Trigger factors in patients with a patent foramen ovale-associated stroke: A case-crossover study.

BACKGROUND: Patent foramen ovale (PFO) is a congenital anatomical variant which is associated with strokes in young adults. Contrary to vascular risk factors and atherosclerosis, a PFO is present from birth. However, it is completely unknown how an anatomical structure that is already present at birth in a large proportion of the population can convert into a PFO that causes stroke in a few. Recent studies reported a significant association between certain trigger factors and ischemic stroke in young adults. This study aims to investigate these triggers in PFO-associated stroke. METHODS: The ODYSSEY study, a multicenter prospective cohort study between 2013 and 2021, included patients aged 18-49 years experiencing their first-ever ischemic event. Participants completed a questionnaire about exposure to potential trigger factors. A case-crossover design was used to assess the relative risks (RR) with 95% confidence intervals (95% CI). The primary outcome was the RR of potential trigger factors for PFO-associated stroke. RESULTS: Overall, 1043 patients completed the questionnaire and had an ischemic stroke, of which 124 patients had a PFO-associated stroke (median age 42.1 years, 45.2% men). For patients with PFO-associated stroke, the RR was 26.0 (95% CI 8.0-128.2) for fever, 24.2 (95% CI 8.5-68.7) for flu-like disease, and 3.31 (95% CI 2.2-5.1) for vigorous exercise. CONCLUSION: In conclusion, flu-like disease, fever, and vigorous exercise may convert an asymptomatic PFO into a stroke-causing PFO in young adults. DATA ACCESS STATEMENT: The raw and anonymized data used in this study can be made available to other researchers on request. Written proposals can be addressed to the corresponding author and will be assessed by the ODYSSEY investigators for appropriateness of use, and a data sharing agreement in accordance with Dutch regulations will be put in place before data are shared.

Blood pressure variability and white matter hyperintensities after ischemic stroke.

Background: High blood pressure variability (BPV) may be a risk factor for stroke and dementia in patients with ischemic stroke, but the underlying mechanism is unknown. We aimed to investigate whether high BPV is associated with presence and progression of white matter hyperintensities (WMH). Methods: We performed a post-hoc analysis on the MRI substudy of the PRoFESS trial, including 771 patients with ischemic stroke who underwent MRI at baseline and after a median of 2.1 years. WMH were rated with a semi-quantitative scale. Visit-to-visit BPV was expressed as the coefficient of variation (interval 3-6 months, median number of visits 7). The association of BPV with WMH burden and progression was assessed with linear and logistic regression analyses adjusted for confounders. Results: BPV was associated with burden of periventricular WMH (ß 0.36 95%CI 0.19-0.53, per one SD increase in BPV) and subcortical (log-transformed) WMH (ß 0.25, 95%CI 0.08-0.42). BPV was not associated with periventricular (OR 1.09, 95%CI 0.94-1.27) and subcortical WMH progression (OR 1.15, 95%CI 0.99-1.35). Associations were independent of mean BP. Conclusion: High visit-to-visit BPV was associated with both subcortical and periventricular WMH burden in patients with ischemic stroke, but not with WMH progression in this study.

Acute care bundles should be used for patients with intracerebral haemorrhage: An expert consensus statement.

PURPOSE: Intracerebral haemorrhage (ICH) is the most devastating form of stroke and a major cause of disability. Clinical trials of individual therapies have failed to definitively establish a specific beneficial treatment. However, clinical trials of introducing care bundles, with multiple therapies provided in parallel, appear to clearly reduce morbidity and mortality. Currently, not enough patients receive these interventions in the acute phase. METHODS: We convened an expert group to discuss best practices in ICH and to develop recommendations for bundled care that can be delivered in all settings that treat acute ICH, with a focus on European healthcare systems. FINDINGS: In this consensus paper, we argue for widespread implementation of formalised care bundles in ICH, including specific metrics for time to treatment and criteria for the consideration of neurosurgical therapy. DISCUSSION: There is an extraordinary opportunity to improve clinical care and clinical outcomes in this devastating disease. Substantial evidence already exists for a range of therapies that can and should be implemented now.

The association between perihaematomal oedema and functional outcome after spontaneous intracerebral haemorrhage: A systematic review and meta-analysis.

PURPOSE: Perihaematomal oedema (PHO) formation has gained increasing interest as a therapeutic target after spontaneous intracerebral haemorrhage (ICH). Whether PHO contributes to poor outcome is unclear. We aimed to determine the association between PHO and outcome in patients with spontaneous ICH. METHOD: We searched five databases up to 17 November 2021 for studies of ⩾10 adults with ICH reporting the presence of PHO and outcome. We assessed risk of bias, extracted aggregate data and used random effects meta-analysis to pool studies that reported odds ratios (OR) with 95% confidence intervals (CI). Primary outcome was poor functional outcome defined as modified Rankin Scale score of 3-6 at 3 months. Additionally, we assessed PHO growth and poor outcome at any time of follow-up. We prospectively registered the protocol in PROSPERO (CRD42020157088). FINDINGS: We identified 12,968 articles, of which we included 27 studies (n = 9534). Eighteen studies reported an association between larger PHO volume and poor outcome, six a neutral result and three an inverse relationship. Larger absolute PHO volume was associated with poor functional outcome at 3 months (OR per mL increase of absolute PHO 1.03, 95% CI 1.00-1.06, I2 44%, four studies). Additionally, PHO growth was associated with poor outcome (OR 1.04, 95% CI 1.02-1.06, I2 0%, seven studies). DISCUSSION: In patients with spontaneous ICH, larger PHO volume is associated with poor functional outcome at 3 months. These findings support the development and investigation of new therapeutic interventions targeting PHO formation to evaluate if reduction of PHO improves outcome after ICH.

Challenges and opportunities in research funding for neurovascular diseases from a clinical researcher's perspective.

BACKGROUND & PURPOSE: Neurovascular research is underfunded, imposing substantial challenges on clinical researchers in the field of neurovascular diseases. We explored what physicians perceive to be the greatest challenges with regard to neurovascular research funding, and how they think the funding crisis in neurovascular research could be overcome. METHODS: We performed an international, multi-disciplinary survey among physicians involved in the medical care of patients with neurovascular diseases. After providing their demographic data, physicians were asked closed-ended questions on their personal opinion regarding challenges in neurovascular research funding, and how these challenges could be overcome. Physicians also described in their own words what they perceived to be the biggest challenges in obtaining funding. Data were analyzed using descriptive statistics and response clustering. RESULTS: Of 233 participating physicians (70.4% male,82.8% senior staff) from 48 countries, 217(97.4%) perceived the discrepancy between required and available funding to be a problem;172(73.8%) considered it a major problem. High competitiveness (61/118 available free text responses[51.7%]), time-consuming application processes (28/118[23.7%]) and administrative requirements (25/118[21.1%]) were identified as key obstacles. Traditional big funding agencies were perceived to be most capable of closing the neurovascular research funding gap, followed by specialty-specific organizations and industry, while philanthropy and crowdfunding were perceived to be less important. CONCLUSION: The gap between required and available funding was perceived to be a major problem in neurovascular research, with high competitiveness, time-consuming funding processes and excessive administrative requirements being the key obstacles to obtaining funding. Traditional funding agencies were perceived to be most capable of closing this funding gap.

A Causal Classification System for Intracerebral Hemorrhage Subtypes.

OBJECTIVE: Determining the underlying causes of intracerebral hemorrhage (ICH) is of major importance, because risk factors, prognosis, and management differ by ICH subtype. We developed a new causal CLASsification system for ICH Subtypes, termed CLAS-ICH, based on recent advances in neuroimaging. METHODS: CLAS-ICH defines 5 ICH subtypes: arteriolosclerosis, cerebral amyloid angiopathy, mixed small vessel disease (SVD), other rare forms of SVD (genetic SVD and others), and secondary causes (macrovascular causes, tumor, and other rare causes). Every patient is scored in each category according to the level of diagnostic evidence: (1) well-defined ICH subtype; (2) possible underlying disease; and (0) no evidence of the disease. We evaluated CLAS-ICH in a derivation cohort of 113 patients with ICH from Massachusetts General Hospital, Boston, USA, and in a derivation cohort of 203 patients from Inselspital, Bern, Switzerland. RESULTS: In the derivation cohort, a well-defined ICH subtype could be identified in 74 (65.5%) patients, including 24 (21.2%) with arteriolosclerosis, 23 (20.4%) with cerebral amyloid angiopathy, 18 (15.9%) with mixed SVD, and 9 (8.0%) with a secondary cause. One or more possible causes were identified in 42 (37.2%) patients. Interobserver agreement was excellent for each category (kappa value ranging from 0.86 to 1.00). Despite substantial differences in imaging modalities, we obtained similar results in the validation cohort. INTERPRETATION: CLAS-ICH is a simple and reliable classification system for ICH subtyping, that captures overlap between causes and the level of diagnostic evidence. CLAS-ICH may guide clinicians to identify ICH causes, and improve ICH classification in multicenter studies. ANN NEUROL 2023;93:16-28.

Tranexamic Acid After Aneurysmal Subarachnoid Hemorrhage: Post-Hoc Analysis of the ULTRA Trial.

BACKGROUND AND OBJECTIVES: The ULTRA-trial showed that ultra-early and short-term tranexamic acid treatment after subarachnoid hemorrhage did not improve clinical outcome at six months. An expected proportion of the included patients had non-aneurysmal subarachnoid hemorrhage In this post-hoc study, we will investigate whether ultra-early and short-term tranexamic acid treatment in patients with aneurysmal subarachnoid hemorrhage improves clinical outcome at six months. METHODS: The ULTRA-trial is a multicenter, prospective, randomized, controlled, open-label trial with blinded outcome assessment, conducted between July 24, 2013 and January 20, 2020. After confirmation of subarachnoid hemorrhage on non-contrast computer tomography, patients were allocated to either ultra-early and short-term tranexamic acid treatment with usual care, or usual care only. In this post-hoc analysis, we included all ULTRA-participants with a confirmed aneurysm on CT angiography and/or digital subtraction angiography. The primary endpoint was clinical outcome at six months, assessed by the modified Rankin Scale, dichotomized into good (0-3) and poor (4-6) outcome. RESULTS: Of the 813 ULTRA-trial patients who had an aneurysmal subarachnoid hemorrhage, 409 (50%) were assigned to the tranexamic acid group and 404 (50%) to the control group. In the intention-to-treat analysis, 233 of 405 (58%) patients in the tranexamic acid group and 238 of 399 (60%) patients in the control group had a good clinical outcome (adjusted odds ratio (aOR) 0·92; 95% confidence interval (C.I.) 0·69 to 1·24). None of the secondary outcomes showed significant differences between the treatment groups: excellent clinical outcome (mRS 0-2) aOR 0.76, 95% C.I. 0.57-1.03, all-cause mortality at 30 days aOR 0.91, 95% C.I. 0.65-1.28), all-cause mortality at six months aOR 1.10 (95% C.I. 0.80-1.52). DISCUSSION: Ultra-early and short-term tranexamic acid treatment did not improve clinical outcome at six months in patients with aneurysmal subarachnoid hemorrhage and therefore, cannot be recommended. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02684812; submission date February 18, 2016, first patient enrollment on July 24th, 2013). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that tranexamic acid does not improve outcomes in patients presenting with aneurysmal subarachnoid hemorrhage.

Triple Therapy Prevention of Recurrent Intracerebral Disease Events Trial: Rationale, design and progress.

BACKGROUND: Patients who suffer intracerebral hemorrhage (ICH) are at very high risk of recurrent ICH and other serious cardiovascular events. A single-pill combination (SPC) of blood pressure (BP) lowering drugs offers a potentially powerful but simple strategy to optimize secondary prevention. OBJECTIVES: The Triple Therapy Prevention of Recurrent Intracerebral Disease Events Trial (TRIDENT) aims to determine the effects of a novel SPC "Triple Pill," three generic antihypertensive drugs with demonstrated efficacy and complementary mechanisms of action at half standard dose (telmisartan 20 mg, amlodipine 2.5 mg, and indapamide 1.25 mg), with placebo for the prevention of recurrent stroke, cardiovascular events, and cognitive impairment after ICH. DESIGN: An international, double-blind, placebo-controlled, randomized trial in adults with ICH and mild-moderate hypertension (systolic BP: 130-160 mmHg), who are not taking any Triple Pill component drug at greater than half-dose. A total of 1500 randomized patients provide 90% power to detect a hazard ratio of 0.5, over an average follow-up of 3 years, according to a total primary event rate (any stroke) of 12% in the control arm and other assumptions. Secondary outcomes include recurrent ICH, cardiovascular events, and safety. RESULTS: Recruitment started 28 September 2017. Up to 31 October 2021, 821 patients were randomized at 54 active sites in 10 countries. Triple Pill adherence after 30 months is 86%. The required sample size should be achieved by 2024. CONCLUSION: Low-dose Triple Pill BP lowering could improve long-term outcome from ICH.

Secondary injury and inflammation after intracerebral haemorrhage: a systematic review and meta-analysis of molecular markers in patient brain tissue.

BACKGROUND: Inflammatory responses to intracerebral haemorrhage (ICH) are potential therapeutic targets. We aimed to quantify molecular markers of inflammation in human brain tissue after ICH compared with controls using meta-analysis. METHODS: We searched OVID MEDLINE (1946-) and Embase (1974-) in June 2020 for studies that reported any measure of a molecular marker of inflammation in brain tissue from five or more adults after ICH. We assessed risk of bias using a modified Newcastle-Ottawa Scale (mNOS; mNOS score 0-9; 9 indicates low bias), extracted aggregate data, and used random effects meta-analysis to pool associations of molecules where more than two independent case-control studies reported the same outcome and Gene Ontology enrichment analysis to identify over-represented biological processes in pooled sets of differentially expressed molecules (International Prospective Register of Systematic Reviews ID: CRD42018110204). RESULTS: Of 7501 studies identified, 44 were included: 6 were case series and 38 were case-control studies (median mNOS score 4, IQR 3-5). We extracted data from 21 491 analyses of 20 951 molecules reported by 38 case-control studies. Only one molecule (interleukin-1ß protein) was quantified in three case-control studies (127 ICH cases vs 41 ICH-free controls), which found increased abundance of interleukin-1ß protein after ICH (corrected standardised mean difference 1.74, 95% CI 0.28 to 3.21, p=0.036, I2=46%). Processes associated with interleukin-1ß signalling were enriched in sets of molecules that were more abundant after ICH. CONCLUSION: Interleukin-1ß abundance is increased after ICH, but analyses of other inflammatory molecules after ICH lack replication. Interleukin-1ß pathway modulators may optimise inflammatory responses to ICH and merit testing in clinical trials.

Differences in cerebral small vessel disease magnetic resonance imaging markers between lacunar stroke and non-Lobar intracerebral hemorrhage.

INTRODUCTION: It is unclear why cerebral small vessel disease (SVD) leads to lacunar stroke in some and to non-lobar intracerebral hemorrhage (ICH) in others. We investigated differences in MRI markers of SVD in patients with lacunar stroke or non-lobar ICH. PATIENTS AND METHODS: We included patients from two prospective cohort studies with either lacunar stroke (RUN DMC) or non-lobar ICH (FETCH). Differences in SVD markers (white matter hyperintensities [WMH], lacunes, cerebral microbleeds [CMB]) between groups were investigated with univariable tests; multivariable logistic regression analysis, adjusted for age, sex, and vascular risk factors; spatial correlation analysis and voxel-wise lesion symptom mapping. RESULTS: We included 82 patients with lacunar stroke (median age 63, IQR 57-72) and 54 with non-lobar ICH (66, 59-75). WMH volumes and distribution were not different between groups. Lacunes were more frequent in patients with a lacunar stroke (44% vs. 17%, adjusted odds ratio [aOR] 5.69, 95% CI [1.66-22.75]) compared to patients with a non-lobar ICH. CMB were more frequent in patients with a non-lobar ICH (71% vs. 23%, aOR for lacunar stroke vs non-lobar ICH 0.08 95% CI [0.02-0.26]), and more often located in non-lobar regions compared to CMB in lacunar stroke. DISCUSSION: Although we obserd different types of MRI markers of SVD within the same patient, ischemic markers of SVD were more frequent in the ischemic type of lacunar stroke, and hemorrhagic markers were more prevalent in the hemorrhagic phenotype of non-lobar ICH. CONCLUSION: There are differences between MRI markers of SVD between patients with a lacunar stroke and those with a non-lobar ICH.

Assessing cortical cerebral microinfarcts on iron-sensitive MRI in cerebral small vessel disease.

Recent studies suggest that a subset of cortical microinfarcts may be identifiable on T2* but invisible on T1 and T2 follow-up images. We aimed to investigate whether cortical microinfarcts are associated with iron accumulation after the acute stage. The RUN DMC - InTENse study is a serial MRI study including individuals with cerebral small vessel disease (SVD). 54 Participants underwent 10 monthly 3 T MRIs, including diffusion-weighted imaging, quantitative R1 (=1/T1), R2 (=1/T2), and R2* (=1/T2*) mapping, from which MRI parameters within areas corresponding to microinfarcts and control region of interests (ROIs) were retrieved within 16 participants. Finally, we compared pre- and post-lesional values with repeated measures ANOVA and post-hoc paired t-tests using the mean difference between lesion and control ROI values. We observed 21 acute cortical microinfarcts in 7 of the 54 participants (median age 69 years [IQR 66-74], 63% male). R2* maps demonstrated an increase in R2* values at the moment of the last available follow-up MRI (median [IQR], 5 [5-14] weeks after infarction) relative to prelesional values (p = .08), indicative of iron accumulation. Our data suggest that cortical microinfarcts are associated with increased R2* values, indicative of iron accumulation, possibly due to microhemorrhages, neuroinflammation or neurodegeneration, awaiting histopathological verification.

Variation in medical management and neurosurgical treatment of patients with supratentorial spontaneous intracerebral haemorrhage.

INTRODUCTION: 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. PATIENTS AND METHODS: 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. RESULTS: 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. DISCUSSION: Our results reflect the lack of evidence about the right treatment strategy in patients with sICH. CONCLUSION: 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.

Long-term mortality in young patients with spontaneous intracerebral haemorrhage: Predictors and causes of death.

INTRODUCTION: 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. PATIENTS AND METHODS: 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. RESULTS: 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. DISCUSSION: 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. CONCLUSION: Young ICH survivors remain at increased mortality risk of vascular and non-vascular death for years after ICH.

Diffusion-weighted imaging lesions and risk of recurrent stroke after intracerebral haemorrhage.

OBJECTIVE: To determine whether the presence of diffusion-weighted imaging-positive (DWI+) lesions is associated with recurrent stroke after intracerebral haemorrhage (ICH). METHODS: The REstart or STop Antithrombotics Randomised Trial (RESTART) assessed the effect of restarting versus avoiding antiplatelet therapy after ICH on major vascular events for up to 5 years. We rated DWI sequences of MRI done before randomisation for DWI+ lesion presence, masked to outcome and antiplatelet use. Cox proportional hazards regression models were used to quantify associations. RESULTS: Of 537 participants in RESTART, 247 (median (IQR) age 75.7 (69.6-81.1) years; 170 men (68.8%); 120 started vs 127 avoided antiplatelet therapy) had DWI sequences on brain MRI at a median of 57 days (IQR 19-103) after ICH, of whom 73 (30%) had one or more DWI+ lesion. During a median follow-up of 2 years (1-3), 18 participants had recurrent ICH and 21 had ischaemic stroke. DWI+ lesion presence was associated with all stroke, (adjusted HR 2.2 (95% CI 1.1 to 4.2)) and recurrent ICH (4.8 (95% CI 1.8 to 13.2)), but not ischaemic stroke (0.9 (95% CI 0.3 to 2.5)). DWI+ lesion presence (0.5 (95% CI 0.2 to 1.3)) vs absence (0.6 (95% CI 0.3 to 1.5), pinteraction=0.66) did not modify the effect of antiplatelet therapy on a composite outcome of recurrent stroke. CONCLUSIONS: DWI+ lesion presence in ICH survivors is associated with recurrent ICH, but not with ischaemic stroke. We found no evidence of modification of effects of antiplatelet therapy on recurrent stroke after ICH by DWI+ lesion presence. These findings provide a new perspective on the significance of DWI+ lesions, which may be markers of microvascular mechanisms associated with recurrent ICH. TRIAL REGISTRATION NUMBER: ISRCTN71907627.

Long-term prognosis after intracerebral haemorrhage.

INTRODUCTION: The aim of this study was to determine the risk of recurrent intracerebral haemorrhage (ICH), ischaemic stroke, all stroke, any vascular event and all-cause mortality in 30-day survivors of ICH, according to age and sex. PATIENTS AND METHODS: We linked national hospital discharge, population and cause of death registers to obtain a cohort of Dutch 30-day survivors of ICH from 1998 to 2010. We calculated cumulative incidences of recurrent ICH, ischaemic stroke, all stroke and composite vascular outcome, adjusted for competing risk of death and all-cause mortality. Additionally, we compared survival with the general population. RESULTS: We included 19,444 ICH-survivors (52% male; median age 72 years, interquartile range 61-79; 78,654 patient-years of follow-up). First-year cumulative incidence of recurrent ICH ranged from 1.5% (95% confidence interval 0.9-2.3; men 35-54 years) to 2.4% (2.0-2.9; women 75-94 years). Depending on age and sex, 10-year risk of recurrent ICH ranged from 3.7% (2.6-5.1; men 35-54 years) to 8.1% (6.9-9.4; women 55-74 years); ischaemic stroke 2.6% to 7.0%, of all stroke 9.9% to 26.2% and of any vascular event 15.0% to 40.4%. Ten-year mortality ranged from 16.7% (35-54 years) to 90.0% (75-94 years). Relative survival was lower in all age-groups of both sexes, ranging from 0.83 (0.80-0.87) in 35- to 54-year-old men to 0.28 (0.24-0.32) in 75- to 94-year-old women. DISCUSSION: ICH-survivors are at high risk of recurrent ICH, of ischaemic stroke and other vascular events, and have a sustained reduced survival rate compared to the general population. CONCLUSION: The high risk of recurrent ICH, other vascular events and prolonged reduced survival-rates warrant clinical trials to determine optimal secondary prevention treatment after ICH.

Contrast leakage distant from the hematoma in patients with spontaneous ICH: A 7 T MRI study.

Disruption of the blood-brain barrier (BBB) might play a role in the pathophysiology of cerebral small vessel disease-related ICH. The aim of this study was to assess presence and extent of contrast agent leakage distant from the hematoma as a marker of BBB disruption in patients with spontaneous ICH. We prospectively performed 7 tesla MRI in adult patients with spontaneous ICH and assessed contrast leakage distant from the hematoma on 3D FLAIR images. Thirty-one patients were included (mean age 60 years, 29% women). Median time between ICH and MRI was 20 days (IQR 9-67 days). Seventeen patients (54%; seven lobar, nine deep, one infratentorial ICH) had contrast leakage, located cortical in 16 and cortical and deep in one patient. Patients with contrast leakage more often had lobar cerebral microbleeds (CMBs; 77%) than those without (36%; RR 2.5, 95% CI 1.1-5.7) and a higher number of lobar CMBs (patients with contrast leakage: median 2, IQR 1-8 versus those without: median 0, IQR 0-2; p = 0.02). This study shows that contrast leakage distant from the hematoma is common in days to weeks after spontaneous ICH. It is located predominantly cortical and related to lobar CMBs and therefore possibly to cerebral amyloid angiopathy.

Nonfocal transient neurological attacks in patients with carotid artery occlusion.

INTRODUCTION: Nonfocal transient neurological attacks (TNAs) are episodes with atypical, nonlocalizing cerebral symptoms. We examined the prevalence of nonfocal TNAs, in patients with and without carotid artery occlusion (CAO). METHODS: We included 67 patients with CAO and 62 patients without CAO. In both groups, patients had a history of transient ischemic attack (TIA) or nondisabling ischemic stroke in the anterior circulation that had occurred >6 months before inclusion. Patients without CAO did not have ipsilateral or contralateral carotid artery stenosis of ≥50%. All patients were interviewed with a standardized questionnaire on the occurrence of nonfocal TNA symptoms during the preceding six months. We calculated risk ratios (RRs) with 95% confidence intervals (CIs) for the occurrence of ≥1 and ≥2 different nonfocal TNAs after adjustments for age, sex, systolic blood pressure and time interval between most recent TIA or ischemic stroke and administration of the questionnaire. RESULTS: Forty-three of all patients (33%) had had one or more nonfocal TNAs in the preceding six months. Nonrotatory dizziness (24%) was reported most often. The prevalence of ≥1 nonfocal TNAs was not significantly different between patients with and without CAO (39% vs. 27%; adjusted RR 1.47, 95% CI 0.83-2.61), but the prevalence of ≥2 or more different nonfocal TNAs was higher in patients with CAO (16% vs. 3%; adjusted RR 4.77, 95% CI 1.20-18.98). In patients with CAO who also had a contralateral carotid or vertebral artery steno-occlusion, nonfocal TNAs occurred more often than in patients without any carotid or vertebral artery steno-occlusion (46% vs. 27%; adjusted RR 2.22, 95% CI 1.08-4.60 for ≥1 and 21% vs. 3%; adjusted RR 8.27, 95% CI 1.83-37.32 for ≥2 nonfocal TNAs). CONCLUSIONS: Patients with CAO more often experienced multiple nonfocal TNAs than patients without CAO.

Antithrombotic treatment for secondary prevention of stroke and other thromboembolic events in patients with stroke or transient ischemic attack and non-valvular atrial fibrillation: A European Stroke Organisation guideline.

Patients with ischemic stroke or transient ischemic attack and non-valvular atrial fibrillation have a high risk of recurrent stroke and other vascular events. The aim of this guideline is to provide recommendations on antithrombotic medication for secondary prevention of stroke and other vascular outcomes in these patients. The working group identified questions and outcomes, graded evidence, and developed recommendations according to the Grading of Recommendations Assessment, Development, and Evaluation approach and the European Stroke Organisation (ESO) standard operating procedure for guidelines. The guideline was reviewed and approved by the ESO guideline board and the ESO executive committee. In patients with atrial fibrillation and previous stroke or transient ischemic attack, oral anticoagulants reduce the risk of recurrence over antiplatelets or no antithrombotic treatment. Non-vitamin K antagonist oral anticoagulants are preferred over vitamin K antagonists because they have a lower risk of major bleeding and death. Recommendations are weak regarding timing of treatment, (re-)starting oral anticoagulants in patients with previous intracerebral haemorrhage, and treatment in specific patient subgroups of those of older age, with cognitive impairment, renal failure or small vessel disease, because of a lack of strong evidence. In conclusion, for patients with atrial fibrillation and ischemic stroke or transient ischemic attack, non-vitamin K antagonist oral anticoagulants are the preferred treatment for secondary prevention of recurrent stroke or thromboembolism. Further research is required to determine the best timing for initiating oral anticoagulants after an acute ischemic stroke, whether or not oral anticoagulants should be (re)started in patients with a history of intracerebral haemorrhage, and the best secondary preventive treatment in specific subgroups.

Investigating the origin and evolution of cerebral small vessel disease: The RUN DMC - InTENse study.

BACKGROUND: Neuroimaging in older adults commonly reveals signs of cerebral small vessel disease (SVD). SVD is believed to be caused by chronic hypoperfusion based on animal models and longitudinal studies with inter-scan intervals of years. Recent imaging evidence, however, suggests a role for acute ischaemia, as indicated by incidental diffusion-weighted imaging lesions (DWI+ lesions), in the origin of SVD. Furthermore, it becomes increasingly recognised that focal SVD lesions likely affect the structure and function of brain areas remote from the original SVD lesion. However, the temporal dynamics of these events are largely unknown. AIMS: (1) To investigate the monthly incidence of DWI+ lesions in subjects with SVD; (2) to assess to which extent these lesions explain progression of SVD imaging markers; (3) to investigate their effects on cortical thickness, structural and functional connectivity and cognitive and motor performance; and (4) to investigate the potential role of the innate immune system in the pathophysiology of SVD. DESIGN/METHODS: The RUN DMC - InTENse study is a longitudinal observational study among 54 non-demented RUN DMC survivors with mild to severe SVD and no other presumed cause of ischaemia. We performed MRI assessments monthly during 10 consecutive months (totalling up to 10 scans per subject), complemented with clinical, motor and cognitive examinations. DISCUSSION: Our study will provide a better understanding of the role of DWI+ lesions in the pathophysiology of SVD and will further unravel the structural and functional consequences and clinical importance of these lesions, with an unprecedented temporal resolution. Understanding the role of acute, potentially ischaemic, processes in SVD may provide new strategies for therapies.