Endovascular treatment versus no endovascular treatment after 6-24 h in patients with ischaemic stroke and collateral flow on CT angiography (MR CLEAN-LATE) in the Netherlands: a multicentre, open-label, blinded-endpoint, randomised, controlled, phase 3 trial.

BACKGROUND: Endovascular treatment for anterior circulation ischaemic stroke is effective and safe within a 6 h window. MR CLEAN-LATE aimed to assess efficacy and safety of endovascular treatment for patients treated in the late window (6-24 h from symptom onset or last seen well) selected on the basis of the presence of collateral flow on CT angiography (CTA). METHODS: MR CLEAN-LATE was a multicentre, open-label, blinded-endpoint, randomised, controlled, phase 3 trial done in 18 stroke intervention centres in the Netherlands. Patients aged 18 years or older with ischaemic stroke, presenting in the late window with an anterior circulation large-vessel occlusion and collateral flow on CTA, and a neurological deficit score of at least 2 on the National Institutes of Health Stroke Scale were included. Patients who were eligible for late-window endovascular treatment were treated according to national guidelines (based on clinical and perfusion imaging criteria derived from the DAWN and DEFUSE-3 trials) and excluded from MR CLEAN-LATE enrolment. Patients were randomly assigned (1:1) to receive endovascular treatment or no endovascular treatment (control), in addition to best medical treatment. Randomisation was web based, with block sizes ranging from eight to 20, and stratified by centre. The primary outcome was the modified Rankin Scale (mRS) score at 90 days after randomisation. Safety outcomes included all-cause mortality at 90 days after randomisation and symptomatic intracranial haemorrhage. All randomly assigned patients who provided deferred consent or died before consent could be obtained comprised the modified intention-to-treat population, in which the primary and safety outcomes were assessed. Analyses were adjusted for predefined confounders. Treatment effect was estimated with ordinal logistic regression and reported as an adjusted common odds ratio (OR) with a 95% CI. This trial was registered with the ISRCTN, ISRCTN19922220. FINDINGS: Between Feb 2, 2018, and Jan 27, 2022, 535 patients were randomly assigned, and 502 (94%) patients provided deferred consent or died before consent was obtained (255 in the endovascular treatment group and 247 in the control group; 261 [52%] females). The median mRS score at 90 days was lower in the endovascular treatment group than in the control group (3 [IQR 2-5] vs 4 [2-6]), and we observed a shift towards better outcomes on the mRS for the endovascular treatment group (adjusted common OR 1·67 [95% CI 1·20-2·32]). All-cause mortality did not differ significantly between groups (62 [24%] of 255 patients vs 74 [30%] of 247 patients; adjusted OR 0·72 [95% CI 0·44-1·18]). Symptomatic intracranial haemorrhage occurred more often in the endovascular treatment group than in the control group (17 [7%] vs four [2%]; adjusted OR 4·59 [95% CI 1·49-14·10]). INTERPRETATION: In this study, endovascular treatment was efficacious and safe for patients with ischaemic stroke caused by an anterior circulation large-vessel occlusion who presented 6-24 h from onset or last seen well, and who were selected on the basis of the presence of collateral flow on CTA. Selection of patients for endovascular treatment in the late window could be primarily based on the presence of collateral flow. FUNDING: Collaboration for New Treatments of Acute Stroke consortium, Dutch Heart Foundation, Stryker, Medtronic, Cerenovus, Top Sector Life Sciences & Health, and the Netherlands Brain Foundation.

COMPARE LAAO: Rationale and design of the randomized controlled trial "COMPARing Effectiveness and safety of Left Atrial Appendage Occlusion to standard of care for atrial fibrillation patients at high stroke risk and ineligible to use oral anticoagulation therapy".

BACKGROUND: Left atrial appendage occlusion (LAAO) provides an alternative to oral anticoagulation (OAC) for stroke prevention in patients with atrial fibrillation (AF). In patients with a long-term or permanent contraindication for OAC randomized controlled trial (RCT) data is lacking. STUDY OBJECTIVES: To assess the efficacy and safety of LAAO in AF patients who are ineligible to use OAC. The co-primary efficacy endpoint is (1) time to first occurrence of stroke (ischemic, hemorrhagic, or undetermined) and (2) time to first occurrence of the composite of stroke, transient ischemic attack (TIA), and systemic embolism (SE). The primary safety endpoint is the 30-day rate of peri-procedural complications. STUDY DESIGN: This is a multicenter, investigator-initiated, open-label, blinded endpoint (PROBE), superiority-driven RCT. Patients with AF, a CHA2DS2-VASc score ≥2 for men and ≥3 for women and a long-term or permanent contraindication for OAC will be randomized in a 2:1 fashion to the device- or control arm. Patients in the device arm will undergo percutaneous LAAO and will receive post-procedural dual antiplatelet therapy (DAPT) per protocol, while those in the control arm will continue their current treatment consisting of no antithrombotic therapy or (D)APT as deemed appropriate by the primary responsible physician. In this endpoint-driven trial design, assuming a 50% lower stroke risk of LAAO compared to conservative treatment, 609 patients will be followed for a minimum of 1 and a maximum of 5 years. Cost-effectiveness and budget impact analyses will be performed to allow decision-making on reimbursement of LAAO for the target population in the Netherlands. SUMMARY: The COMPARE LAAO trial will investigate the clinical superiority in preventing thromboembolic events and cost-effectiveness of LAAO in AF patients with a high thromboembolic risk and a contraindication for OAC use. NCT TRIAL NUMBER: NCT04676880.

Contrast-induced encephalopathy-neuroimaging findings and clinical relevance.

Contrast-induced encephalopathy (CIE) is a rare encephalopathic condition after the administration of a contrast agent. The diagnosis of CIE is challenging because of the heterogeneity and non-specificity of the clinical presentation. The clinical course is usually favorable with full recovery within 48-72 h in most patients, although comorbidity is of relevance and contributes to the clinical outcome. It is expected that the incidence of CIE is currently increasing, due to an increase in endovascular and diagnostic imaging procedures using iodinated contrast. It is important to include CIE in the differential diagnosis when patients deteriorate during, or immediately after, contrast administration, even when only a small amount of non-ionic contrast agent is used. When CIE is considered to be the most likely explanation for the clinical symptoms, it is advised to refrain from unnecessary additional contrast studies such as angiography or perfusion CT.

Acute ischaemic stroke and its challenges for the intensivist.

Acute ischaemic stroke (AIS) is responsible for almost 90% of all strokes and is one of the leading causes of death and disability. Acute ischaemic stroke is caused by a critical alteration in focal cerebral blood flow (ischaemia) from a variety of causes, resulting in infarction. The primary cerebral injury due to AIS occurs in the first hours, therefore early reperfusion importantly impacts on patient outcome ('Time is brain' concept). Secondary cerebral damage progressively evolves over the following hours and days due to cerebral oedema, haemorrhagic transformation, and cerebral inflammation. Systemic complications, such as pneumonia, sepsis, and deep venous thrombosis, could also affect outcome. The risk of a recurrent ischaemic stroke is in particular high in the first days, which necessitate particular attention. The role of intensive care unit physicians is therefore to avoid or reduce the risk of secondary damage, especially in the areas where the brain is functionally impaired and 'at risk' of further injury. Therapeutic strategies therefore consist of restoration of blood flow and a bundle of medical, endovascular, and surgical strategies, which-when applied in a timely and consistent manner-can prevent secondary deterioration due to cerebral and systemic complications and recurrent stroke and improve short- and long-term outcomes. A multidisciplinary collaboration between neurosurgeons, interventional radiologists, neurologists, and intensivists is necessary to elaborate the best strategy for the treatment of these patients.

Added Value of a Blinded Outcome Adjudication Committee in an Open-Label Randomized Stroke Trial.

BACKGROUND AND PURPOSE: Blinded outcome assessment in trials with prospective randomized open blinded end point design is challenging. Unblinding can result in misclassified outcomes and biased treatment effect estimates. An outcome adjudication committee assures blinded outcome assessment, but the added value for trials with prospective randomized open blinded end point design and subjective outcomes is unknown. We aimed to assess the degree of misclassification of modified Rankin Scale (mRS) scores by a central assessor and its impact on treatment effect estimates in a stroke trial with prospective randomized open blinded end point design. METHODS: We used data from the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands). The primary outcome was the mRS at 90 days. Standardized, algorithm-based telephone interviews to assess the mRS were conducted from a central location by an experienced research nurse, unaware but not formally blinded to treatment allocation (central assessor). Masked reports of these interviews were adjudicated by a blinded outcome committee. Misclassification was defined as an incorrect classification of the mRS by the central assessor. The effect of endovascular treatment on the mRS was assessed with multivariable ordinal logistic regression. RESULTS: In MR CLEAN, 53/500 (10.6%) of the mRS scores were misclassified. The degree and direction of misclassification did not differ between treatment arms (P=0.59). Benefit of endovascular treatment was shown on the mRS when scored by the central assessor (adjusted common odds ratio, 1.60 [95% CI, 1.16-2.21]) and the outcome adjudication committee (adjusted common odds ratio, 1.67 [95% CI, 1.21-2.20]). CONCLUSIONS: Misclassification by the central assessor was small, randomly distributed over treatment arms, and did not affect treatment effect estimates. This study suggests that the added value of a blinded outcome adjudication committee is limited in a stroke trial with prospective randomized open blinded end point design applying standardized, algorithm-based outcome assessment by a central assessor, who is unaware but not formally blinded to treatment allocation. Registration: URL: https://www.isrctn.com; Unique identifier: ISRCTN10888758.

Sex Differences in Risk Profile, Stroke Cause and Outcome in Ischemic Stroke Patients With and Without Migraine.

Background: An increased risk of stroke in patients with migraine has been primarily found for women. The sex-dependent mechanisms underlying the migraine-stroke association, however, remain unknown. This study aims to explore these sex differences to improve our understanding of pathophysiological mechanisms behind the migraine-stroke association. Methods: We included 2,492 patients with ischemic stroke from the prospective multicenter Dutch Parelsnoer Institute Initiative study, 425 (17%) of whom had a history of migraine. Cardiovascular risk profile, stroke cause (TOAST classification), and outcome [modified Rankin scale (mRS) at 3 months] were compared with both sexes between patients with and without migraine. Results: A history of migraine was not associated with sex differences in the prevalence of conventional cardiovascular risk factors. Women with migraine had an increased risk of stroke at young age (onset < 50 years) compared with women without migraine (RR: 1.7; 95% CI: 1.3-2.3). Men with migraine tended to have more often stroke in the TOAST category other determined etiology (RR: 1.7; 95% CI: 1.0-2.7) in comparison with men without migraine, whereas this increase was not found in women with migraine. Stroke outcome was similar for women with or without migraine (mRS ≥ 3 RR 1.1; 95% CI 0.7-1.5), whereas men seemed to have a higher risk of poor outcome compared with their counterparts without migraine (mRS ≥ 3 RR: 1.5; 95% CI: 1.0-2.1). Conclusion: Our results indicate possible sex differences in the pathophysiology underlying the migraine-stroke association, which are unrelated to conventional cardiovascular risk factors. Further research in larger cohorts is needed to validate these findings.

Cost-effectiveness of artificial intelligence aided vessel occlusion detection in acute stroke: an early health technology assessment.

BACKGROUND: Limited evidence is available on the clinical impact of artificial intelligence (AI) in radiology. Early health technology assessment (HTA) is a methodology to assess the potential value of an innovation at an early stage. We use early HTA to evaluate the potential value of AI software in radiology. As a use-case, we evaluate the cost-effectiveness of AI software aiding the detection of intracranial large vessel occlusions (LVO) in stroke in comparison to standard care. We used a Markov based model from a societal perspective of the United Kingdom predominantly using stroke registry data complemented with pooled outcome data from large, randomized trials. Different scenarios were explored by varying missed diagnoses of LVOs, AI costs and AI performance. Other input parameters were varied to demonstrate model robustness. Results were reported in expected incremental costs (IC) and effects (IE) expressed in quality adjusted life years (QALYs). RESULTS: Applying the base case assumptions (6% missed diagnoses of LVOs by clinicians, $40 per AI analysis, 50% reduction of missed LVOs by AI), resulted in cost-savings and incremental QALYs over the projected lifetime (IC: - $156, - 0.23%; IE: + 0.01 QALYs, + 0.07%) per suspected ischemic stroke patient. For each yearly cohort of patients in the UK this translates to a total cost saving of $11 million. CONCLUSIONS: AI tools for LVO detection in emergency care have the potential to improve healthcare outcomes and save costs. We demonstrate how early HTA may be applied for the evaluation of clinically applied AI software for radiology.

Design and rationale of DUTCH-AF: a prospective nationwide registry programme and observational study on long-term oral antithrombotic treatment in patients with atrial fibrillation.

INTRODUCTION: Anticoagulation therapy is pivotal in the management of stroke prevention in atrial fibrillation (AF). Prospective registries, containing longitudinal data are lacking with detailed information on anticoagulant therapy, treatment adherence and AF-related adverse events in practice-based patient cohorts, in particular for non-vitamin K oral anticoagulants (NOAC). With the creation of DUTCH-AF, a nationwide longitudinal AF registry, we aim to provide clinical data and answer questions on the (anticoagulant) management over time and of the clinical course of patients with newly diagnosed AF in routine clinical care. Within DUTCH-AF, our current aim is to assess the effect of non-adherence and non-persistence of anticoagulation therapy on clinical adverse events (eg, bleeding and stroke), to determine predictors for such inadequate anticoagulant treatment, and to validate and refine bleeding prediction models. With DUTCH-AF, we provide the basis for a continuing nationwide AF registry, which will facilitate subsequent research, including future registry-based clinical trials. METHODS AND ANALYSIS: The DUTCH-AF registry is a nationwide, prospective registry of patients with newly diagnosed 'non-valvular' AF. Patients will be enrolled from primary, secondary and tertiary care practices across the Netherlands. A target of 6000 patients for this initial cohort will be followed for at least 2 years. Data on thromboembolic and bleeding events, changes in antithrombotic therapy and hospital admissions will be registered. Pharmacy-dispensing data will be obtained to calculate parameters of adherence and persistence to anticoagulant treatment, which will be linked to AF-related outcomes such as ischaemic stroke and major bleeding. In a subset of patients, anticoagulation adherence and beliefs about drugs will be assessed by questionnaire. ETHICS AND DISSEMINATION: This study protocol was approved as exempt for formal review according to Dutch law by the Medical Ethics Committee of the Leiden University Medical Centre, Leiden, the Netherlands. Results will be disseminated by publications in peer-reviewed journals and presentations at scientific congresses. TRIAL REGISTRATION NUMBER: Trial NL7467, NTR7706 (https://www.trialregister.nl/trial/7464).

Distribution of Cardioembolic Stroke: A Cohort Study.

BACKGROUND: A cardiac origin in ischemic stroke is more frequent than previously assumed, but it is not clear which patients benefit from cardiac work-up if obvious cardiac pathology is absent. We hypothesized that thromboembolic stroke with a cardiac source occurs more frequently in the posterior circulation compared with thromboembolic stroke of another etiology. METHODS: We performed a multicenter observational study in 3,311 consecutive patients with ischemic stroke who were enrolled in an ongoing prospective stroke registry of 8 University hospitals between September 2009 and November 2014 in The Netherlands. In this initiative, the so-called Parelsnoer Institute-Cerebrovascular Accident Study Group, clinical data, imaging, and biomaterials of patients with stroke are prospectively and uniformly collected. We compared the proportions of posterior stroke location in patients with a cardiac stroke source with those with another stroke etiology and calculated risk ratios (RR) with corresponding 95% CI with Poisson regression analyses. To assess which patient or disease characteristics were most strongly associated with a cardiac etiology in patients with ischemic stroke, we performed a stepwise backward regression analysis. RESULTS: For the primary aim, 1,428 patients were eligible for analyses. The proportion of patients with a posterior stroke location among patients with a cardiac origin of their stroke (28%) did not differ statistically significant to those with another origin (25%), age and sex adjusted RR 1.16; 95% CI 0.96-1.41. For the secondary aim, 1,955 patients were eligible for analyses. No recent history of smoking, no hyperlipidemia, coronary artery disease, a higher age, and a higher National Institutes of Health Stroke Scale (NIHSS) score were associated with a cardiac etiology of ischemic stroke. CONCLUSIONS: We could not confirm our hypothesis that thromboembolic stroke localized in the posterior circulation is associated with a cardioembolic source of ischemic stroke, and therefore posterior stroke localization on itself does not necessitate additional cardiac examination. The lack of determinants of atherosclerosis, for example, no recent history of smoking and no hyperlipidemia, coronary artery disease, a higher age, and a higher NIHSS score are stronger risk factors for a cardiac source of ischemic stroke.

Diagnostic Accuracy of the Explicit Diagnostic Criteria for Transient Ischemic Attack: A Validation Study.

Background and Purpose- The clinical diagnosis of a transient ischemic attack (TIA) can be difficult. Evidence-based criteria hardly exist. We evaluated if the recently proposed Explicit Diagnostic Criteria for TIA (EDCT), an easy to perform clinical tool focusing on type, duration, and mode of onset of clinical features, would facilitate the clinical diagnosis of TIA. Methods- We used data from patients suspected of a TIA by a general practitioner and referred to a TIA service in the region of Utrecht, the Netherlands, who participated in the MIND-TIA (Markers in the Diagnosis of TIA) study. Information about the clinical features was collected with a standardized questionnaire within 72 hours after onset. A panel of 3 experienced neurologists ultimately determined the definite diagnosis based on all available diagnostic information including a 6-month follow-up period. Two researchers scored the EDCT. Sensitivity, specificity, and predictive values of the EDCT were assessed using the panel diagnosis as reference. A secondary analysis was performed with modified subcriteria of the EDCT. Results- Of the 206 patients, 126 (61%) had a TIA (n=104) or minor stroke (n=22), and 80 (39%) an alternative diagnosis. Most common alternative diagnoses were migraine with aura (n=24; 30.0%), stress related or somatoform symptoms (n=16; 20.0%), and syncope (n=9; 11.3%). The original EDCT had a sensitivity of 98.4% (95% CI, 94.4-99.8) and a specificity of 61.3% (49.7-71.9). Negative and positive predictive values were 96.1% (86.0-99.0) and 80.0% (75.2-84.1), respectively. The modified EDCT showed a higher specificity of 73.8% (62.7-83.0) with the same sensitivity and a similar negative predictive value of 96.7%, but a higher positive predictive value of 85.5% (80.3-89.5). Conclusions- The EDCT has excellent sensitivity and negative predictive value and could be a valuable diagnostic tool for the diagnosis of TIA.

Serum biomarkers in patients suspected of transient ischaemic attack in primary care: a diagnostic accuracy study.

OBJECTIVE: The diagnosis of transient ischaemic attack (TIA) based on symptoms and signs can be challenging and would greatly benefit from a rapid serum biomarker of brain ischaemia. We aimed to quantify the added diagnostic value of serum biomarkers in patients suspected of TIA beyond symptoms and signs. METHODS: This is a cross-sectional diagnostic accuracy study with a 6-month follow-up period. Participants were patients suspected of TIA by the general practitioner (GP) in whom a blood sample could be collected within 72 hours from symptom onset. A research nurse visited the participant for the blood sample and a standardised interview. The GP referred participants to the regional TIA service. An expert panel of three neurologists classified cases as TIA, minor stroke or any other diagnosis, based on all available diagnostic information including the GP's and neurologist's correspondence and the follow-up period. We used multivariable logistic regression analyses to quantify the diagnostic accuracy of clinical predictors and the improvement of accuracy by seven biomarkers (NR2, NR2 antibodies, PARK7, NDKA, UFD1, B-FABP and H-FABP). RESULTS: 206 patients suspected of TIA participated, of whom 126 (61.2%) were diagnosed with TIA (n=104) or minor stroke (n=22) by the expert panel. The median time from symptom onset to the blood sample collection was 48.0 (IQR 28.3-56.8) hours. None of the seven biomarkers had discriminative value in the diagnosis of TIA, with C-statistics ranging from 0.45 to 0.58. The final multivariable model (C-statistic 0.83 (0.78-0.89)) consisted of eight clinical predictors of TIA/minor stroke: increasing age, a history of coronary artery disease, sudden onset of symptoms, occurrence of symptoms in full intensity, dysarthria, no history of migraine, absence of loss of consciousness and absence of headache. Addition of the individual biomarkers did not further increase the C-statistics. CONCLUSIONS: Currently available blood biomarkers have no added diagnostic value in suspected TIA. TRIAL REGISTRATION NUMBER: NCT01954329.

A Modified Encephalo-Duro-Synangiosis Technique Induced Neovascularization in Symptomatic Atherosclerotic Carotid Artery Occlusion: A Phase I trial.

OBJECTIVE: To the best of our knowledge, the present study is the first to assess the safety and feasibility of a modified encephalo-galeo-duro-synangiosis operation in patients with atherosclerotic carotid artery occlusion. METHODS: Eight patients who had experienced new ipsilateral cerebrovascular events after the diagnosis of carotid artery occlusion were recruited. To facilitate extracranial-to-intracranial collateralization, 5 or 6 burr holes were made, and the dura mater and arachnoid were opened. The patients were closely monitored for complications and underwent conventional angiography, magnetic resonance imaging, and perfusion-weighted magnetic resonance imaging at baseline and 1 year of follow-up. After 10 years, the patients who were still alive were interviewed and assessed for functional outcomes and neurological status. RESULTS: No surgery-related adverse events were observed, apart from temporary headache and subcutaneous effusion. Four of six patients had developed an extracranial-to-intracranial collateral blood vessels on angiography, and these patients had no incident ischemic events during the follow-up period. During the long-term follow-up period (10 years), 3 patients had died. Of those living, 4 of the 5 patients reported total resolution of the symptoms, with no incident ischemic events. One patient still experienced disability from an ischemic stroke that occurred as a result of the 1-year follow-up angiography. CONCLUSIONS: Encephalo-duro-galeo-synangiosis for symptomatic carotid occlusion seems to be safe and feasible and might be able to induce extracranial-to-intracranial collaterals in patients with carotid artery occlusion. Further studies are needed to define the optimal therapeutic window and yield of burr hole surgery in the treatment of symptomatic carotid occlusive disease as an adjuvant to extracranial-intracranial bypass.

Brain CT perfusion improves intracranial vessel occlusion detection on CT angiography.

BACKGROUND AND PURPOSE: To evaluate whether brain CT perfusion (CTP) aids in the detection of intracranial vessel occlusion on CT angiography (CTA) in acute ischemic stroke. MATERIALS AND METHODS: Medical-ethical committee approval of our hospital was obtained and informed consent was waived. Patients suspected of acute ischemic stroke who underwent non-contrast CT(NCCT), CTA and whole-brain CTP in our center in the year 2015 were included. Three observers with different levels of experience evaluated the imaging data of 110 patients for the presence or absence of intracranial arterial vessel occlusion with two strategies. In the first strategy, only NCCT and CTA were available. In the second strategy, CTP maps were provided in addition to NCCT and CTA. Receiver-operating-characteristic (ROC) analysis was used for the evaluation of diagnostic accuracy. RESULTS: Overall, a brain perfusion deficit was scored present in 87-89% of the patients with an intracranial vessel occlusion, more frequently observed in the anterior than in the posterior circulation. Performance of intracranial vessel occlusion detection on CTA was significantly improved with the availability of CTP maps as compared to the first strategy (P=0.023), due to improved detection of distal and posterior circulation vessel occlusions (P-values of 0.032 and 0.003 respectively). No added value of CTP was found for intracranial proximal vessel occlusion detection, with already high accuracy based on NCCT and CTA alone. CONCLUSION: The performance of intracranial vessel occlusion detection on CTA was improved with the availability of brain CT perfusion maps due to the improved detection of distal and posterior circulation vessel occlusions.

Brain atrophy and strategic lesion location increases risk of parkinsonism in cerebral small vessel disease.

INTRODUCTION: Incident parkinsonism in patients with comparable cerebral small vessel disease (SVD) burden is not fully explained by presence of SVD alone. We therefore investigated if severity of SVD, SVD location, incidence of SVD and/or brain atrophy plays a role in this distinct development of parkinsonism. METHODS: Participants were from the RUN DMC study, a prospective cohort of 503 individuals with SVD. Parkinsonism was diagnosed according to the UKPDS brain bank criteria. Fine and Gray method was used to assess the association between SVD and incident parkinsonism. Differences in white matter hyperintensities (WMH) progression and brain atrophy were calculated with a linear mixed effect analysis. RESULTS: After a median follow-up of 8.6 years, 32 of 501 participants developed parkinsonism (6.4%). The highest WMH load was found in the frontal lobe for both groups. Presence of more than one lacune at baseline was higher in the group who developed parkinsonism, especially in the frontal lobe (22% versus 3%, p < 0.001) and basal ganglia (12.5% versus 1%, p-value <0.001). The annual rate of total brain atrophy was significantly higher for those who developed parkinsonism compared to those who did not (8.7 ml [95%CI 7.1-10.3] and 4.9 ml [95%CI 4.5-5.3], respectively). While WMH progression was not different, incidence of lacunes and microbleeds was higher in the group with parkinsonism. CONCLUSION: The risk of parkinsonism in patients with SVD is especially increased when WMH and lacunes are present in the frontal lobe. A higher brain atrophy rate might further increase this risk.

Risk of Nursing Home Admission in Cerebral Small Vessel Disease.

Background and Purpose- Since cerebral small vessel disease (SVD) is associated with cognitive and motor impairment and both might ultimately lead to nursing home admission, our objective was to investigate the association of SVD markers with nursing home admission. Methods- The RUN DMC study (Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort) is a prospective cohort of 503 independent living individuals with SVD. Date of nursing home admission was retrieved from the Dutch municipal personal records database. Risk of nursing home admission was calculated using a competing risk analysis, with mortality as a competing risk. Results- During follow-up (median 8.7 years, interquartile range 8.5-8.9), 31 participants moved to a nursing home. Before nursing home admission, 19 participants were diagnosed with dementia, 6 with parkinsonism, and 10 with stroke. Participants with the lowest white matter volume had an 8-year risk of nursing home admission of 13.3% (95% CI, 8.6-18.9), which was significantly different from participants with middle or highest white matter volume (respectively, 4.8% [95% CI, 2.3-8.8] and 0%; P<0.001). After adjusting for baseline age and living condition, the association of white matter volume and total brain volume with nursing home admission was significant, with, respectively, hazard ratios of 0.88 [95% CI, 0.84-0.95] ( P value 0.025) and 0.92 [95% CI, 0.85-0.98] ( P<0.001) per 10 mL. The association of white matter hyperintensities and lacunes with nursing home admission was not significant. Conclusions- This study demonstrates that in SVD patients, independent from age and living condition, a lower white matter volume and a lower total brain volume is associated with an increased risk of nursing home admission. Nursing home admission is a relevant outcome in SVD research since it might be able to combine both cognitive and functional consequences of SVD in 1 outcome.

Plasma Aß (Amyloid-ß) Levels and Severity and Progression of Small Vessel Disease.

BACKGROUND AND PURPOSE: Cerebral small vessel disease (SVD) is a frequent pathology in aging and contributor to the development of dementia. Plasma Aß (amyloid ß) levels may be useful as early biomarker, but the role of plasma Aß in SVD remains to be elucidated. We investigated the association of plasma Aß levels with severity and progression of SVD markers. METHODS: We studied 487 participants from the RUN DMC study (Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort) of whom 258 participants underwent 3 MRI assessments during 9 years. We determined baseline plasma Aß38, Aß40, and Aß42 levels using ELISAs. We longitudinally assessed volume of white matter hyperintensities semiautomatically and manually rated lacunes and microbleeds. We analyzed associations between plasma Aß and SVD markers by ANCOVA adjusted for age, sex, and hypertension. RESULTS: Cross-sectionally, plasma Aß40 levels were elevated in participants with microbleeds (mean, 205.4 versus 186.4 pg/mL; P<0.01) and lacunes (mean, 194.8 versus 181.2 pg/mL; P<0.05). Both Aß38 and Aß40 were elevated in participants with severe white matter hyperintensities (Aß38, 25.3 versus 22.7 pg/mL; P<0.01; Aß40, 201.8 versus 183.3 pg/mL; P<0.05). Longitudinally, plasma Aß40 levels were elevated in participants with white matter hyperintensity progression (mean, 194.6 versus 182.9 pg/mL; P<0.05). Both Aß38 and Aß40 were elevated in participants with incident lacunes (Aß38, 24.5 versus 22.5 pg/mL; P<0.05; Aß40, 194.9 versus 181.2 pg/mL; P<0.01) and Aß42 in participants with incident microbleeds (62.8 versus 60.4 pg/mL; P<0.05). CONCLUSIONS: Plasma Aß levels are associated with both presence and progression of SVD markers, suggesting that Aß pathology might contribute to the development and progression of SVD. Plasma Aß levels might thereby serve as inexpensive and noninvasive measure for identifying individuals with increased risk for progression of SVD.

Increased Risk of Pregnancy Complications After Stroke: The FUTURE Study (Follow-Up of Transient Ischemic Attack and Stroke Patients and Unelucidated Risk Factor Evaluation).

BACKGROUND AND PURPOSE: The study goal was to investigate the prevalence of pregnancy complications and pregnancy loss in women before, during, and after young ischemic stroke/transient ischemic attack. METHODS: In the FUTURE study (Follow-Up of Transient Ischemic Attack and Stroke Patients and Unelucidated Risk Factor Evaluation), a prospective young stroke study, we assessed the occurrence of pregnancy, miscarriages, and pregnancy complications in 223 women aged 18 to 50 years with a first-ever ischemic stroke/transient ischemic attack. Pregnancy complications (gestational hypertension, diabetes mellitus, preeclampsia, and hemolysis, elevated liver enzymes, low platelet count syndrome) were assessed before, during, and after stroke using standardized questionnaires. Primary outcome was occurrence of pregnancy complications and the rate of pregnancy loss compared with the Dutch population. Secondary outcome was the risk of recurrent vascular events after stroke, stratified by a history of hypertensive disorder in pregnancy. RESULTS: Data were available for 213 patients. Mean age at event was 39.6 years (SD=7.8) and mean follow-up 9.5 years (SD=8.5). Miscarriages occurred in 35.2% and fetal death in 6.2% versus 13.5% and 0.9% in the Dutch population, respectively (P<0.05). In nulliparous women after stroke (n=22), in comparison with Dutch population, there was a high prevalence of hypertensive disorders in pregnancy (33.3 versus 12.2%; P<0.05), hemolysis, elevated liver enzymes, low platelet count syndrome (9.5 versus 0.5%; P<0.05), and early preterm delivery <32 weeks (9.0 versus 1.4%; P<0.05). In primi/multiparous women (n=141) after stroke, 29 events occurred (20-year cumulative risk 35.2%; 95% confidence interval, 21.3-49.0), none during subsequent pregnancies, and a history of a hypertensive disorder in pregnancy did not modify this risk (log-rank P=0.62). CONCLUSIONS: When compared with the general population, women with young stroke show higher rates of pregnancy loss throughout their lives. Also, after stroke, nulliparous women more frequently experienced serious pregnancy complications.

Prothrombotic factors do not increase the risk of recurrent ischemic events after cryptogenic stroke at young age: the FUTURE study.

BACKGROUND: The role of hypercoagulable states and preceding infections in the etiology of young stroke and their role in developing recurrent ischemic events remains unclear. Our aim is to determine the prevalence of these conditions in patients with cryptogenic stroke at young age and to assess the long-term risk of recurrent ischemic events in patients with and without a hypercoagulable state or a recent pre-stroke infection with Borrelia or Syphilis. PATIENTS AND METHODS: We prospectively included patients with a first-ever transient ischemic attack or ischemic stroke, aged 18-50, admitted to our hospital between 1995 and 2010. A retrospective analysis was conducted of prothrombotic factors and preceding infections. Outcome was recurrent ischemic events. RESULTS: Prevalence of prothrombotic factors did not significantly differ between patients with a cryptogenic stroke and with an identified cause (24/120 (20.0%) and 32/174 (18.4%) respectively). In patients with a cryptogenic stroke the long-term risk [mean follow-up of 8.9 years (SD 4.6)] of any recurrent ischemic event or recurrent cerebral ischemia did not significantly differ between patients with and without a hypercoagulable state or a recent infection. In patients with a cryptogenic stroke 15-years cumulative risk of any recurrent ischemic event was 24 and 23% in patients with and without any prothrombotic factor respectively. CONCLUSIONS: The prevalence of prothrombotic factors and preceding infections did not significantly differ between stroke patients with a cryptogenic versus an identified cause of stroke and neither is significantly associated with an increased risk of recurrent ischemic events after cryptogenic stroke.

Risk factors and mechanisms of stroke in young adults: The FUTURE study.

Incidence of ischemic stroke and transient ischemic attack in young adults is rising. However, etiology remains unknown in 30-40% of these patients when current classification systems designed for the elderly are used. Our aim was to identify risk factors according to a pediatric approach, which might lead to both better identification of risk factors and provide a stepping stone for the understanding of disease mechanism, particularly in patients currently classified as "unknown etiology". Risk factors of 656 young stroke patients (aged 18-50) of the FUTURE study were categorized according to the "International Pediatric Stroke Study" (IPSS), with stratification on gender, age and stroke of "unknown etiology". Categorization of risk factors into ≥1 IPSS category was possible in 94% of young stroke patients. Chronic systemic conditions were more present in patients aged <35 compared to patients ≥35 (32.6% vs. 15.6%, p < 0.05). Among 226 patients classified as "stroke of unknown etiology" using TOAST, we found risk factors in 199 patients (88%) with the IPSS approach. We identified multiple risk factors linked to other mechanisms of stroke in the young than in the elderly . This can be a valuable starting point to develop an etiologic classification system specifically designed for young stroke patients.

Executive Function Declines in the First 6 Months After a Transient Ischemic Attack or Transient Neurological Attack.

BACKGROUND AND PURPOSE: Although by definition transient, both transient ischemic attack (TIA) and transient neurological attack (TNA) are associated with cognitive impairment. Determinants and course of cognitive function afterward are, however, unclear. We prospectively determined cognitive performance after TIA and TNA in relation to clinical diagnosis and diffusion-weighted imaging (DWI) results. METHODS: TIA and TNA patients aged ≥45 years without prior stroke or dementia underwent comprehensive cognitive assessment and magnetic resonance imaging within 7 days after the qualifying event. Cognitive tests were repeated after 6 months. Domain-specific compound z scores based on the baseline mean and SD were calculated. Repeated-measures analysis was used to test for differences in domain-specific cognitive performance over time between DWI-positive and DWI-negative patients, as well as between TIA and TNA patients. RESULTS: One hundred twenty-one patients were included (mean age (SD), 64.6 years (9.2 years), 60% TIA and 40% TNA) of whom 32 (26%) had a DWI lesion. Executive function performance decreased over time (mean change in compound score -0.23; P=0.01 adjusted for age, sex, education), whereas attention improved (0.11; P=0.02), and information processing speed and episodic memory remained unchanged. Patients with a DWI lesion had worse executive function at baseline than those without a DWI lesion (compound scores -0.26 versus 0.08; P=0.048), which persisted throughout the study period (P=0.04). Clinical diagnosis (TIA or TNA) was not related to cognitive function over time. CONCLUSIONS: Executive function declines during the first 6 months after TIA or TNA. Patients with an initial DWI lesion have persisting worse executive function than those without.