Transcranial Doppler detects micro emboli in patients with asymptomatic carotid stenoses undergoing endarterectomy.

OBJECTIVE: The objective of this study was to assess the primary endpoint defined as the detection of micro-embolic signals (MES) by the use of transcranial Doppler (TCD) in patients with asymptomatic carotid stenosis (≥70%) scheduled for carotid endarterectomy. The secondary endpoint consisted of testing the association of MES with stenosis severity, histopathological, and ultrasound characteristics. METHODS: This was a single-center, single-arm, prospective, observational trial. Computed tomography angiography and ultrasound assessment (Geroulakos classification) were mandatory as well as being under best medical therapy. MES number and characteristics were investigated in Holter mode TCD-X device with a standard 1.5 MHz probe. The time points of evaluation were: 24 hours preoperative, 24 hours postoperative, and 30 days postoperative. The histopathological analysis was performed according to the modified American Heart Association classification. One-way analysis of variance tested MES differences over time. Univariable and multivariable logistic regression tested variables potentially associated with MES. RESULTS: A total of 120 patients demonstrated a significant reduction of the mean number of MES (3.35 ± 10.04 and 0.82 ± 2.39; pre- and post-carotid endarterectomy, respectively), becoming undetectable at 30 days (P = .001). Hypoechogenic plaques assessed by ultrasound were a significant risk factor for MES (P = .001). The features of plaque vulnerability, such as hemorrhagic component (P = .011), neovascularization (P = .025), signs of inflammation (P = .027), and rupture of the fibrous cap (P = .002) were predictors of MES. Cap rupture was the only predictor in the multivariate analysis (odds ratio, 5.98; P = .030). The stenosis severity was not associated with MES (P = .95) CONCLUSIONS: Patients under best medical therapy had a preoperative embolic activity becoming no more detectable after surgery. Both ultrasound and histologic markers of vulnerability were predictors of MES, and stenosis severity was not associated. TCD gives better insight into the real embolic risk, and future studies should evaluate clinical results coming from its implementation with standard imaging techniques. CLINICALTRIAL: gov registration number NCT05134493.

Micro-Embolic Signals and Dissection: Association or Causation for Stroke? A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVE: Although the mechanism of stroke in cervical artery dissection (CAD) has been hypothesized to be embolization rather than hemodynamic compromise, there are a limited number of studies supporting this hypothesis. Detection of micro-embolic signals (MESs) using transcranial Doppler (TCD) helps in understanding the mechanism in these patients. A systematic review and meta-analysis were performed to estimate the prevalence of MES and its association with stroke outcomes in patients with acute stroke/TIA secondary to dissection. METHODS: A comprehensive literature search was conducted for studies before January 26, 2021, in PubMed, Embase, Google Scholar, Cochrane Library, and ClinicalTrials.gov. Studies were identified that used TCD to detect MES in stroke/TIA patients secondary to CAD. Pooled prevalence was calculated. Entire statistical analysis was conducted in R version 3.6.2. RESULTS: Eleven studies involving 112 patients (50 MES+, 62 MES-) were included in our meta-analysis. The pooled prevalence of MES among acute stroke/TIA patients secondary to dissection was 46.0% (95% CI 26.0-67.0%). The presence of MES was associated with an increased risk of early ischemic recurrence in patients with CAD. We could not estimate the functional outcome and mortality associated with the presence of MES due to the scarcity of data. CONCLUSIONS: Our meta-analysis showed 46% prevalence of MES in the studies which looked at acute stroke/TIA secondary to CAD using TCD. This finding supports the assumption that embolism may be a major cause of stroke in patients with dissection although this could be determined only in a small population.

Transcranial Doppler ultrasound: Clinical applications from neurological to cardiological setting.

Transcranial Doppler (TCD) ultrasonography is a rapid, noninvasive, real-time, and low-cost imaging technique. It is performed with a low-frequency (2 MHz) probe in order to evaluate the cerebral blood flow (CBF) and its pathological alterations, through specific acoustic windows. In the recent years, TCD use has been expanded across many clinical settings. Actually, the most widespread indication for TCD exam is represented by the diagnosis of paradoxical embolism, due to patent foramen ovale, in young patients with cryptogenic stroke. In addition, TCD has also found useful applications in neurological care setting, including the following: cerebral vasospasm following acute subarachnoid hemorrhage, brain trauma, cerebrovascular atherosclerosis, and evaluation of CBF and cerebral autoregulation after an ischemic stroke event. The present review aimed to describe the most recent evidences of TCD utilization from neurological to cardiological setting.

Transient ischemic attack presenting as recurrent migratory numbness by seconds: a rare case confirmed by transcranial Doppler micro-emboli monitoring.

BACKGROUND: Transient ischemic attack (TIA) is a brief episode of cerebral ischemia. However, if a symptom is not presented as drop attack or hemiplegia, and alarming to the patient and the physician, how short of a symptom duration would raise the concern of a physician for TIA? It will be more complicated if the location of the neurological deficit is vagrant. This report highlights a rare TIA case which presented a very short duration of migratory patchy distribution numbness. CASE PRESENTATION: A middle-aged gentleman was presented with recurrent patchy distribution numbness on the right side of the body for 2 months, with the episode lasting as short as about 10 s. The location of the numbness was erratic and migratory. Magnetic resonance angiography (MRA) revealed mild stenosis on the left middle cerebral artery (MCA). Transcranial Doppler (TCD) micro-emboli monitoring detected positive micro-emboli signals (MES), leading to the confirmation of a TIA diagnosis. After a standard dual antiplatelet treatment combined with enhanced lipid reduction therapy with statins, MES disappeared on dynamic TCD emboli monitoring, and no more episodes of TIA have been noticed on the follow-ups. CONCLUSION: TIA caused by micro-emboli can display as recurrent migratory neurological deficit within seconds. TCD micro-emboli monitoring is very helpful to differentiate this situation from TIA mimics with follow-ups, as well as to locate unstable plague.

Detection of Cerebral High-Intensity Transient Signals by NeoDoppler during Cardiac Catheterization and Cardiac Surgery in Infants.

There is a risk of gaseous and solid micro-embolus formation during transcatheter cardiac interventions and surgery in children with congenital heart disease (CHD). Our aim was to study the burden of high-intensity transient signals (HITS) during these procedures in infants. We used a novel color M-mode Doppler (CMD) technique by NeoDoppler, a non-invasive ultrasound system based on plane wave transmissions for transfontanellar continuous monitoring of cerebral blood flow in infants. The system displays CMD with 24 sample volumes and a Doppler spectrogram. Infants with CHD undergoing transcatheter interventions (n = 15) and surgery (n = 13) were included. HITS were manually detected based on an "embolic signature" in the CMD with corresponding intensity increase in the Doppler spectrogram. Embolus-to-blood ratio (EBR) defined HITS size. A total of 1169 HITS with a median EBR of 9.74 dB (interquartile range [IQR]: 5.10-15.80 dB) were detected. The median number of HITS in the surgery group was 45 (IQR: 11-150), while in the transcatheter group the median number was 12 (IQR: 7-24). During cardiac surgery, the highest number of HITS per hour was seen from initiation of cardiopulmonary bypass to aortic X-clamp. In this study we detected frequent HITS and determined the feasibility of using NeoDoppler monitoring for HITS detection.

Micro-embolic signal monitoring in stroke subtypes: A systematic review and meta-analysis of 58 studies.

Introduction: Micro-embolic signals (MESs) detected using transcranial Doppler (TCD) help in risk stratification in stroke patients. A systematic review and meta-analysis were performed to estimate the prevalence of MES and its association with stroke recurrence, functional outcome, and mortality in different stroke subtypes. Methods: A comprehensive literature search was conducted before 26th January 2021 in PubMed, Embase, Google Scholar, Cochrane Library, and ClinicalTrials.gov. Studies were identified that used TCD to detect MES in stroke/TIA patients. Pooled prevalence and odds ratio (OR) along with 95% confidence interval (95% CI) were calculated for different outcome measures. The entire statistical analysis was conducted in R version 3.6.2. Findings: Fifty-eight studies involving 5123 patients (1329 MES+, 3794 MES-) were included in our meta-analysis. The pooled prevalence of MES among all acute stroke/TIA patients was 30% (95% CI 25-34%). The pooled prevalence adjusted after the trim-and-fill analysis among all acute stroke/TIA patients was 18% (95% CI 14-23%). The prevalence of MES was high among all stroke subtypes except in patients with small vessel disease (SVD). In patients with new-onset stroke/TIA, the presence of MES was associated with a high risk of recurrence of cerebral ischemia (OR 4.03; 95% CI 2.38-6.82). Although no significant association was observed for the presence of MES with increased mortality (OR 2.37; 95% CI 0.75-7.50) and poor functional outcome (OR 2.11; 95% CI 0.20-22.50) among patients with new-onset stroke/TIA, this could only be determined in a smaller sample size of 477 patients. Conclusions: Our meta-analysis showed a 30% prevalence of MES following acute stroke/TIA. The presence of MES increased the chance of recurrence of cerebral ischemia but was not associated with poor functional outcomes and mortality in the studied subgroup.

Simultaneous assessment of plaque morphology, cerebral micro-embolic signal status and platelet biomarkers in patients with recently symptomatic and asymptomatic carotid stenosis.

The relationship between plaque morphology, cerebral micro-embolic signals (MES) and platelet biomarkers in carotid stenosis patients warrants investigation.We combined data from two prospective, observational studies to assess carotid plaque morphology and relationship with cerebral MES and platelet biomarkers in patients with recently symptomatic (≤4 weeks of transient ischaemic attack (TIA)/ischaemic stroke) versus asymptomatic carotid stenosis. Plaque morphology on ultrasound was graded with Grey-Scale Median (GSM) and Gray-Weale (GW) scoring. Bilateral transcranial Doppler ultrasound classified patients as 'MES+ve' or 'MES-ve'. Full blood counts were analysed and flow cytometry quantified CD62P and CD63 expression, leucocyte-platelet complexes and reticulated platelets.Data from 42 recently symptomatic carotid stenosis patients were compared with those from 36 asymptomatic patients. There were no differences in median GSM scores between symptomatic and asymptomatic patients (25 vs. 30; P = 0.31) or between MES+ve vs. MES-ve symptomatic patients (36 vs. 25; P = 0.09). Symptomatic patients with GSM-echodense plaques (GSM ≥25) had higher platelet counts (228 vs. 191 × 109/L), neutrophil-platelet (3.3 vs. 2.7%), monocyte-platelet (6.3 vs. 4.55%) and lymphocyte-platelet complexes (2.91 vs. 2.53%) than 'asymptomatic patients with GSM-echodense plaques' (P ≤ 0.03).Recently, symptomatic carotid stenosis patients with 'GSM-echodense plaques' have enhanced platelet production/secretion/activation compared with their asymptomatic counterparts. Simultaneous assessment with neurovascular imaging and platelet biomarkers may aid risk-stratification in carotid stenosis.

Relationship between 'on-treatment platelet reactivity', shear stress, and micro-embolic signals in asymptomatic and symptomatic carotid stenosis.

BACKGROUND: Assessment of 'high on-treatment platelet reactivity (HTPR)' could enhance understanding of the pathophysiology of first or recurrent vascular events in carotid stenosis patients on antiplatelet therapy. METHODS: This prospective, multi-centre study assessed antiplatelet-HTPR status and its relationship with micro-emboli signals (MES) in asymptomatic vs. symptomatic ≥ 50-99% carotid stenosis. Platelet function/reactivity was assessed under 'moderately high shear stress' with the PFA-100® and 'low shear stress' with VerifyNow® and Multiplate® analysers. Bilateral 1-h transcranial Doppler ultrasound of the middle cerebral arteries classified patients as MES + ve or MES - ve. RESULTS: Data from 34 asymptomatic patients were compared with 43 symptomatic patients in the 'early phase' (≤ 4 weeks) and 37 patients in the 'late phase' (≥ 3 months) after TIA/ischaemic stroke. Median daily aspirin doses were higher in early symptomatic (225 mg; P < 0.001), but not late symptomatic (75 mg; P = 0.62) vs. asymptomatic patients (75 mg). There was a lower prevalence of aspirin-HTPR in early (28.6%; P = 0.028), but not late symptomatic (38.9%; P = 0.22) compared with asymptomatic patients (56.7%) on the PFA-100®, but not on the VerifyNow® or Multiplate® (P ≤ 0.53). Early symptomatic patients had a higher prevalence of aspirin-HTPR on the PFA-100® (28.6%) vs. VerifyNow® (9.5%; P = 0.049), but not Multiplate® assays (11.9%, P = 0.10). There was no difference in aspirin-HTPR prevalence between any symptomatic vs. asymptomatic MES + ve or MES - ve subgroup. DISCUSSION: Recently symptomatic moderate-severe carotid stenosis patients had a lower prevalence of aspirin-HTPR than their asymptomatic counterparts on the PFA-100®, likely related to higher aspirin doses. The prevalence of antiplatelet-HTPR was positively influenced by higher shear stress levels, but not MES status.

Circulating Microparticles in Patients with Symptomatic Carotid Disease Are Related to Embolic Plaque Activity and Recent Cerebral Ischaemia.

BACKGROUND AND PURPOSE: In order to assess the association of microparticles derived from activated platelets (PMP) or endothelial cells (EMP) with risk markers for recurrent embolic events in patients with symptomatic carotid artery disease, we studied the associations between PMP/EMP and three risk markers: plaque haemorrhage (PH), micro-embolic signals and cerebral diffusion abnormalities. METHODS: Patients with recently symptomatic high-grade carotid artery stenosis (60-99%, 42 patients, 31 men; mean age 75 ± 8 years) and 30 healthy volunteers (HV, 11 men; mean age 56 ± 12 years) were prospectively recruited. Patients were characterised by carotid magnetic resonance imaging (presence of PH [MRI PH]), brain diffusion MRI (cerebral ischaemia [DWI+]) and transcranial Doppler ultrasound (micro-embolic signals [MES+]). PMP and EMP were classified by flow cytometry and expressed as log-transformed counts per microlitre. RESULTS: MES+ patients (n = 18) had elevated PMP (MES+ 9.61 ± 0.57) compared to HV (8.80 ± 0.73; p < 0.0001) and to MES- patients (8.55 ± 0.85; p < 0.0001). Stroke patients had elevated PMP (9.49 ± 0.64) and EMP (6.13 ± 1.0) compared to non-stroke patients (PMP 8.81 ± 0.73, p = 0.026, EMP 5.52 ± 0.65, p = 0.011) and HV (PMP 8.80 ± 0.73, p = 0.007, and EMP 5.44 ± 0.47, p = 0.006). DWI+ patients (n = 16) showed elevated PMP (DWI+ 9.53 ± 0.64; vs. HV, p = 0.002) and EMP (DWI+ 5.91 ± 0.99 vs. HV 5.44 ± 0.47; p = 0.037). Only PMP but not EMP were higher in DWI+ versus DWI- patients (8.67 ± 0.90; p = 0.002). No association was found between PMP and EMP with MRI PH. CONCLUSIONS: PMP and EMP were associated with stroke and recent cerebrovascular events (DWI+) but only PMP were also associated with ongoing (MES+) thrombo-embolic activity suggesting a differential biomarker potential for EMP to index cerebral ischaemia while PMP may predict on-going thrombo-embolic activity.