Safety and efficacy of active blood-pressure reduction to the recommended thresholds for intravenous thrombolysis in patients with acute ischaemic stroke in the Netherlands (TRUTH): a prospective, observational, cluster-based, parallel-group study.

BACKGROUND: Intravenous thrombolysis is contraindicated in patients with ischaemic stroke with blood pressure higher than 185/110 mm Hg. Prevailing guidelines recommend to actively lower blood pressure with intravenous antihypertensive agents to allow for thrombolysis; however, there is no robust evidence for this strategy. Because rapid declines in blood pressure can also adversely affect clinical outcomes, several Dutch stroke centres use a conservative strategy that does not involve the reduction of blood pressure. We aimed to compare the clinical outcomes of both strategies. METHODS: Thrombolysis and Uncontrolled Hypertension (TRUTH) was a prospective, observational, cluster-based, parallel-group study conducted across 37 stroke centres in the Netherlands. Participating centres had to strictly adhere to an active blood-pressure-lowering strategy or to a non-lowering strategy. Eligible participants were adults (≥18 years) with ischaemic stroke who had blood pressure higher than 185/110 mm Hg but were otherwise eligible for intravenous thrombolysis. The primary outcome was functional status at 90 days, measured using the modified Rankin Scale and assessed through telephone interviews by trained research nurses. Secondary outcomes were symptomatic intracranial haemorrhage, the proportion of patients treated with intravenous thrombolysis, and door-to-needle time. All ordinal logistic regression analyses were adjusted for age, sex, stroke severity, endovascular thrombectomy, and baseline imbalances as fixed-effect variables and centre as a random-effect variable to account for the clustered design. Analyses were done according to the intention-to-treat principle, whereby all patients were analysed according to the treatment strategy of the participating centre at which they were treated. FINDINGS: Recruitment began on Jan 1, 2015, and was prematurely halted because of a declining inclusion rate and insufficient funding on Jan 5, 2022. Between these dates, we recruited 853 patients from 27 centres that followed an active blood-pressure-lowering strategy and 199 patients from ten centres that followed a non-lowering strategy. Baseline characteristics of participants from the two groups were similar. The 90-day mRS score was missing for 15 patients. The adjusted odds ratio (aOR) for a shift towards a worse 90-day functional outcome was 1·27 (95% CI 0·96-1·68) for active blood-pressure reduction compared with no active blood-pressure reduction. 798 (94%) of 853 patients in the active blood-pressure-lowering group were treated with intravenous thrombolysis, with a median door-to-needle time of 35 min (IQR 25-52), compared with 104 (52%) of 199 patients treated in the non-lowering group with a median time of 47 min (29-78). 42 (5%) of 852 patients in the active blood-pressure-lowering group had a symptomatic intracranial haemorrhage compared with six (3%) of 199 of those in the non-lowering group (aOR 1·28 [95% CI 0·62-2·62]). INTERPRETATION: Insufficient evidence was available to establish a difference between an active blood-pressure-lowering strategy-in which antihypertensive agents were administered to reduce blood pressure below 185/110 mm Hg-and a non-lowering strategy for the functional outcomes of patients with ischaemic stroke, despite higher intravenous thrombolysis rates and shorter door-to-needle times among those in the active blood-pressure-lowering group. Randomised controlled trials are needed to inform the use of an active blood-pressure-lowering strategy. FUNDING: Fonds NutsOhra.

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.

Short-Term and Long-Term Risk of Recurrent Vascular Event by Cause After Ischemic Stroke in Young Adults.

Importance: Cause of ischemic stroke in young people is highly variable; however, the risk of recurrence is often presented with all subtypes of stroke grouped together in classification systems such as the Trial of ORG (danaparoid sodium [Orgaran]) 10172 in Acute Stroke Treatment (TOAST) criteria, which limits the ability to individually inform young patients with stroke about their risk of recurrence. Objective: To determine the short-term and long-term risk of recurrent vascular events after ischemic stroke at a young age by stroke cause and to identify factors associated with recurrence. Design, Setting, and Participants: This cohort study used data from the Observational Dutch Young Symptomatic Stroke Study, a prospective, multicenter, hospital-based cohort study, conducted at 17 hospitals in the Netherlands between 2013 and 2021. Eligible participants included 30-day survivors of an initial, neuroimaging-proven ischemic stroke (aged 18-49 years). Data analysis was conducted from June to July 2023. Exposure: Diagnosis of a first-ever, ischemic stroke via neuroimaging. Main Outcome and Measures: The primary outcome was short-term (within 6 months) and long-term (within 5 years) recurrence risk of any vascular event, defined as fatal or nonfatal recurrent ischemic stroke, transient ischemic attack, myocardial infarction, and revascularization procedure. Predefined characteristics were chosen to identify factors associated with risk of recurrence (cause of stroke, age, sex, stroke severity, and cardiovascular health factors). Results: A total of 1216 patients (median [IQR] age, 44.2 [38.4-47.7] years; 632 male [52.0%]; 584 female [48.0%]) were included, with a median (IQR) follow-up of 4.3 (2.6-6.0) years. The 6-month risk of any recurrent ischemic event was 6.7% (95% CI, 5.3%-8.1%), and the 5-year risk was 12.2% (95% CI, 10.2%-14.2%)The short-term risk was highest for patients with cervical artery dissections (13.2%; 95% CI, 7.6%-18.7%). Other factors associated with a recurrent short-term event were atherothrombotic stroke, rare causes of stroke, and hypertension. The long-term cumulative risk was highest for patients with atherothrombotic stroke (22.7%; 95% CI, 10.6%-34.7%) and lowest for patients with cryptogenic stroke (5.8%; 95% CI, 3.0%-8.5%). Cardioembolic stroke was associated with a recurrent long-term event, as were diabetes and alcohol abuse. Conclusions and Relevance: The findings of this cohort study of 1216 patients with an ischemic stroke at a young age suggest that the risk of recurrent vascular events was high and varied by cause of stroke both for short-term and long-term follow-up, including causes that remained concealed when combined into 1 category in the routinely used TOAST criteria. This knowledge will allow for more personalized counseling of young patients with stroke.

Cognitive trajectory in the first year after first-ever ischaemic stroke in young adults: the ODYSSEY study.

BACKGROUND: Limited data exists on cognitive recovery in young stroke patients. We aimed to investigate the longitudinal course of cognitive performance during the first year after stroke at young age and identify predictors for cognitive recovery. METHODS: We conducted a multicentre prospective cohort study between 2013 and 2021, enrolling patients aged 18-49 years with first-ever ischaemic stroke. Cognitive assessments were performed within 6 months and after 1 year following the index event, covering seven cognitive domains. Composite Z-scores using normative data determined cognitive impairment (Z-score<-1.5). A Reliable Change Index (RCI) assessed cognitive recovery (RCI>1.96) or decline (RCI<-1.96). RESULTS: 393 patients (median age 44.3 years, IQR 38.4-47.2) completed cognitive assessments with a median time interval of 403 days (IQR 364-474) between assessments. Based on RCI, a similar proportion of patients showed improvement and decline in each cognitive domain, while the majority exhibited no cognitive change. Among cognitively impaired patients at baseline, improvements were observed in processing speed (23.1%), visuoconstruction (40.1%) and executive functioning (20.0%). Younger age was associated with better cognitive recovery in visuoconstruction, and larger lesion volume was related to cognitive recovery in processing speed. No other predictors for cognitive recovery were identified. CONCLUSIONS: Cognitive impairment remains prevalent in young stroke even 1 year after the event. Most patients showed no cognitive change, however, recovery may have occurred in the early weeks after stroke, which was not assessed in our study. Among initially cognitively impaired patients, cognitive recovery is observed in processing speed, visuoconstruction and executive functioning. It is still not possible to predict cognitive recovery in individual patients.

Subacute cognitive impairment after first-ever transient ischemic attack or ischemic stroke in young adults: The ODYSSEY study.

Introduction: We aimed to investigate the prevalence of cognitive impairment in the subacute phase after transient ischemic attack (TIA) and ischemic stroke (IS), factors associated with a vascular cognitive disorder, and the prevalence of subjective cognitive complaints and their relation with objective cognitive performance. Patients and methods: In this multicenter prospective cohort study, we recruited patients with first-ever TIA and IS, aged 18-49 years, between 2013 and 2021 for cognitive assessment up to 6 months after index event. We calculated composite Z-scores for seven cognitive domains. We defined cognitive impairment as a composite Z-score < -1.5. We defined major vascular cognitive disorder as a Z-score < -2.0 in one or more cognitive domains. Results: Fifty three TIA and 545 IS patients completed cognitive assessment with mean time to assessment of 89.7 (SD 40.7) days. The median NIHSS at admission was 3 (interquartile range, 1-5). Cognitive impairment was common in five domains (up to 37%), with similar proportion in TIA and IS patients. Patients with major vascular cognitive disorder had a lower education level, higher NIHSS scores and more frequent lesions in the left frontotemporal lobe than without vascular cognitive disorder (p < 0.05 FDR-corrected). Subjective memory and executive cognitive complaints were present in about two-thirds of the patients, but were weakly associated with objective cognitive performance (ß: -0.32 and -0.21, respectively). Discussion and conclusion: In the subacute phase after TIA or stroke in young adults, cognitive impairment and subjective cognitive complaints are prevalent, but they are weakly associated with each other.

Risk Factors and Causes of Ischemic Stroke in 1322 Young Adults.

BACKGROUND: Identification of risk factors and causes of stroke is key to optimize treatment and prevent recurrence. Up to one-third of young patients with stroke have a cryptogenic stroke according to current classification systems (Trial of ORG 10172 in Acute Stroke Treatment [TOAST] and atherosclerosis, small vessel disease, cardiac pathology, other causes, dissection [ASCOD]). The aim was to identify risk factors and leads for (new) causes of cryptogenic ischemic stroke in young adults, using the pediatric classification system from the IPSS study (International Pediatric Stroke Study). METHODS: This is a multicenter prospective cohort study conducted in 17 hospitals in the Netherlands, consisting of 1322 patients aged 18 to 49 years with first-ever, imaging confirmed, ischemic stroke between 2013 and 2021. The main outcome was distribution of risk factors according to IPSS classification in patients with cryptogenic and noncryptogenic stroke according to the TOAST and ASCOD classification. RESULTS: The median age was 44.2 years, and 697 (52.7%) were men. Of these 1322 patients, 333 (25.2%) had a cryptogenic stroke according to the TOAST classification. Additional classification using the ASCOD criteria reduced the number patients with cryptogenic stroke from 333 to 260 (19.7%). When risk factors according to the IPSS were taken into account, the number of patients with no potential cause or risk factor for stroke reduced to 10 (0.8%). CONCLUSIONS: Among young adults aged 18 to 49 years with a cryptogenic ischemic stroke according to the TOAST classification, risk factors for stroke are highly prevalent. Using a pediatric classification system provides new leads for the possible causes in cryptogenic stroke, and could potentially lead to more tailored treatment for young individuals with stroke.

Trigger Factors for Stroke in Young Adults: A Case-Crossover Study.

BACKGROUND AND OBJECTIVES: Causes of stroke in young adults differ from those in the elderly individuals, and in a larger percentage, no cause can be determined. To gain more insight into the etiology of (cryptogenic) stroke in the young population, we investigated whether trigger factors, such as short-lasting exposure to toxins or infection, may play a role. METHODS: Patients aged 18-49 years with a first-ever ischemic stroke or intracerebral hemorrhage (ICH) in 17 participating centers in the Netherlands completed a questionnaire about exposure to 9 potential trigger factors in hazard periods and on a regular yearly basis. A case-crossover design was used to assess relative risks (RRs) with 95% confidence intervals (95% CIs) by the Mantel-Haenszel case-crossover method, for any stroke (ischemic stroke and ICH combined) and for different etiologic subgroups of ischemic stroke. RESULTS: One thousand one hundred forty-six patients completed the questionnaire (1,043 patients with an ischemic stroke and 103 with an ICH, median age 44.0 years, 52.6% men). For any stroke, an increased risk emerged within 1 hour of cola consumption (RR 2.0, 95% CI 1.5-2.8) and vigorous physical exercise (RR 2.6, 95% CI 2.2-3.0), within 2 hours after sexual activity (RR 2.4, 95% CI 1.6-3.5), within 4 hours after illicit drug use (RR 2.8, 95% CI 1.7-4.9), and within 24 hours after fever or flu-like disease (RR 14.1, 95% CI 10.5-31.2; RR 13.9, 95% CI 8.9-21.9). Four trigger factors increased the risk of other determined and cryptogenic ischemic stroke, 3 that of cardioembolic stroke, 2 that of large vessel atherosclerosis and likely atherothrombotic stroke combined and stroke with multiple causes, and none that of stroke due to small vessel disease. DISCUSSION: We identified cola consumption, vigorous physical exercise, sexual activity, illicit drug use, fever, and flu-like disease as potential trigger factors for stroke in the young population and found differences in the type and number of trigger factors associated with different etiologic subgroups of ischemic stroke. These findings might help in better understanding the pathophysiologic mechanisms of (cryptogenic) stroke in the young population.

Impact of the lockdown on acute stroke treatments during the first surge of the COVID-19 outbreak in the Netherlands.

INTRODUCTION: We investigated the impact of the Corona Virus Disease 2019 (COVID-19) pandemic and the resulting lockdown on reperfusion treatments and door-to-treatment times during the first surge in Dutch comprehensive stroke centers. Furthermore, we studied the association between COVID-19-status and treatment times. METHODS: We included all patients receiving reperfusion treatment in 17 Dutch stroke centers from May 11th, 2017, until May 11th, 2020. We collected baseline characteristics, National Institutes of Health Stroke Scale (NIHSS) at admission, onset-to-door time (ODT), door-to-needle time (DNT), door-to-groin time (DGT) and COVID-19-status at admission. Parameters during the lockdown (March 15th, 2020 until May 11th, 2020) were compared with those in the same period in 2019, and between groups stratified by COVID-19-status. We used nationwide data and extrapolated our findings to the increasing trend of EVT numbers since May 2017. RESULTS: A decline of 14% was seen in reperfusion treatments during lockdown, with a decline in both IVT and EVT delivery. DGT increased by 12 min (50 to 62 min, p-value of < 0.001). Furthermore, median NIHSS-scores were higher in COVID-19 - suspected or positive patients (7 to 11, p-value of 0.004), door-to-treatment times did not differ significantly when stratified for COVID-19-status. CONCLUSIONS: During the first surge of the COVID-19 pandemic, a decline in acute reperfusion treatments and a delay in DGT was seen, which indicates a target for attention. It also appeared that COVID-19-positive or -suspected patients had more severe neurologic symptoms, whereas their EVT-workflow was not affected.

Risk, Clinical Course, and Outcome of Ischemic Stroke in Patients Hospitalized With COVID-19: A Multicenter Cohort Study.

BACKGROUND AND PURPOSE: The frequency of ischemic stroke in patients with coronavirus disease 2019 (COVID-19) varies in the current literature, and risk factors are unknown. We assessed the incidence, risk factors, and outcomes of acute ischemic stroke in hospitalized patients with COVID-19. METHODS: We included patients with a laboratory-confirmed SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) infection admitted in 16 Dutch hospitals participating in the international CAPACITY-COVID registry between March 1 and August 1, 2020. Patients were screened for the occurrence of acute ischemic stroke. We calculated the cumulative incidence of ischemic stroke and compared risk factors, cardiovascular complications, and in-hospital mortality in patients with and without ischemic stroke. RESULTS: We included 2147 patients with COVID-19, of whom 586 (27.3%) needed treatment at an intensive care unit. Thirty-eight patients (1.8%) had an ischemic stroke. Patients with stroke were older but did not differ in sex or cardiovascular risk factors. Median time between the onset of COVID-19 symptoms and diagnosis of stroke was 2 weeks. The incidence of ischemic stroke was higher among patients who were treated at an intensive care unit (16/586; 2.7% versus nonintensive care unit, 22/1561; 1.4%; P=0.039). Pulmonary embolism was more common in patients with (8/38; 21.1%) than in those without stroke (160/2109; 7.6%; adjusted risk ratio, 2.08 [95% CI, 1.52-2.84]). Twenty-seven patients with ischemic stroke (71.1%) died during admission or were functionally dependent at discharge. Patients with ischemic stroke were at a higher risk of in-hospital mortality (adjusted risk ratio, 1.56 [95% CI, 1.13-2.15]) than patients without stroke. CONCLUSIONS: In this multicenter cohort study, the cumulative incidence of acute ischemic stroke in hospitalized patients with COVID-19 was ≈2%, with a higher risk in patients treated at an intensive care unit. The majority of stroke patients had a poor outcome. The association between ischemic stroke and pulmonary embolism warrants further investigation.

Apixaban versus no anticoagulation after anticoagulation-associated intracerebral haemorrhage in patients with atrial fibrillation in the Netherlands (APACHE-AF): a randomised, open-label, phase 2 trial.

BACKGROUND: In patients with atrial fibrillation who survive an anticoagulation-associated intracerebral haemorrhage, a decision must be made as to whether restarting or permanently avoiding anticoagulation is the best long-term strategy to prevent recurrent stroke and other vascular events. In APACHE-AF, we aimed to estimate the rates of non-fatal stroke or vascular death in such patients when treated with apixaban compared with when anticoagulation was avoided, to inform the design of a larger trial. METHODS: APACHE-AF was a prospective, randomised, open-label, phase 2 trial with masked endpoint assessment, done at 16 hospitals in the Netherlands. Patients who survived intracerebral haemorrhage while treated with anticoagulation for atrial fibrillation were eligible for inclusion 7-90 days after the haemorrhage. Participants also had a CHA2DS2-VASc score of at least 2 and a score on the modified Rankin scale (mRS) of 4 or less. Participants were randomly assigned (1:1) to receive oral apixaban (5 mg twice daily or a reduced dose of 2·5 mg twice daily) or to avoid anticoagulation (oral antiplatelet agents could be prescribed at the discretion of the treating physician) by a central computerised randomisation system, stratified by the intention to start or withhold antiplatelet therapy in participants randomised to avoiding anticoagulation, and minimised for age and intracerebral haemorrhage location. The primary outcome was a composite of non-fatal stroke or vascular death, whichever came first, during a minimum follow-up of 6 months, analysed using Cox proportional hazards modelling in the intention-to-treat population. APACHE-AF is registered with ClinicalTrials.gov (NCT02565693) and the Netherlands Trial Register (NL4395), and the trial is closed to enrolment at all participating sites. FINDINGS: Between Jan 15, 2015, and July 6, 2020, we recruited 101 patients (median age 78 years [IQR 73-83]; 55 [54%] were men and 46 [46%] were women; 100 [99%] were White and one [1%] was Black) a median of 46 days (IQR 21-74) after intracerebral haemorrhage. 50 were assigned to apixaban and 51 to avoid anticoagulation (of whom 26 [51%] started antiplatelet therapy). None were lost to follow-up. Over a median follow-up of 1·9 years (IQR 1·0-3·1; 222 person-years), non-fatal stroke or vascular death occurred in 13 (26%) participants allocated to apixaban (annual event rate 12·6% [95% CI 6·7-21·5]) and in 12 (24%) allocated to avoid anticoagulation (11·9% [95% CI 6·2-20·8]; adjusted hazard ratio 1·05 [95% CI 0·48-2·31]; p=0·90). Serious adverse events that were not outcome events occurred in 29 (58%) of 50 participants assigned to apixaban and 29 (57%) of 51 assigned to avoid anticoagulation. INTERPRETATION: Patients with atrial fibrillation who had an intracerebral haemorrhage while taking anticoagulants have a high subsequent annual risk of non-fatal stroke or vascular death, whether allocated to apixaban or to avoid anticoagulation. Our data underline the need for randomised controlled trials large enough to allow identification of subgroups in whom restarting anticoagulation might be either beneficial or hazardous. FUNDING: Dutch Heart Foundation (grant 2012T077).

Severely Disturbed Sleep in Patients With Acute Ischemic Stroke on Stroke Units: A Pilot Study.

Introduction: Previous studies revealed a high prevalence of sleep-wake disturbances in subacute and chronic stroke. We analyzed sleep quantity and quality in patients with hyperacute ischemic stroke on stroke units. Methods: We categorized sleep stages as N1, N2, N3, and REM according to the 2017 criteria of the American Academy of Sleep Medicine in 23 continuous, overnight EEG registrations from 18 patients, starting within 48 h since the onset of cortical ischemic stroke. Associations between presence and duration of sleep stages, and secondary deterioration or functional outcome were analyzed. Results: Physiological sleep cycles were seen in none of the patients. Otherwise, sleep stages alternated chaotically, both during day- and during nighttime, with a sleep efficiency of 30% and 10.5 ± 4.4 (mean ± SD) awakenings per hour of sleep. We cannot differentiate between stroke related and external factors. Only few interruptions could be related to planned nightly wake up calls, but turbulence on stroke units may have played a role. Six patients (seven nights) did not reach deep sleep (N3), 10 patients (13 nights) did not reach REM sleep. If reached, the mean durations of deep and REM sleep were short, with 37 (standard deviation (SD) 25) and 18 (SD15) minutes, respectively. Patients with secondary deterioration more often lacked deep sleep (N3) than patients without secondary deterioration [4 (57%) vs. 2 (25%)], but without statistical significance (p = 0.12). Conclusion: We show that sleep is severely disturbed in patients with acute ischemic stroke admitted to stroke units. Larger studies are needed to clarify associations between deprivation of deep sleep and secondary deterioration.

Contralesional Brain Activity in Acute Ischemic Stroke.

BACKGROUND: The noninjured, contralateral hemisphere is increasingly acknowledged in the process of recovery from acute ischemic stroke. We estimated the value of conventional electroencephalography (EEG) recordings for identifying contralateral hemisphere involvement in relation to functional recovery. METHODS: We analyzed 2-min epochs from 21 electrode EEG registrations of 18 patients with acute hemispheric ischemic stroke and compared with 18 age-matched controls. Outcome was dichotomized as good (modified Rankin Scale [mRS] 0-2) or poor (mRS 3-5 or death) at 3 months. Effects of the infarct on the ipsi-and contralateral hemispheres were analyzed by the delta/alpha ratio (DAR) and 2 measures of functional connectivity (magnitude squared coherence [MSC] and weighted phase lag index [WPLI]). RESULTS: DAR was higher in patients than in controls, both in the ipsilateral and in the contralateral hemisphere (median 4.5 ± 6.7 ipsilateral and 2.4 ± 2.0 contralateral vs. 0.5 ± 0.5 in the control group, p < 0.001), indicating robust EEG changes in both lesioned and non-lesioned hemisphere. MSC and WPLI in the alpha and beta frequency bands were lower in patients than in controls in both hemispheres, indicating clear disturbances of functional connectivity (p < 0.05). In the poor outcome group, contralateral MSC and WPLI were lower than in the good outcome group, although these differences did not reach statistical significance. CONCLUSIONS: Short conventional EEG measurements show robust changes of brain activity and functional connectivity in both ipsilateral and contralateral hemispheres of patients with acute ischemic stroke. Changes of remote functional connectivity tend to interact with functional recovery. Future studies should estimate predictive values for individual patients and interactions with plasticity enhancing treatments.

Detecting Cortical Spreading Depolarization with Full Band Scalp Electroencephalography: An Illusion?

INTRODUCTION: There is strong evidence suggesting detrimental effects of cortical spreading depolarization (CSD) in patients with acute ischemic stroke and severe traumatic brain injury. Previous studies implicated scalp electroencephalography (EEG) features to be correlates of CSD based on retrospective analysis of EEG epochs after having detected "CSD" in time aligned electrocorticography. We studied the feasibility of CSD detection in a prospective cohort study with continuous EEG in 18 patients with acute ischemic stroke and 18 with acute severe traumatic brain injury. METHODS: Full band EEG with 21 silver/silver chloride electrodes was started within 48 h since symptom onset. Five additional electrodes were used above the infarct. We visually analyzed all raw EEG data in epochs of 1 h. Inspection was directed at detection of the typical combination of CSD characteristics, i.e., (i) a large slow potential change (SPC) accompanied by a simultaneous amplitude depression of >1Hz activity, (ii) focal presentation, and (iii) spread reflected as appearance on neighboring electrodes with a delay. RESULTS: In 3,035 one-hour EEG epochs, infraslow activity (ISA) was present in half to three quarters of the registration time. Typically, activity was intermittent with amplitudes of 40-220 µV, approximately half was oscillatory. There was no specific spatial distribution. Relevant changes of ISA were always visible in multiple electrodes, and not focal, as expected in CSD. ISA appearing as "SPC" was mostly associated with an amplitude increase of faster activities, and never with suppression. In all patients, depressions of spontaneous brain activity occurred. However, these were not accompanied by simultaneous SPC, occurred simultaneously on all channels, and were not focal, let alone spread, as expected in CSD. CONCLUSION: With full band scalp EEG in patients with cortical ischemic stroke or traumatic brain injury, we observed various ISA, probably modulating cortical excitability. However, we were unable to identify unambiguous characteristics of CSD.

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.

Subjective Cognitive Impairment, Depressive Symptoms, and Fatigue after a TIA or Transient Neurological Attack: A Prospective Study.

INTRODUCTION: Subjective cognitive impairment (SCI), depressive symptoms, and fatigue are common after stroke and are associated with reduced quality of life. We prospectively investigated their prevalence and course after a transient ischemic attack (TIA) or nonfocal transient neurological attack (TNA) and the association with diffusion-weighted imaging (DWI) lesions. METHODS: The Cognitive Failures Questionnaire, Hospital Anxiety and Depression Scale, and Subjective Fatigue subscale from the Checklist Individual Strength were used to assess subjective complaints shortly after TIA or TNA and six months later. With repeated measure analysis, the associations between DWI lesion presence or clinical diagnosis (TIA or TNA) and subjective complaints over time were determined. RESULTS: We included 103 patients (28 DWI positive). At baseline, SCI and fatigue were less severe in DWI positive than in DWI negative patients, whereas at follow-up, there were no differences. SCI (p = 0.02) and fatigue (p = 0.01) increased in severity only in DWI positive patients. There were no differences between TIA and TNA. CONCLUSIONS: Subjective complaints are highly prevalent in TIA and TNA patients. The short-term prognosis is not different between DWI-positive and DWI negative patients, but SCI and fatigue increase in severity within six months after the event when an initial DWI lesion is present.

Diffusion-weighted imaging in transient neurological attacks.

Transient ischemic attack (TIA) can be difficult to diagnose. Episodes of acute atypical or nonfocal neurological symptoms, referred to as transient neurological attack (TNA), are as prevalent as TIAs. Diffusion-weighted imaging (DWI) provides evidence of acute cerebral ischemia in a third of TIA patients. We now report that DWI shows acute ischemia in 23% of patients clinically diagnosed as TNA by experienced stroke neurologists. This questions the accuracy of clinically diagnosing TIA and suggests added value for early magnetic resonance imaging after an episode of acute onset atypical or nonfocal neurological symptoms.

Cohort study ON Neuroimaging, Etiology and Cognitive consequences of Transient neurological attacks (CONNECT): study rationale and protocol.

BACKGROUND: Transient ischemic attacks (TIA) are characterized by acute onset focal neurological symptoms and complete recovery within 24 hours. Attacks of nonfocal symptoms not fulfilling the criteria for TIA but lacking a clear alternative diagnosis are called transient neurological attacks (TNA). Although TIA symptoms are transient in nature, cognitive complaints may persist. In particular, attacks consisting of both focal and nonfocal symptoms (mixed TNA) have been found to be associated with an increased risk of dementia. We aim to study the prevalence, etiology and risk factors of cognitive impairment after TIA or TNA. METHODS/DESIGN: CONNECT is a prospective cohort study on cognitive function after TIA and TNA. In total, 150 patients aged ≥45 years with a recent (<7 days after onset) TIA or TNA and no history of stroke or dementia will be included. We will classify events as: TIA, nonfocal TNA, or mixed TNA. Known short lasting paroxysmal neurological disorders like migraine aura, seizures and Ménière disease are excluded from the diagnosis of TNA. Patients will complete a comprehensive neuropsychological assessment and undergo MRI <7 days after the qualifying event and again after six months. The primary clinical outcomes will be cognitive function at baseline and six months after the primary event. Imaging outcomes include the prevalence and evolution of DWI lesions, white matter hyperintensities and lacunes, as well as resting state networks functionality and white matter microstructural integrity. Differences between types of event and DWI, as well as determinants of both clinical and imaging outcomes, will be assessed. DISCUSSION: CONNECT can provide insight in the prevalence, etiology and risk factors of cognitive impairment after TIA and TNA and thereby potentially identify a new group of patients at increased risk of cognitive impairment.

The Preventive Antibiotics in Stroke Study (PASS): a pragmatic randomised open-label masked endpoint clinical trial.

BACKGROUND: In adults with acute stroke, infections occur commonly and are associated with an unfavourable functional outcome. In the Preventive Antibiotics in Stroke Study (PASS) we aimed to establish whether or not preventive antimicrobial therapy with a third-generation cephalosporin, ceftriaxone, improves functional outcome in patients with acute stroke. METHODS: In this multicentre, randomised, open-label trial with masked endpoint assessment, patients with acute stroke were randomly assigned to intravenous ceftriaxone at a dose of 2 g, given every 24 h intravenously for 4 days, in addition to stroke unit care, or standard stroke unit care without preventive antimicrobial therapy; assignments were made within 24 h after symptom onset. The primary endpoint was functional outcome at 3 months, defined according to the modified Rankin Scale and analysed by intention to treat. The primary analysis was by ordinal regression of the primary outcome. Secondary outcomes included death, infection rates, antimicrobial use, and length of hospital stay. Participants and caregivers were aware of treatment allocation but assessors of outcome were masked to group assignment. This trial is registered with controlled-trials.com, number ISRCTN66140176. FINDINGS: Between July 6, 2010, and March 23, 2014, a total of 2550 patients from 30 sites in the Netherlands, including academic and non-academic medical centres, were randomly assigned to the two treatment groups: 1275 patients to ceftriaxone and 1275 patients to standard treatment (control group). 12 patients (seven in the ceftriaxone group and five in the control group) withdrew consent immediately after randomisation, leaving 2538 patients available for the intention-to-treat-analysis (1268 in the ceftriaxone group and 1270 in the control group). 2514 (99%) of 2538 patients (1257 in each group) completed 3-month follow-up. Preventive ceftriaxone did not affect the distribution of functional outcome scores on the modified Rankin Scale at 3 months (adjusted common odds ratio 0·95 [95% CI 0·82-1·09], p=0·46). Preventive ceftriaxone did not result in an increased occurrence of adverse events. Overgrowth infection with Clostridium difficile occurred in two patients (<1%) in the ceftriaxone group and none in the control group. INTERPRETATION: Preventive ceftriaxone does not improve functional outcome at 3 months in adults with acute stroke. The results of our trial do not support the use of preventive antibiotics in adults with acute stroke. FUNDING: Netherlands Organization for Health Research and Development, Netherlands Heart Foundation, and the European Research Council.

Observational Dutch Young Symptomatic StrokE studY (ODYSSEY): study rationale and protocol of a multicentre prospective cohort study.

BACKGROUND: The proportion of strokes occurring in younger adults has been rising over the past decade. Due to the far longer life expectancy in the young, stroke in this group has an even larger socio-economic impact. However, information on etiology and prognosis remains scarce. METHODS/DESIGN: ODYSSEY is a multicentre prospective cohort study on the prognosis and risk factors of patients with a first-ever TIA, ischemic stroke or intracerebral hemorrhage aged 18 to 49 years. Our aim is to include 1500 patients. Primary outcome will be all cause mortality and risk of recurrent vascular events. Secondary outcome will be the risk of post-stroke epilepsy and cognitive impairment. Patients will complete structured questionnaires on outcome measures and risk factors. Both well-documented and less well-documented risk factors and potentially acute trigger factors will be investigated. Patients will be followed every 6 months for at least 3 years. In addition, an extensive neuropsychological assessment will be administered both at baseline and 1 year after the stroke/TIA. Furthermore we will include 250 stroke-free controls, who will complete baseline assessment and one neuropsychological assessment. DISCUSSION: ODYSSEY is designed to prospectively determine prognosis after a young stroke and get more insight into etiology of patients with a TIA, ischemic stroke and intracerebral hemorrhage in patients aged 18 to 49 years old in a large sample size.

Prevalence of prediabetes and newly diagnosed diabetes in patients with a transient ischemic attack or stroke.

BACKGROUND: Patients with a transient ischemic attack (TIA) or stroke and prediabetes or newly diagnosed diabetes are at high risk of recurrent stroke or cardiovascular events. This underlines the importance of accurate screening for impaired glucose metabolism in clinical practice. Fasting plasma glucose levels are currently the most commonly measured glycemic parameter to detect prediabetes or diabetes, even if 2-hour postload glucose and glycosylated hemoglobin levels can be used as well. We assessed the prevalence of prediabetes and newly diagnosed diabetes with different screening methods, including fasting plasma glucose, 2-hour postload glucose and glycosylated hemoglobin levels in consecutive patients with recent TIA, ischemic stroke or intracerebral hemorrhage admitted to the stroke unit or visiting the specialized TIA outpatient clinic in the Erasmus Medical Center, Rotterdam, The Netherlands. METHODS: We measured fasting plasma glucose, 2-hour postload glucose and glycosylated hemoglobin levels in 269 patients with a TIA, 374 with ischemic stroke and 57 with intracerebral hemorrhage, all without a history of diabetes mellitus. Prediabetes was defined as fasting plasma glucose levels of 5.6-6.9 mmol/l and/or 2-hour postload glucose levels of 7.8-11.0 mmol/l and/or glycosylated hemoglobin levels of 5.7-6.4%. Newly diagnosed diabetes was defined as fasting plasma glucose levels of ≥7.0 mmol/l and/or 2-hour postload levels of ≥11.1 mmol/l and/or glycosylated hemoglobin levels of ≥6.5%. The diagnosis was based on a one-time measurement. RESULTS: Based on fasting plasma glucose, 2-hour postload glucose and glycosylated hemoglobin levels combined, 365 patients (52%) were identified as prediabetics and 188 (27%) as having newly diagnosed diabetes. Patients with intracerebral hemorrhage had more often newly diagnosed diabetes compared with patients with an ischemic stroke or a TIA [27 (47%) and 161 (25%), respectively; p < 0.001]; the prevalence of prediabetes was similar. Newly diagnosed diabetes was identified more frequently by 2-hour postload glucose levels (n = 162; 23%) than by fasting plasma glucose (n = 49; 7%) or glycosylated hemoglobin levels (n = 36; 5%). About one third of the patients with normal fasting glucose levels has impaired glucose tolerance or elevated glycosylated hemoglobin levels. CONCLUSIONS: Prediabetes and newly diagnosed diabetes are highly prevalent in patients with a TIA or stroke. The majority of these patients would not have been identified by fasting plasma glucose levels alone. Both 2-hour postload glucose and glycosylated hemoglobin levels identify more patients with a disturbed glucose metabolism.