h of symptom onset were enrolled. Blood samples were collected at hospital admission. Single Molecule Array technology was used for determining serum GFAP concentrations.

A total number of 155 patients were included (70 intracranial hemorrhage, 75 ischemic stroke, 10 stroke mimics). GFAP serum concentrations were elevated in intracranial hemorrhage patients compared to ischemic stroke patients [median (interquartile range) 2.36 µg/L (0.61–7.16) vs. 0.18 µg/L (0.11–0.38), p < 0.001]. Stroke mimics patients had a median GFAP serum level of 0.14 µg/L (0.09–0.26). GFAP values below the cut-off of 0.33 µg/L (area under the curve 0.871) ruled out intracranial hemorrhage with a negative predictive value of 89.7%, (at a sensitivity for detecting intracranial hemorrhage of 90.0%).

The high negative predictive value of a GFAP test system allows ruling out patients with intracranial hemorrhage.

In settings where immediate brain imaging is not available, this would enable to implement secondary prevention (e.g., aspirin) in suspected ischemic stroke patients as soon as possible.

Intracerebral haemorrhage (ICH) in young adults is rare but has devastating consequences. We investigated long-term mortality rates, causes of death and predictors of long-term mortality in young spontaneous ICH survivors.

We included consecutive patients aged 18–55 years from the Prognosis of Intracerebral Haemorrhage cohort (PITCH), a prospective observational cohort of patients admitted to Lille University Hospital (2004–2009), who survived at least 30 days after spontaneous ICH. We studied long-term mortality with Kaplan-Meier analyses, collected causes of death, performed uni-/multivariable Cox-regression analyses for the association of baseline characteristics with long-term mortality.

Of 560 patients enrolled in the PITCH, 75 patients (75% men) met our inclusion criteria (median age 50 years, interquartile range [IQR] 44–53 years). During a median follow-up of 8.2 years (IQR 5.0–10.1), 26 patients died (35%), with a standardized mortality ratio of 13.0 (95% confidence interval [95% CI] 8.5–18.0) compared to peers from the general population. Causes of death were vascular in 7 (27%) patients, non-vascular in 13 (50%) and unknown in 6 (23%). Global cerebral atrophy (hazard ratio [HR] 3.0, 95% CI 1.1–8.6), modified Rankin Score >2 before ICH (HR 3.4, 95% CI 1.0–11.0), and excessive alcohol consumption (HR 3.3, 95% CI 1.1–10.2) were independently associated with long-term mortality.

We found a 13-fold higher mortality risk for young ICH survivors compared to the general French population. Predictors of long-term mortality were pre-existing conditions, not ICH-characteristics.

Young ICH survivors remain at increased mortality risk of vascular and non-vascular death for years after ICH.

Prehospital stroke scales have been proposed to identify stroke patients with a large vessel occlusion to allow direct transport to an intervention centre capable of endovascular treatment (EVT). It is unclear whether these scales are able to detect not only proximal, but also more distal treatable occlusions. Our aim was to assess the sensitivity of prehospital stroke scales for different EVT-eligible occlusion locations in the anterior circulation.

The MR CLEAN Registry is a prospective, observational study in all centres that perform EVT in the Netherlands. We included adult patients with an anterior circulation stroke treated between March 2014 and November 2017. We used National Institutes of Health Stroke Scale scores at admission to reconstruct previously published prehospital stroke scales. We compared the sensitivity of each scale for different occlusion locations. Occlusions were assessed with CT angiography by an imaging core laboratory blinded to clinical findings.

We included 3021 patients for the analysis of 14 scales. All scales had the highest sensitivity to detect internal carotid artery terminus occlusions (ranging from 0.21 to 0.97) and lowest for occlusions of the M2 segment (0.08 to 0.84, p-values < 0.001).

Discussion and conclusion: Although prehospital stroke scales are generally sensitive for proximal large vessel occlusions, they are less sensitive to detect more distal occlusions.

Systemic contraceptives increase the risk of ischemic stroke but little is known about the characteristics, mechanisms and long-term outcome post stroke of patients on hormonal contraception. We sought to To assess characteristics and outcome of acute ischemic stroke (AIS) in young women using systemic hormonal contraceptives (SHC) and compare them to strokes in non-contraceptive users.

Using the Acute STroke Registry and Analysis of Lausanne (ASTRAL), we analyzed demographics, risk factors, clinical, radiological and treatment data of consecutive female patients of <50 years between 2003 to 2015. We compared groups with and without SHC in a logistic regression analysis.

Of the 179 female patients of <50 years during the observation period, 57 (39.6%) used SHC, 71.9% of whom, a combined oral contraceptive pill. On logistic regression contraceptive users were significantly younger but had comparable stroke severity. They had less migraine with aura and tobacco use, and more hyperlipidaemia. Also, contraceptive users had significantly less intra and extracranial stenosis and occlusion on arterial imaging, but more focal hypoperfusion on CT-perfusion. Undetermined mechanism of stroke was more frequent with SHC users, whereas rare mechanisms were more frequent in non-users. The contraceptive user group had a more favourable adjusted 12-month outcome with significantly fewer ischemic recurrences after stopping systemic contraception in all.

Contraceptive users with ischemic strokes are younger and have lesser tobacco use and migraine with aura and more hyperlipidemia. Their stroke mechanism is more often undetermined using a standardised work-up, and their adjusted long-term outcome is more favourable with less stroke recurrence.

Previous studies showed insufficient control of cardiovascular risk factors (CVRF) and high stroke recurrence rates among ischemic stroke patients in Germany. Currently, no structured secondary prevention program exists in clinical routine. We present the trial design and pilot phase results of a complex intervention to improve stroke care after hospital discharge in Germany.

SANO is a cluster-randomized trial with 30 participating regions across Germany aiming to enrol 2,790 patients (drks.de, DRKS00015322). Study intervention combines both structural and patient-centred elements. Study development was based on the Medical Research Council framework for complex interventions. In 15 intervention regions, a cross-sectoral multidisciplinary network is established to enhance CVRF control as well as detection and treatment of post-stroke complications. Recommendations on CVRF are based on high-quality secondary prevention guidelines. Study physicians use motivational interviewing and agree with patients on therapeutic targets. While hospitalised, patients also receive dietary counselling and a health-passport to track their progress. During regular visits, CVRF management and potential complications are monitored. The intervention is compared to 15 regions providing usual care. The primary endpoint is the combination of recurrent stroke, myocardial infarction and death assessed 12 months after enrolment and adjudicated in a blinded manner.

Eighteen patients were enrolled in a pilot phase that demonstrated feasibility of patient recruitment and study procedures.

SANO is investigating a program to reduce outcome events after ischemic stroke by implementing a complex intervention. If successful, the program may be implemented in routine care on national level in Germany.

Inflammation contributes to unstable atherosclerotic plaque and stroke. In randomised trials in patients with coronary disease, canukinumab (an interleukin-1B antagonist) and colchicine (a tubulin inhibitor with pleiotropic anti-inflammatory effects) reduced recurrent vascular events.

Hypothesis: Anti-inflammatory therapy with low-dose colchicine plus usual care will reduce recurrent vascular events in patients with non-severe, non-cardioembolic stroke and TIA compared with usual care alone.

CONVINCE is a multi-centre international (in 17 countries) Prospective, Randomised Open-label, Blinded-Endpoint assessment (PROBE) controlled Phase 3 clinical trial in 3154 participants. The intervention is colchicine 0.5 mg/day and usual care versus usual care alone (antiplatelet, lipid-lowering, antihypertensive treatment, lifestyle advice). Included patients are at least 40 years, with non-severe ischaemic stroke (modified Rankin score ≤3) or high-risk TIA (ABCD2 > 3, or positive DWI, or cranio-cervical artery stenosis) within 72 hours-28 days of randomisation, with qualifying stroke/TIA most likely caused by large artery stenosis, lacunar disease, or cryptogenic embolism. Exclusions are stroke/TIA caused by cardio-embolism or other defined cause (e.g. dissection), contra-indication to colchicine (including potential drug interactions), or incapacity for participation in a clinical trial. The anticipated median follow-up will be 36 months. The primary analysis will be by intention-to-treat.

The primary outcome is time to first recurrent ischaemic stroke, myocardial infarction, cardiac arrest, or hospitalisation with unstable angina (non-fatal or fatal).

CONVINCE will provide high-quality randomised data on the efficacy and safety of anti-inflammatory therapy with colchicine for secondary prevention after stroke.

First-patient first-visit was December 2016. Recruitment to complete in 2021, follow-up to complete in 2023.

The aim of the present European Stroke Organisation Transient Ischaemic Attack (TIA) management guideline document is to provide clinically useful evidence-based recommendations on approaches to triage, investigation and secondary prevention, particularly in the acute phase following TIA. The guidelines were prepared following the Standard Operational Procedure for a European Stroke Organisation guideline document and according to GRADE methodology. As a basic principle, we defined TIA clinically and pragmatically for generalisability as transient neurological symptoms, likely to be due to focal cerebral or ocular ischaemia, which last less than 24 hours. High risk TIA was defined based on clinical features in patients seen early after their event or having other features suggesting a high early risk of stroke (e.g. ABCD2 score of 4 or greater, or weakness or speech disturbance for greater than five minutes, or recurrent events, or significant ipsilateral large artery disease e.g. carotid stenosis, intracranial stenosis). Overall, we strongly recommend using dual antiplatelet treatment with clopidogrel and aspirin short term, in high-risk non-cardioembolic TIA patients, with an ABCD2 score of 4 or greater, as defined in randomised controlled trials (RCTs). We further recommend specialist review within 24 hours after the onset of TIA symptoms. We suggest review in a specialist TIA clinic rather than conventional outpatients, if managed in an outpatient setting. We make a recommendation to use either MRA or CTA in TIA patients for additional confirmation of large artery stenosis of 50% or greater, in order to guide further management, such as clarifying degree of carotid stenosis detected with carotid duplex ultrasound. We make a recommendation against using prediction tools (eg ABCD2 score) alone to identify high risk patients or to make triage and treatment decisions in suspected TIA patients as due to limited sensitivity of the scores, those with score value of 3 or less may include significant numbers of individual patients at risk of recurrent stroke, who require early assessment and treatment. These recommendations aim to emphasise the importance of prompt acute assessment and relevant secondary prevention. There are no data from randomised controlled trials on prediction tool use and optimal imaging strategies in suspected TIA.