Konstantinos Vadikolias

Safety and Efficacy of Ultrasound-Enhanced Thrombolysis A Comprehensive Review and Meta-Analysis of Randomized and Nonrandomized Studies

Background and Purpose— Ultrasound-enhanced thrombolysis is a promising new approach to facilitate reperfusion therapies for acute ischemic stroke. So far, 3 different ultrasound technologies were used to increase the thrombolytic activity of tissue plasminogen activator (tPA), including transcranial Doppler (TCD), transcranial color-coded duplex (TCCD), and low-frequency ultrasound. We performed a meta-analysis to evaluate the safety and efficacy of ultrasound-enhanced thrombolysis compared to the current standard of care (intravenous tPA). Subjects and Methods— Through Medline, Embase, and Cochrane database search, we identified and abstracted all studies of ultrasound-enhanced thrombolysis in acute cerebral ischemia. Principal investigators were contacted if data not available through peer-reviewed publication were needed. Symptomatic intracerebral hemorrhage (sICH) and recanalization rates were compared between tPA, tPA+TCD±microspheres (&mgr;S), tPA+TCCD±&mgr;S, and tPA+low-frequency ultrasound. Results— A total of 6 randomized (n=224) and 3 nonrandomized (n=192) studies were identified. The rates of symptomatic intracerebral hemorrhage in randomized studies were as follows: tPA+TCD, 3.8% (95% CI, 0%–11.2%); tPA+TCCD, 11.1% (95% CI, 0%–28.9%); tPA+low-frequency ultrasound, 35.7% (95% CI, 16.2%– 61.4%); and tPA alone, 2.9% (95% CI, 0%–8.4%). Complete recanalization rates were higher in patients receiving combination of TCD with tPA 37.2% (95% CI, 26.5%– 47.9%) compared with patients treated with tPA alone 17.2% (95% CI, 9.5%–24.9%). In 8 trials of high-frequency (TCD/TCCD) ultrasound-enhanced thrombolysis, tPA+TCD/TCCD±&mgr;S was associated with a higher likelihood of complete recanalization (pooled OR, 2.99; 95% CI, 1.70–5.25; P=0.0001) when compared to tPA alone. High-frequency ultrasound-enhanced thrombolysis was not associated with an increased risk of symptomatic intracerebral hemorrhage (pooled OR, 1.26; 95% CI, 0.44–3.60; P=0.67). Conclusions— The present safety and signal-of-efficacy data of high-frequency ultrasound-enhanced thrombolysis should be taken into account in the design of future randomized controlled trials.

Influence of sleep disturbance on quality of life of patients with epilepsy

The frequency of sleep disturbances in patients with epilepsy and their impact on quality of life (QoL) have been documented in a few reports, and the results are conflicting. We identified 124 consecutive epilepsy out-patients who visited the epilepsy out-patient clinics at the University Hospital of Alexandroupolis, the AHEPA Hospital in Thessaloniki and the Aeginitio Hospital in Athens. We measured excessive daytime sleepiness (EDS) with the Epworth Sleepiness Scale (ESS), obstructive sleep apnea (OSA) with the Sleep Apnea scale of the Sleep Disorders Questionnaire (SA-SDQ), and insomnia with the Athens Insomnia Scale (AIS). We evaluated quality of life by the Quality of Life in Epilepsy Inventory (QOLIE-31). EDS was found in 16.9% (21/124) of epileptic patients, OSA in 28.2% (35/124), and insomnia in 24.6% (30/122). In multivariate analysis, we found that insomnia was an independent negative factor for Total score (p<0.001), Overall QoL (p=0.002), Emotional well-being (p<0.001), Energy/fatigue (p<0.001), Cognitive functioning (p=0.04) and Social functioning (p=0.03), and OSA only for Cognitive functioning (p=0.01). According to our findings, EDS, OSA, and insomnia are frequent in epileptic patients. Epileptic patients with sleep disturbance, mainly insomnia, have significant QoL impairment.

Low Ankle-Brachial Index predicts early risk of recurrent stroke in patients with acute cerebral ischemia

OBJECTIVE Low ankle-brachial blood pressure index (ABI) identifies patients with symptomatic and asymptomatic peripheral arterial disease (PAD). We sought to investigate the association of low ABI with early risk of stroke recurrence in patients with acute cerebral ischemia (ACI) and without history of symptomatic PAD. METHODS Consecutive patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA) and no previous history of PAD were prospectively evaluated with ABI measurements. Demographic characteristics, vascular risk factors and secondary prevention therapies were documented. An ABI ≤0.90 in either leg was considered as evidence of asymptomatic PAD, and an ABI >0.90 was considered as normal. Patients with elevated ABI (>1.30) were excluded. The outcome of interest was recurrent stroke during 30-day follow-up. RESULTS A total of 176 patients with acute cerebral ischemia (mean age 64±14 years, 59.1% men, 76.7% AIS) were evaluated. Asymptomatic PAD was detected in 14.8% (95%CI: 10.2-20.8%) of the studied population. The following factors were independently associated with low ABI on multivariate logistic regression models, after adjustment for potential confounders: coronary artery disease (p=0.008), diabetes mellitus (p=0.017) and increasing age (p=0.042). The cumulative 30-day recurrence rate was higher in patients with low ABI (19.2%; 95%CI: 4.1-34.3) compared to the rest (3.3%; 95%CI: 0.4-6.2%; p=0.001). Atherothrombotic stroke (ASCO grade I; p<0.001), increasing age (p=0.002) and low ABI (p=0.004) were independent predictors of stroke recurrence on multivariate Cox regression models adjusting for confounders. CONCLUSIONS Low ABI appears to be associated with a higher risk of early recurrent stroke in patients with ACI and no history of symptomatic PAD.

Detection of Carotid Artery Plaque Ulceration Using 3‐Dimensional Ultrasound

Three‐dimensional (3D) ultrasound imaging is a new technique that maximizes the information and image quality of traditional 2‐dimensional (2D) B‐mode scanning. The aim of this study was to evaluate the ability of the 3D ultrasound technique to characterize ulcerated atherosclerotic carotid plaque.

Association of Ultrasonographic Parameters with Subclinical White-Matter Hyperintensities in Hypertensive Patients

Background and Purpose. Cerebral white matter hyperintensities (WMHs) are regarded as typical MRI expressions of small-vessel disease (SVD) and are common in hypertensive patients. Hypertension induces pathologic changes in macrocirculation and in microcirculation. Changes in microcirculation may lead to SVD of brain and consequently to hypertensive end-organ damage. This damage is regarded the result of interactions between the macrovascular and microvascular levels. We sought to investigate the association of cerebral WMHs with ultrasonographic parameters of cerebral macrocirculation evaluated by carotid duplex ultrasound (CDU) and transcranial doppler (TCD). Subjects and Methods. The study was prospective, cross-sectional and consecutive and included hypertensive patients with brain MRI with WMHs. Patients underwent CDU and TCD. The clinical variables recorded were demographic characteristics (age, gender, race) and vascular risk factors (hypertension, diabetic mellitus, hypercholesterolemia, current smoking, and body mass index). Excluded from the study were patients with history of clinical stroke (including lacunar stroke and hemorrhagic) or transient ischemic attack (either hemispheric or ocular), hemodynamically significant (>50%) extra- or intracranial stenosis, potential sources of cardioembolism, and absent transtemporal windows. WMHs were quantified with the use of a semiquantitative visual rating method. Ultrasound parameters investigated were (1) common carotid artery (CCA) diameter and intima-media thickness, (2) blood flow velocity in the CCA and internal carotid artery (ICA), and (3) blood flow velocity and pulsatility index of middle cerebral artery (MCA). Results. A total of 52 patients fulfilled the study inclusion criteria (mean age 71.4 ± 4.5 years, 54% men, median WMH-score: 20). The only two ultrasound parameters that were independently associated with WMH score in multivariate linear regression models adjusting for demographic characteristics and vascular risk factors were increased mean common carotid artery (CCA) diameter (beta = 0.784, SE = 0.272, P = 0.006, R 2 = 23.9%) and increased middle cerebral artery pulsatility index (MCA-PI; beta = 0.262, SE = 0.110, P = 0.025, R 2 = 9.0%). Among all ultrasound parameters the highest AUC (areas under the receiver operating characteristic curve) were documented for MCA-PI (AUC = 0.82, 95% CI = 0.68−0.95, P < 0.001) and mean CCA diameter (AUC = 0.80, 95% CI = 0.67−0.92, P < 0.001). Conclusions. Our study showed that in hypertensive individuals with brain SVD the extent of structural changes in cerebral microcirculation as reflected by WMHs burden is associated with the following ultrasound parameters of cerebral macrocirculation: CCA diameter and MCA-PI.

Statin pretreatment is associated with better outcomes in large artery atherosclerotic stroke

Objective: Even though statin pretreatment is associated with better functional outcomes and lower risk of mortality in acute ischemic stroke, there are limited data evaluating this association in acute ischemic stroke due to large artery atherosclerosis (LAA), which carries the highest risk of early stroke recurrence. Methods: Consecutive patients with acute LAA were prospectively evaluated from 7 tertiary-care stroke centers during a 3-year period. Statin pretreatment, demographics, vascular risk factors, and admission and discharge stroke severity were recorded. The outcome events of interest were neurologic improvement during hospitalization (quantified as the relative decrease in NIH Stroke Scale score at discharge in comparison to hospital admission), favorable functional outcome (FFO) (defined as modified Rankin Scale score of 0–1), recurrent stroke, and death at 1 month. Statistical analyses were performed using univariable and multivariable Cox regression models adjusting for potential confounders. All analyses were repeated following propensity score matching. Results: Statin pretreatment was documented in 192 (37.2%) of 516 consecutive patients with LAA (mean age: 65 ± 13 years; 60.8% men; median NIH Stroke Scale score: 9 points, interquartile range: 5–18). Statin pretreatment was associated with greater neurologic improvement during hospitalization and higher rates of 30-day FFO in unmatched and matched (odds ratio for FFO: 2.44; 95% confidence interval [CI]: 1.07–5.53) analyses. It was also related to lower risk of 1-month mortality and stroke recurrence in unmatched and matched analyses (hazard ratio for recurrent stroke: 0.11, 95% CI: 0.02–0.46; hazard ratio for death: 0.24, 95% CI: 0.08–0.75). Conclusion: Statin pretreatment in patients with acute LAA appears to be associated with better early outcomes regarding neurologic improvement, disability, survival, and stroke recurrence.

Safety of transcranial Doppler ‘bubble study’ for identification of right to left shunts: an international multicentre study

Background and purpose A recent retrospective study using an online list service established by the American Academy of Neurology has suggested that ischaemic cerebrovascular events may occur in patients who undergo ‘bubble studies’ (BS) with either transcranial Doppler (TCD) or transoesophageal echocardiography (TOE). The safety of TCD-BS for right to left shunt (RLS) identification was evaluated prospectively in an international multicentre study. Methods Consecutive patients with cerebral ischaemia (ischaemic stroke or transient ischaemic attack (TIA)) were screened for potential ischaemic cerebrovascular events following injection of microbubbles during TCD-BS for identification of RLS at three tertiary care stroke centres. TCD-BS was performed according to the standardised International Consensus Protocol. TOE-BS was performed in selected cases for confirmation of TCD-BS. Results 508 patients hospitalised with acute cerebral ischaemia (mean age 46±12 years, 59% men; 63% ischaemic stroke, 37% TIA) were investigated with TCD-BS within 1 week of ictus. RLS was identified in 151 cases (30%). TOE-BS was performed in 101 out of 151 patients with RLS identified on TCD-BS (67%). It was positive in 99 patients (98%). The rate of ischaemic cerebrovascular complications during or after TCD-BS was 0% (95% CI by the adjusted Wald method: 0–0.6%). Structural cardiac abnormalities were identified in 38 patients, including atrial septal aneurysm (n=23), tetralogy of Fallot (n=1), intracardiac thrombus (n=2), ventricular septal defect (n=3) and atrial myxoma (n=1). Conclusion TCD-BS is a safe screening test for identification of RLS, independent of the presence of cardiac structural abnormalities.

End-Diastolic Velocity Increase Predicts Recanalization and Neurological Improvement in Patients With Ischemic Stroke With Proximal Arterial Occlusions Receiving Reperfusion Therapies

Background and Purpose— It is unknown how little flow velocity improvement is necessary to achieve recanalization and clinical recovery. We sought to investigate which flow velocity parameter was associated with complete recanalization/reperfusion and neurological improvement in patients receiving reperfusion therapies. Methods— Patients with proximal intracranial occlusions were treated with systemic or intra-arterial tissue plasminogen activator within 6 hours from symptom onset. Consecutive peak systolic and end-diastolic (EDV) velocities were measured during continuous transcranial Doppler monitoring. Recanalization was graded with Thrombolysis in Brain Ischemia grades. Neurological and functional outcomes were assessed by the National Institutes of Health Stroke Scale and modified Rankin Scale scores. Results— Of 36 patients (mean age 57±19 years, median National Institutes of Health Stroke Scale 15 points, interquartile range 9), 13 (36%) achieved complete recanalization and those had greater EDV increase during transcranial Doppler monitoring (15±11 cm/s versus 6±10 cm/s; P=0.001). Peak systolic velocity increase with complete recanalization was 25±11 cm/s (versus 20±25 cm/s with partial recanalization/persisting occlusion; P=0.123). Neurological improvement at 24 hours positively correlated to EDV increase (Spearman r=0.337, P=0.044) but not to peak systolic velocity (r=0.197, P=0.250). EDV increase at the end of monitoring was higher in patients with favorable functional outcome at 3 months (13±13 cm/s versus 4±8 cm/s; P=0.021). After adjustment for potential confounders, including age, stroke risk factors, and baseline stroke severity, a 10-cm/s increase in EDV was independently associated with a 3-point decline in the National Institutes of Health Stroke Scale score at 24 hours from baseline (95% CI: 0 to 5; P=0.045). Conclusions— A modest increase in the EDV as opposed to peak systolic velocity is associated with complete recanalization/reperfusion, early neurological improvement, and favorable functional outcome. Diastolic flow augmentation may represent a novel target for development of reperfusion therapies.

A three-dimensional ultrasonographic quantitative analysis of non-ulcerated carotid plaque morphology in symptomatic and asymptomatic carotid stenosis

BACKGROUND AND PURPOSE Studies evaluating the association between carotid plaque composition and occurrence of ischemic cerebrovascular disease reveal inconsistent results. This study correlates the carotid echomorphology with the degree of stenosis in symptomatic and asymptomatic patients. METHODS We included consecutive patients with hemispheric stroke or asymptomatic carotid artery stenosis assessed with 2D ultrasound. The echomorphology was assessed with mean gray value (MGV) of the three-dimensional (3D) volume. We used the free-hand approach for 3D image and volume acquisition. Analyses of the stored carotid plaque volumes were carried out offline using the Virtual Organ Computer-aided Analysis (VOCAL) program. RESULTS We studied 110 symptomatic and 104 asymptomatic atherosclerotic carotid plaques. MGV was lower in symptomatic carotid plaques causing <70% stenosis compared to plaques causing > or =70% stenosis (25.95+/-7.40 vs. 32.16+/-11.35, p=0.002). There was no difference in MGV between plaques producing <60% and those with > or =60% in asymptomatic patients (32.08+/-8.36 vs. 31.46+/-9.25, p=0.724). There were significant differences in MGV between symptomatic and asymptomatic plaques causing <60 or <70% stenosis; MGV was lower in symptomatic patients. CONCLUSIONS Lower plaque echogenicity is observed in symptomatic than in asymptomatic patients with moderate degree of carotid stenosis, indicating that it is a significant factor for the production of cerebral ischemia. Our method could be useful in assessing the risk of cerebral ischemia and the response of carotid artery atherosclerosis to medical therapies.

Clopidogrel Load for Emboli Reduction in Patients With Symptomatic Carotid Stenosis Undergoing Urgent Carotid Endarterectomy

Background and Purpose— Microembolic signals (MES) on transcranial Doppler are an independent risk factor for recurrent stroke in patients with extracranial symptomatic/asymptomatic carotid artery stenosis (CARAS). Clopidogrel load (300 mg) combined with dual antiplatelet therapy has been shown to reduce MES in patients with symptomatic CARAS. We sought to determine feasibility of clopidogrel load in decreasing asymptomatic embolization in patients with symptomatic CARAS undergoing urgent carotid endarterectomy within the first 2 weeks from the index event. Subjects and Methods— Consecutive patients with symptomatic CARAS (70%–99%) and presence of MES on 1-hour baseline (<24 hours from the index event) transcranial Doppler monitoring of ipsilateral middle cerebral artery were treated with clopidogrel load followed by clopidogrel (75 mg)±aspirin (100 mg) during the elapsed time period between hospital admission and urgent carotid endarterectomy at 3 tertiary-care stroke centers. Repeat 1-hour transcranial Doppler monitoring was performed the day before surgery. Bleeding complications during surgery and recurrent strokes or transient ischemic attacks during the first month of ictus were prospectively recorded. Results— A total of 11 symptomatic CARAS patients (mean age, 66±7 years; 73% men; 64% acute ischemic strokes) were treated with clopidogrel load followed by dual (67%) or single (33%) antiplatelet therapy. MES count was significantly reduced between baseline (median count, 8 MES/h; interquartile range, 6–19) and repeat transcranial Doppler monitoring (0 MES/h; interquartile range, 0–3; P=0.003). No bleeding complications, recurrent strokes, or transient ischemic attacks were documented. Conclusions— Our pilot observational study provides preliminary nonrandomized data regarding the potential efficacy of clopidogrel load to reduce asymptomatic embolization in patients with symptomatic CARAS before urgent carotid endarterectomy.