Routine transthoracic echocardiography in ischaemic stroke or transient ischaemic attack of undetermined cause: a prospective multicentre study.

BACKGROUND: Guidelines recommend routine transthoracic echocardiography (TTE) after ischaemic stroke or transient ischaemic attack of undetermined cause; yet, only limited scientific evidence exists. Therefore, we aimed to determine in these patients the prevalence of TTE-detected major cardiac sources of embolism (CSE), which are abnormalities leading to therapeutic changes. METHODS: Six Dutch hospitals conducted a prospective observational study that enrolled patients with ischaemic stroke or transient ischaemic attack of undetermined cause. Patients underwent TTE after comprehensive diagnostic evaluation on stroke units, including blood chemistry, 12-lead electrocardiogram (ECG), ≥ 24 h continuous ECG monitoring, brain imaging and cervical artery imaging. Primary outcome measure was the proportion of patients with TTE-detected major CSE. RESULTS: From March 2018 to October 2020, 1084 patients, aged 66.6 ± 12.5 years, were enrolled; 456 (42.1%) patients were female and 869 (80.2%) had ischaemic stroke. TTE detected major CSE in only 11 (1.0%) patients. Ten (90.9%) of these patients also had major ECG abnormalities (previous infarction, major repolarisation abnormalities, or previously unknown left bundle branch block) that would have warranted TTE assessment regardless of stroke evaluation. Such ECG abnormalities were present in 11.1% of the total study population. A single patient (0.1%) showed a major CSE despite having no ECG abnormality. CONCLUSIONS: This multicentre cross-sectional study in patients who-after workup on contemporary stroke units-were diagnosed with ischaemic stroke or transient ischaemic attack of undetermined cause found TTE-detected major CSE in only 1% of all patients. Most of these patients also had major ECG abnormalities. These findings question the value of routine TTE assessment in this clinical setting.

Atrial fibrillation detected with outpatient cardiac rhythm monitoring in patients with ischemic stroke or TIA of undetermined cause.

OBJECTIVES: Guidelines advise cardiac rhythm monitoring for 3 up to 30 days for detecting atrial fibrillation (AF) in patients with ischemic stroke of undetermined cause. However, the optimal monitoring duration is unknown. We aimed to determine the AF detection rate during 7-day outpatient cardiac rhythm monitoring in this patient group. METHODS: Participants from a large tertiary hospital in a prospective observational study (ATTEST) underwent outpatient cardiac rhythm monitoring after a negative standard diagnostic evaluation (i.e., 12-lead electrocardiogram and in-hospital telemetry). Primary outcome was the rate of newly detected AF. RESULTS: We examined 373 patients [age: 67.8±11.6 years; women: 166(44.5%); stroke: 278(74.5%)]. Median monitoring duration was 7 days (Inter Quartile Range (IQR) 7-7), performed after median of 36 days (IQR 27-47). AF was newly detected in 17(4.6%) patients, 5.4% of patients with ischemic stroke and 2.1% of patients with TIA. 53% of AF was detected on day-1, after day-3 73% of new AF was found. First AF episodes were detected up to day-7. Diabetes and increasing age were independent predictors of new AF. CONCLUSION: After ischemic stroke or TIA of undetermined cause, 7-day outpatient cardiac rhythm monitoring detected new AF in 4.6%. Patients with AF had significantly more cardiovascular risk factors. Although about 50% of first AF episodes occurred during the first day of monitoring, new AF was detected up to day-7, implying that the recommended minimum of 3 days cardiac rhythm monitoring after ischemic stroke of undetermined cause is insufficient. Subsequent long-term rhythm monitoring should be considered in selected patients.

Cardiac imaging in ischemic stroke or transient ischemic attack of undetermined cause: Systematic review & meta-analysis.

BACKGROUND: Patients with ischemic stroke or transient ischemic attack (TIA) of undetermined cause often undergo cardiac imaging in search of a cardioembolic source. As the choice of the most appropriate imaging approach is controversial and therapeutic implications have changed over time, we aimed to identify in patients with "cryptogenic stroke or TIA" the yield of transthoracic or transesophageal echocardiography (TTE or TEE) and cardiac computed tomography (CT). METHODS AND RESULTS: We performed a systematic review and meta-analysis according to the PRISMA guidelines. Included were studies that assessed consecutive patients with ischemic stroke or TIA of undetermined cause to evaluate the yield of TTE, TEE, or cardiac CT for detecting cardioembolic sources. For each type of cardioembolic source the pooled prevalence was calculated. Only six out of 1458 studies fulfilled the inclusion criteria (1022 patients). One study reported the yield of TTE, four of TEE, and one of both TTE and TEE; no study assessed cardiac CT. Mean patient age ranged from 44.3-71.2 years, 49.2-59.7% were male. TTE detected 43 cardioembolic sources in 316 patients (4 (1.3%) major, 39 (12.3%) minor), and TEE 248 in 937 patients (55 (5.9%) major, 193 (20.6%) minor). The most prevalent major cardioembolic source was left atrial appendage thrombus, yet results were heterogeneous among studies. CONCLUSIONS: TTE and TEE infrequently detect major cardioembolic sources that require a change of therapy. Findings should be interpreted with caution due to the limited number of studies. A large-sized prospective clinical trial is warranted to support evidence-based decision-making.

Detection of Major Cardioembolic Sources in Real-World Patients with Ischemic Stroke or Transient Ischemic Attack of Undetermined Cause.

BACKGROUND/AIM: Current guidelines recommend transthoracic echocardiography (TTE) and ambulatory rhythm monitoring following ischemic stroke or transient ischemic attack (TIA) of undetermined cause for identifying cardioembolic sources (CES). Due to ongoing controversies about this routine strategy, we evaluated its yield in a real-world setting. METHODS: In a tertiary medical center, we retrospectively evaluated consecutive patients with ischemic stroke or TIA of undetermined cause, who (after standard work-up) underwent TTE, ambulatory rhythm monitoring, or both. CES were classified as major if probably related to ischemic events and warranting a change of therapy. RESULTS: Between January 2014 and December 2017, 674 patients had ischemic stroke or TIA of undetermined cause. Of all 484 patients (71.8%) who underwent TTE, 9 (1.9%) had a major CES. However, 7 of them had already been identified for cardiac evaluation due to new major electrocardiographic abnormalities or cardiac symptoms. Thus, only 2 patients (0.4%) truly benefitted from unselected TTE screening. Ambulatory rhythm monitoring was performed in 411 patients (61.0%) and revealed AF in 10 patients (2.4%). CONCLUSION: Detecting a major CES is essential because appropriate treatment lowers the risk of recurrent stroke. Nonetheless, in this real-world study that aimed at routine use of TTE and ambulatory rhythm monitoring in patients with ischemic stroke or TIA of undetermined cause, the prevalence of major CES was low. Most patients with major CES on TTE already had an indication for referral to a cardiologist, suggesting that major CES might also have been identified with a much more selective use of TTE.

The additional value of an algorithm for atrial fibrillation at the stroke unit.

BACKGROUND AND PURPOSE: The rate of newly detected (paroxysmal) atrial fibrillation (AF) during inpatient cardiac telemetry is low. The objective of this study was to evaluate the additional diagnostic yield of an automated detection algorithm for AF on telemetric monitoring compared with routine detection by a stroke unit team in patients with recent ischemic stroke or TIA. METHODS: Patients admitted to the stroke unit of Medisch Spectrum Twente with acute ischemic stroke or TIA and no history of AF were prospectively included. All patients had telemetry monitoring, routinely assessed by the stroke unit team. The ST segment and arrhythmia monitoring (ST/AR) algorithm was active, with deactivated AF alarms. After 24 h the detections were analyzed and compared with routine evaluation. RESULTS: Five hundred and seven patients were included (52.5% male, mean age 70.2 ± 12.9 years). Median monitor duration was 24 (interquartile range 22-27) h. In 6 patients (1.2%) routine analysis by the stroke unit team concluded AF. In 24 patients (4.7%), the ST/AR Algorithm suggested AF. Interrater reliability was low (κ, 0.388, p < 0.001). Suggested AF by the algorithm turned out to be false positive in 11 patients. In 13 patients (2.6%) AF was correctly diagnosed by the algorithm. None of the cases detected by routine analysis were missed by the algorithm. CONCLUSIONS: Automated AF detection during 24-h telemetry in ischemic stroke patients is of additional value to detect paroxysmal AF compared with routine analysis by the stroke unit team alone. Automated detections need to be carefully evaluated.

CX3C chemokine receptor 1 deficiency modulates microglia morphology but does not affect lesion size and short-term deficits after experimental stroke.

BACKGROUND: The fractalkine/CX3C chemokine receptor 1 (CX3CR1) pathway has been identified to play an essential role in the chemotaxis of microglia, leukocyte trafficking and microglia/macrophage recruitment. It has also been shown to be important in the regulation of the inflammatory response in the early phase after experimental stroke. The present study was performed to investigate if CX3CR1 deficiency affects microglia during the first 14 days with consequences for tissue damage after experimental stroke. RESULTS: CX3CR1 deficiency significantly increased the number of intersections of GFP positive microglia in the proximal peri-infarct area at 2, 7 and 14 days following tMCAO compared to heterozygous and wildtype littermates. In addition, the length of microglial branches increased until day 7 in CX3CR1 knockout mice while the presence of a functional CX3CR1 allele resulted in a gradual reduction of their length following tMCAO. After stroke, wildtype, heterozygous and CX3CR1 deficient mice did not show differences in the composite neuroscore and assessment of infarct volumes from CX3CR1 wildtype, heterozygous and deficient mice revealed no differences between the genotypes 7 and 14 days after stroke. CONCLUSION: Results demonstrate that CX3CR1 deficiency affects the morphology of GFP positive microglia located in the proximal peri-infarct region during the first 14 days after tMCAO. Our data also indicate that CX3CR1 deficiency does not affect definite infarct volumes. Modulation of the CX3CR1 pathway may have implication for microglia function contributing to mechanisms of tissue reorganization in the post-ischemic brain.

Treatment with AMD3100 attenuates the microglial response and improves outcome after experimental stroke.

BACKGROUND: Recovery of lost neurological function after stroke is limited and dependent on multiple mechanisms including inflammatory processes. Selective pharmacological modulation of inflammation might be a promising approach to improve stroke outcome. METHODS: We used 1,1'-[1,4-phenylenebis(methylene)]bis[1,4,8,11-tetraazacyclotetradecane] (AMD3100), an antagonist to the C-X-C chemokine receptor type 4 (CXCR4) and potential allosteric agonist to CXCR7, administered to mice twice daily from day 2 after induction of photothrombosis (PT). In addition to functional outcome, the dynamics of post-stroke microglia response were monitored in vivo by 2-photon-laser-microscopy in heterozygous transgenic CX3CR1-green fluorescent protein (GFP) mice (CX3CR1(GFP/+)) and complemented with analyses for fractalkine (FKN) and pro-inflammatory cytokines. RESULTS: We found a significantly enhanced recovery and modified microglia activation without affecting infarct size in mice treated with AMD3100 after PT. AMD3100 treatment significantly reduced the number of microglia in the peri-infarct area accompanied by stabilization of soma size and ramified cell morphology. Within the ischemic infarct core of AMD3100 treated wild-type mice we obtained significantly reduced levels of the endogenous CX3CR1 ligand FKN and the pro-inflammatory cytokines interleukin (IL)-1ß and IL-6. Interestingly, in CX3CR1-deficient mice (homozygous transgenic CX3CR1-GFP mice) subjected to PT, the levels of FKN were significantly lower compared to their wild-type littermates. Moreover, AMD3100 treatment did not induce any relevant changes of cytokine levels in CX3CR1 deficient mice. CONCLUSION: After AMD3100 treatment, attenuation of microglia activation contributes to enhanced recovery of lost neurological function in experimental stroke possibly due to a depression of FKN levels in the brain. We further hypothesize that this mechanism is dependent on a functional receptor CX3CR1.